Stelara is unique among the first drugs to be negotiated in that it is available in both subcutaneous and intravenous formulations. The human interleukin-12 and -23 antagonist is approved for subcutaneous use for the treatment of people at least 6 years old with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and people at least 6 with active psoriatic arthritis. It also is approved for the treatment of adults with moderately to severely active Crohn’s disease and adults with moderately to severely active ulcerative colitis, for whom treatment is initiated with a single intravenous dose, followed by subcutaneous maintenance dosing.
]]>Stelara is unique among the first drugs to be negotiated in that it is available in both subcutaneous and intravenous formulations. The human interleukin-12 and -23 antagonist is approved for subcutaneous use for the treatment of people at least 6 years old with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and people at least 6 with active psoriatic arthritis. It also is approved for the treatment of adults with moderately to severely active Crohn’s disease and adults with moderately to severely active ulcerative colitis, for whom treatment is initiated with a single intravenous dose, followed by subcutaneous maintenance dosing.
For 2026 and 2027, negotiated drug prices will be for self-administered products that fall under Medicare Part D. Starting in 2028, provider-administered Part B drugs will be included in the process. But has that distinction been blurred a bit with Stelara?
During CMS’s Nov. 14 patient-focused listening session for Stelara, Madelaine A. Feldman, M.D., a clinical assistant professor of medicine at Tulane University School of Medicine and provider with The Rheumatology Group in New Orleans, pointed out that the practice of white bagging “has the effect of making provider-administered drugs that are administered in-office appear as Part D drugs because they're filled via specialty pharmacy rather than provider-acquired. Simply put, white bagging puts Part B drugs in Part D clothing.”
Feldman, who is also immediate past president of and current vice president of advocacy and government affairs for the Coalition of State Rheumatology Organizations (CSRO), maintained that specialty pharmacy-filled Part B drugs should be kept separate from traditional self-administered Part D medications and offered two methods by which this could be achieved:
(1) Merging the prescription drug event (PDE) data with Part B claims data. “A mechanism exists to do this since the agency is already using PDE data combined with Part B claims data to implement the low spend Medicare drug exclusion,” she explained.
(2) Revise the PDE collection tool to include information indicating that white bagging was used.
“If CMS does not exclude white bag drugs from the Part D side for the purposes of the negotiation program, then PBMs [and] specialty pharmacies will be able to access maximum fair prices, potentially leading to an increased prevalence of white bagging, which has an entire list of problems associated with it that are bad for beneficiaries and program stewardship,” asserted Feldman.
She tells AIS Health, a division of MMIT, that those issues include potential delays in care since drugs will not be shipped until patients have paid their bill. And unlike buy and bill, when a provider purchases medications and stores them until they are ready for use, white bagging can also result in treatment delays when dose changes occur, since white bagging includes a specific dose for a specific patient. In addition, “if the drug choice changes or the patient has to stop that drug for other reasons, all of that medicine goes to waste because it cannot be given to another patient.” She also maintains that white bagging costs more for self-insured employers, making it a fiduciary issue if they are mandating the practice.
White bagging also has implications for the Medicare self-administered drug (SAD) exclusion list, she stated. When a drug is self-administered more than 50% of the time, it can be placed on the SAD list, which means that the drug cannot be covered under Part B. “With white bagging falsely elevating Part D usage, this could result in the loss of coverage for Part B medications for many more folks who can't administer due to disability,” she said during the session. “Essentially, if specialty pharmacies can access MFPs [maximum fair prices] on these dual-administration drugs, it could increase white bagging, making it appear as though these medications are self-administered more than half the time when they are not, merely filled by specialty pharmacy.”
In 2021, Medicare added Stelara to the SAD list. However, contends Feldman, that should not have happened.
“According to the Medicare policy manual, for a drug to be considered ‘self-injectable,’ it had to be administered by the patient, not the spouse, friend, neighbor or brought to the doctor's office,” she explains. But a CSRO survey found that only 60% of Part D Stelara patients injected themselves — a potentially difficult task due to joint pain and swelling — a finding echoed in a Johnson & Johnson survey of “thousands” of Medicare patients, says Feldman. And “Stelara subcutaneous is much more difficult to self-inject than a pen, so the number is probably higher,” she adds.
Those self-administration findings, she says, “would have changed the threshold for Stelara going on the SAD list.”
In an April 26, 2021, letter to CMS, CSRO called for an overhaul of the SAD list: “CMS’ SAD List policies have not kept pace with real-world use of medicines that have multiple indications and formulations. Specifically, they have the unintended consequence of discriminating against patients who are unable to self-administer certain medications based on their disease. For this reason, CMS should eliminate the SAD List concept and establish a new policy that better accounts for innovation in medication therapy.”
In CSRO’s comments on the 2024 Physician Fee Schedule, submitted Sept. 11, 2023, it maintained that “CMS’ interpretation and implementation of the [SAD] statute hinders access and exacerbates disparities in the care and treatment of rheumatologic conditions, and directly conflict with this Administration’s efforts to improve health equity and drug affordability.”
The group pointed out that CMS has not provided Medicare administrative contractors instructions on accounting for patients who “have a disability or face other social and economic challenges that limit access to the self-administered formulation” and urged the agency to “reconsider” its policies for the SAD list to address such situations. “While not intentional, this policy inadvertently discriminates against beneficiaries with chronic illnesses who are unable to obtain and/or utilize the self-administered formulation of a drug.”
So is it possible that CMS considered income from both self-administered and white-bagged Stelara when it put the agent on the list of drugs to negotiate? Yes, says Feldman.
“It was possible that the subcutaneous [formulation] and the 130 mg IV vial given in the doctor’s office was obtained through specialty pharmacy by the docs who didn't want to buy and bill and that was counted towards the self-injectable side (Part D) — not the provider-administered side (Part B),” she says.
Interestingly, in a list of National Drug Codes “for which any negotiated maximum fair price would apply,” CMS includes eight NDCs for Stelara. Among those codes are ones for the 130 mg vial for intravenous use with Crohn’s and ulcerative colitis.
“We believe that it [the 130 mg vial] is a Part B drug because patients do not mix and then start their own IVs,” says Feldman. “Consequently, the negotiation for that vial should not be occurring during the self-admin drug negotiations.”
Ultimately, she says, two issues exist with Stelara. First, “for the IV and subcutaneous formulations that were provider administered, there would have been providers obtaining through specialty pharmacy and not billing Part B, making it look like this was a self-injectable.” And second, among patients “who did obtain it through Part D or specialty pharmacy from the doctor, 40% never injected themselves, disqualifying those from being counted as a self-injectable.”
“The 130 mg vial that was included in the IRA was for IV use only. IV formulations were not supposed to be negotiated until 2026, and it is possible that all of the specialty pharmacy acquisition was counted as self-injectable,” Feldman says. “That designation is incorrect because the vial was meant for IV use not subcutaneous injection — but because it was obtained from specialty pharmacy, Medicare could have miscounted it as self-injectable.”
Contact Feldman through CSRO at info@csro.info.
]]>DIR includes rebates and price concessions that occur after the point of sale. According to CMS, total DIR “has been growing significantly in recent years.…In 2020, pharmacy price concessions accounted for about 4.8 percent of total Part D gross drug costs ($9.5 billion), up from 0.01 percent ($8.9 million) in 2010.”
]]>Specialty pharmacies and oncology practices dispensing costly specialty medications have long complained that Medicare Part D direct and indirect remuneration (DIR) fees are not appropriate for these drugs. Efforts to do away with these retroactive fees were finally successful, but revamped reimbursement has brought a new problem — underwater reimbursement — claims the Community Oncology Alliance (COA).
DIR includes rebates and price concessions that occur after the point of sale. According to CMS, total DIR “has been growing significantly in recent years.…In 2020, pharmacy price concessions accounted for about 4.8 percent of total Part D gross drug costs ($9.5 billion), up from 0.01 percent ($8.9 million) in 2010.”
Historically, “DIR fees were trying to get a handle on costs,” explained Judith Alberto, director of clinical initiatives at COA, who also helps lead the Community Oncology Pharmacy Association (COPA) at COA, during a recent webinar. “It was supposed to be a really good thing for practices. I think over the years when PBMs stepped in, they started to assign these quality metrics that were based on primary care, and it really wasn't apropos for the oncology practice.
“And so what are the expectations of some of these quality metrics?” she continued. “Our cancer patients can't possibly hit that. We know they need to stop therapy and take breaks. We know they can't be on chronic medications sometimes when they're being treated for cancer. We know they don't take their cancer medications like they take their antihypertensive medications. And so oncology pharmacies get dinged for certain of these metrics that they can't control. And that's good quality. We don't want them to continue taking medications that may harm them. And so what the PBMs are doing with these DIR fees are extracting these penalties for really practicing high quality cancer care.”
Pharmacists’ wishes were finally met when CMS issued a final rule (87 Fed. Reg. 27704, May 9, 2022) requiring that Medicare Part D plan sponsors and PBMs assess DIR fees at the point of sale rather than retroactively. The rule went into effect at the beginning of this year.
But now pharmacies are still dealing with DIR fees from 2023, as well as the new point-of-sale negotiated prices, which are not “reasonable and relevant,” charges COA.
DIR fees have long been a black box, charge critics. According to Alberto, “it’s impossible to really determine” what DIR fees will be. Prior to 2024, “DIR fees were typically assessed anywhere from three to six months post point of sale, and we all know that they can have a very big swing in range,” she said. “Practices, unfortunately, also have no choice but to pay these fees in order to stay in network. We know what that struggle is like, not being able to improve their quality scores or not being able to fight this practice. These quality metrics are completely arbitrary, and they have nothing to do with the quality of cancer care.”
While PBMs and plan sponsors have been unable to assess DIR fees retroactively as of Jan. 1, pharmacies are still responsible for those fees from 2023, at the same time that they are dealing with real-time point-of-sale reimbursement for 2024. At the beginning of the year, COA began hearing from its board members and member practices about the new reimbursement, which is leaving many practices underwater, said Alberto. “We knew early on…to expect the DIR hangover; that wasn’t a surprise.” When coupled with new point-of-sale reimbursement, this is “a double whammy.”
Alberto explained that COA had sent out information on the issue late last year and had a January meeting “dedicated solely to DIR fees and the possible pitfalls.”
“So now what we're seeing and what's being reported from our practices is drastically lower reimbursement rates from this year than what we saw last year,” she explained. “This really appears to be a new lowball reimbursement as a direct result of eliminating the retroactive DIR fees that began in January this year.”
Kathy Oubre, CEO of the Pontchartrain Cancer Center, a COA board member and co-chair of COA’s drug policy and regulatory committee, said during the webinar that in early January, she began to see scripts “that we filled in November or December, and all of a sudden the landscape looked really different for us, and drugs that, at least in my case, we had filled 30, 60 days prior to were all of a sudden under water and not under water by a little bit. You know, a big enough margin that it got my attention.”
COPA began digging into deidentified data that was aggregated by a third party, and so far, it’s been “pretty eye-opening,” she said.
The group looked at data from November and December 2023 for plan, subplan, drug, estimated DIR fee and a weighted average of net average wholesale price reimbursement, which it estimates to be about AWP minus 20%. Then it gathered January 2024 data for plan, subplan, drug and the weighted average of AWP net reimbursement.
“We saw about AWP minus 25% on average, but we also saw it extend all the way up to about minus 28%,” she said. “Drugs that we historically have prescribed to our patients we were now running into issues with.”
The largest decline in reimbursement, said Oubre, was seen with The Cigna Group’s Express Scripts, although declines were seen also with CVS Health Corp.’s Caremark and Humana Inc. She attributed the Express Scripts decrease to its winning Centene’s book of business over Caremark last year, which became effective Jan. 1. She cited four plans in particular: Med D Prime, 3858 A4, 3858 MA and 3858 MD. “Their reimbursement wasn't great in those plans in ’23, but it appears that through this Centene award, it increased the volume of prescriptions that ran through those plans,” she said.
Still, Oubre noted, the impact on practices varies based on their payer mix.
“This was a much larger swing in reimbursement than we anticipated,” said Oubre. The problem, she said, is that PBMs “can do this. You get that contract, and there’s no negotiations there. ‘This is your offering. And if you want to participate in our network, this is the way it looks. And we're not forcing you to participate in the network.’”
“Losing a mere percentage point on a $10,000 oral cancer drug due to ESI’s low-ball reimbursement puts many (or even most) of these drugs ‘under water,’” said COA in a letter to Express Scripts sent shortly after the webinar. The group also sent a letter to CMS on the issue.
COA claimed that Express Scripts “is paying community oncology practices and others unreasonable, unsustainable, and indefinite reimbursement rates as part of Medicare Part D participation. We believe that ESI has unreasonably reduced reimbursement to make up for the previous retroactive” DIR fees, which is “threatening access to care and pharmacy services for millions of Americans with cancer and other serious medical conditions.”
If practices do not accept the contracts, their patients must get their medications through Express Scripts’ Accredo mail-order specialty pharmacy, creating a “win-win situation” for the PBM while putting up “huge obstacles for patients with cancer and others with serious diseases from receiving integrated, optimal, high-quality medical care.”
COA requested “an amicable dialogue” with Express Scripts leadership “to show that the 2024 Pharmacy Provider Agreement contract does not comply with clear federal law and guidance under Medicare Part D, which requires that reimbursement be ‘reasonable and relevant.’” It asks the PBM to amend the contract terms so they comply with all applicable laws.
“We are seeking a constructive dialogue with ESI to identify a viable solution,” wrote the group. “While our goal is to resolve this amicably, COA is so concerned about this issue that it is prepared to pursue legislative action with Congress and even legal remedies in federal court, alleging a variety of meritorious causes of action, including, but not limited to, violations of state and federal laws, violation of the AWPL [Any Willing Pharmacy Law], and breach of contract.”
“While it is drug manufacturers — not pharmacy benefit managers — that control purchase discounts they make available based on the list prices they set for medicines, we are committed to reimbursing our wide network of pharmacy partners fairly,” an Express Scripts spokesperson tells AIS Health, a division of MMIT. “To comply with the new CMS rules, our approach is intended to keep pharmacy payments equivalent while maintaining our commitment to monitoring pharmacy quality. To that end, we offer clinically based programs that reward pharmacies for meeting quality measures. As we’ve shared directly with the Community Oncology Alliance, we welcome a constructive dialogue with them and their members.”
In its letter to CMS, COA urged it “to fulfill its duty to oversee Part D plans (‘PDP’) and First Tier Entities to ensure they adhere to the applicable Medicare Part D laws and guidance.” The group called on the agency to issue guidance on what PBMs and PDP sponsors “must do to ensure that Part D terms and conditions are ‘reasonable and relevant,’” and it asked for an investigation of Express Scripts’ reimbursement practices.
Nicolas Ferreyros, managing director of policy, advocacy, and communications at the Community Oncology Alliance, clarified during the webinar that it’s not only oncology practices that are being impacted. “We have talked to other specialties, and this is being seen in other places. So this is definitely affecting a lot more than just us.” COA is working on the issue with other industry groups such as the National Community Pharmacists Association (NCPA), as well as independent pharmacies.
If practices are interested in sharing their data on reimbursement changes, COA has a worksheet available to fill out and submit to Alberto at jalberto@coacancer.org.
]]>Since 2015, biosimilars have saved $23.6 billion, with $9.4 billion of that total coming in 2023 alone. Last year saw the long-awaited competition to the top-selling Humira (adalimumab) from AbbVie Inc., with nine biosimilars launching, two of them with interchangeable status, an important differentiator to providers. “As the top-selling drug in the world with annual sales of $20 billion in 2022, the potential monetary impact of increased market competition cannot be overstated,” says the report.
]]>Since 2015, biosimilars have saved $23.6 billion, with $9.4 billion of that total coming in 2023 alone. Last year saw the long-awaited competition to the top-selling Humira (adalimumab) from AbbVie Inc., with nine biosimilars launching, two of them with interchangeable status, an important differentiator to providers. “As the top-selling drug in the world with annual sales of $20 billion in 2022, the potential monetary impact of increased market competition cannot be overstated,” says the report.
Manufacturers have employed three different pricing strategies for those agents: a high wholesale acquisition cost similar to Humira’s WAC, a low WAC that undercuts Humira’s price by as much as 85% and a dual WAC that uses both of those strategies. It remains to be seen which will be most successful.
By the end of 2023, only seven biosimilars had been granted interchangeability (as well as three more so far in 2024), perhaps due to trial costs and additional steps companies need to undergo.
The report highlighted federal efforts around biosimilars, including Sen. Mike Lee’s (R-Utah) reintroduction of the Biosimilar Red Tape Elimination Act (S. 2305) in July 2023, which is focused on increasing competition among biologics and lowering consumer costs for them and would “deem biosimilars as interchangeable with their branded equivalent upon their approval by the FDA.”
The report also drilled down on retina specialists’ perspectives, finding that 98% of respondents were at least moderately familiar with biosimilars, but only 61% had prescribed the agents. And only 61% agreed that biosimilars can contribute to improving patient care.
However, it also found that 79% of respondents were open to attending workshops or training sessions on biosimilars to improve their knowledge of and confidence in using them.
The two biosimilars of Lucentis (ranibizumab) from Genentech USA, Inc., a member of the Roche Group — Biogen’s Byooviz (ranibizumab-nuna) and Coherus BioSciences, Inc.’s Cimerli (ranibizumab-eqrn), both of which have interchangeability status — were prescribed by about 40% of respondents, compared to the 10% who have prescribed biosimilars of Genentech’s Avastin (bevacizumab).
AIS Health, a division of MMIT, spoke with Dracey Poore, director of biosimilars at Cardinal Health, for her insights on these and other findings in the report.
AIA Health: What were some particularly interesting and/or surprising findings in the report, and why?
Poore: There are some particularly interesting things we have found from the report. Firstly, when we look at the retina specialist research, we see that though nearly 80% of survey participants said they are “extremely” or “very” familiar with biosimilars, fewer than 60% have prescribed a biosimilar for the treatment of a retinal disorder. This underscores the importance of education and advocacy to increase prescribers’ comfortability in prescribing biosimilars to patients.
Secondly, 75% of participants agreed that biosimilars can improve health care system sustainability, yet survey participants said a reimbursement rate of 125% or more from CMS would incentivize them to prescribe a biosimilar over the reference products.
AIS Health: Are there any payer lessons learned from the uptake of the adalimumab biosimilars?
Poore: The landscape of adalimumab biosimilars has seen rapid change over the past year. When we look at uptake of biosimilars generally, historically national preferred formularies (NPFs) have taken several years to designate a biosimilar as a preferred choice. However, this changed with the adalimumab biosimilars. Coverage for these biosimilars has experienced swift uptake, with the major PBMs adding adalimumab biosimilars to their NPF lists the first year of launch. Evolving payer coverage for biosimilars is key to increased utilization.
AIS Health: The FDA recently approved the first citrate-free, high-concentration interchangeable version of Humira, Alvotech and Teva’s Simlandi. Do you think it will be more successful in picking up market share than the first nine adalimumab biosimilars? Why or why not?
Poore: Product attributes such as concentration, citrate-free and interchangeability are all factors that could impact a biosimilar’s utilization. For example, more than 80% of patients currently use high concentration adalimumab. Additionally, per our research, providers prefer products with interchangeability designations. Lastly citrate-free formulations may be less painful, which could lead to them being preferred by patients. For Simlandi, time will tell how successful it is at achieving market share, but favorable product attributes may help it do so.
AIS Health: Were any of the retina specialists’ reasons for hesitancy in prescribing biosimilars of particular concern? If so, what, and how can that hesitancy be countered?
Poore: Of the reasons retina specialists had hesitancy in prescribing biosimilars, the one that I find to be most concerning is lack of confidence in biosimilars’ safety and efficacy, especially considering 80% of survey respondents mentioned not encountering any challenges obtaining information or education about biosimilars. Clearly, there is a gap that must be addressed in advocacy and education so that prescribers better understand biosimilars and their safety and efficacy.
From our research, two of the most trusted sources of information retina specialists use when considering the use of biosimilars in their practice are “clinical trials and research studies” and “professional medical associations.” Perhaps there is an opportunity here to use these sources of information to better educate regarding the safety and efficacy of biosimilars.
AIS Health: With many insurers preferring reference drugs for retinal disorders over their biosimilars, what information/education/experience is needed for insurance providers to be more willing to prefer biosimilars for these conditions? How much does cost factor in, and how do the costs for reference drugs and their biosimilars compare?
Poore: There has been an improvement in PBM acceptance of biosimilars. For example, CVS prefers Byooviz and Cimerli over the reference product Lucentis. As long as biosimilars are priced as a cost-effective alternative, we expect to see this trend continue, as cost is the driving factor for biosimilars.
AIS Health: Was there anything surprising about retina specialists’ responses around using biosimilars off label?
Poore: Eighty percent of retina specialists stated that they were very comfortable or somewhat comfortable deducing the totality of evidence to use biosimilars off-label in retinal disease. Retina specialists have over 15 years of experience using Avastin off-label to treat their patients, so this was reassuring.
AIS Health: The American Society of Retina Specialists (ASRS) has spoken out against “the ocular use of currently available Avastin biosimilars that have not been tested in the eye,” as has the American Academy of Ophthalmology. How much of an influence has this had on retina specialists? Should Avastin biosimilars conduct these tests?
Poore: The ASRS advocates to keep repackaged Avastin available for patients with less common retinal disorders. Retina specialists have expressed that there is no need to utilize Avastin biosimilars in the eye because the branded Avastin is inexpensive.
AIS Health: At least one company, Outlook Therapeutics, is developing an ophthalmic formulation of bevacizumab, Lytenava (bevacizumab-vikg) or ONS-5010. If the FDA were to approve it, how would that impact off-label ophthalmic Avastin use and, thus, spending on this class?
Poore: An ophthalmic formulation of bevacizumab would be a great asset for the market and enable prescribers to treat their patients effectively in an on-label manner. The spending impact would depend on the pricing strategy of Lytenava at the time of launch.
AIS Health: Among biosimilars in the pipeline, the report notes ones for Stelara (ustekinumab) and Eylea (aflibercept). Among the others, are there certain ones that payers should be readying for? If so, what and why?
Poore: Payers should be readying for biosimilars that have the highest spend biologics as their reference products, because the savings from those products means generating the highest cost savings to the health care system. The highest spend biologics that we are anticipating biosimilars for are Stelara, Eylea, Novolog and Prolia/Xgeva. The next highest spend product is Xolair, which is estimated to launch in 2025. These products are our best opportunity to realize the savings biosimilars offer the health care system.
AIS Health: Is there anything I’ve neglected to ask that you’d like to add?
Poore: We continue to see the adoption of biosimilars increase and the corresponding savings as more biosimilars come to market. Continued education is important for their acceptance and uptake. The future of biosimilars is bright.
Contact Poore via Allision Matthews at allison@mediasourcetv.com.
]]>On Dec. 15, 2023, the FDA approved Pfizer Inc. and Astellas Pharma Inc.’s Padcev (enfortumab vedotin-ejfv) in combination with Merck & Co., Inc.’s Keytruda (pembrolizumab) for the treatment of people with locally advanced or metastatic urothelial cancer (la/mUC). The agency gave accelerated approval to this combination for people with la/mUC who are not eligible for cisplatin-containing chemotherapy on April 3, 2023. The newest approval converts that accelerated approval to full and expands the labeled indication to include the treatment of people eligible for cisplatin chemotherapy. The application had priority review and breakthrough therapy designation.
]]>On Dec. 15, 2023, the FDA approved Pfizer Inc. and Astellas Pharma Inc.’s Padcev (enfortumab vedotin-ejfv) in combination with Merck & Co., Inc.’s Keytruda (pembrolizumab) for the treatment of people with locally advanced or metastatic urothelial cancer (la/mUC). The agency gave accelerated approval to this combination for people with la/mUC who are not eligible for cisplatin-containing chemotherapy on April 3, 2023. The newest approval converts that accelerated approval to full and expands the labeled indication to include the treatment of people eligible for cisplatin chemotherapy. The application had priority review and breakthrough therapy designation.
The Phase III EV-302/KEYNOTE-A39 clinical trial found that Padcev in combination with Keytruda almost doubled median overall survival (OS) and median progression-free survival (PFS) in people who had previously untreated la/mUC compared with platinum-containing chemotherapy.
Dosing for Padcev, a Nectin-4-directed antibody and microtubule inhibitor conjugate, is 1.25 mg/kg via a 30-minute infusion on days one and eight of a 21-day cycle, and for Keytruda, a programmed death receptor-1 (PD-1) inhibitor, dosing is 200 mg via a 30-minute infusion every three weeks or 400 mg every six weeks.
Urothelial carcinoma is the most common form of bladder cancer, accounting for about 90% of cases.
For the Managed Care Oncology Index: Q1 2023, from March 2, 2023, to March 30, 2023, Zitter Insights polled 35 commercial payers covering 116.7 million lives, 26 Medicare payers covering 42.3 million lives, 50 oncologists and 52 practice managers about their management of and prescribing for bladder cancer. Payers said that an annualized net price for Padcev + Keytruda between $189,000 and $204,000 would be appropriately priced, while a price more than $281,000 would be too expensive, leading to their not covering or highly restricting the regimen.
More than half — 58% — of payers said that managing branded bladder cancer treatments is an average priority for them. Those with 71% of commercial lives reported that they are somewhat aggressive in their management of the therapies, meaning that while all products are covered, some may be preferred over others through tiering, step edits and/or prior authorization.
The survey, which was conducted before the Padcev/Keytruda approvals, revealed that 81% of payers and 56% of oncologists expressed average satisfaction with available treatments for bladder cancer. Respondents also expressed a variety of perceptions about the level of unmet need for the treatment of the condition (see chart).
“Although Keytruda has been previously used for advanced/metastatic bladder cancer, this new combination indication represents a further indication expansion for the checkpoint inhibitor, which has already impacted the cost of cancer care through numerous indication expansions since its first approval in advanced melanoma” on Sept. 4, 2014, observes Winston Wong, Pharm.D., president of W-Squared Group. “However, this represents the first major advancement in patients with advanced and metastatic bladder cancer, as well as demonstrating the significant clinical benefit of the antibody-drug conjugate therapy. The clinical significance is a nearly doubling of the OS and PFS over conventional chemotherapy and is being touted as the ‘new’ standard of care.”
Platinum-based chemotherapy “has been the standard of care for first-line treatment of la/mUC,” says Mesfin Tegenu, CEO and chairman of RxParadigm, Inc., but studies have found that almost half of people with metastatic bladder are not eligible for treatment with cisplatin. “The approval of Padcev plus Keytruda represents a significant milestone, as it is the first nonplatinum-based chemotherapy combination regimen approved as first-line treatment for advanced urothelial cancer. It offers patients a promising new treatment option and has the potential to transform the treatment landscape for advanced bladder cancer.”
“Urothelial carcinoma is becoming an increasingly growing priority in payer management, particularly as bladder cancer ranks as the sixth most prevalent cancer in the U.S., with urothelial bladder cancer being the most common type,” says Tegenu. “In recent years, the landscape of bladder cancer treatment has rapidly evolved, highlighted by the FDA's approval of multiple immunotherapies and targeted therapies. These drugs represent a significant advancement in oncology, as they are less cytotoxic than traditional chemotherapy. However, these drugs are very costly, and biosimilar/generic competition is not anticipated for several years due to extended patent lives. Given the high cost of existing and pipeline drugs, it’s crucial for payers to stay up to date with new FDA approvals and updated guidelines and to implement management strategies such as prior authorization and step therapy to optimize patient outcomes while reducing overall health care costs.”
According to Wong, cancer is one of the top three therapeutic categories in terms of cost of care, making all types of it top areas of concern for payers. “Heavy use of the immune checkpoint inhibitors” in bladder cancer boosts it as a somewhat high-priority cancer. Treatment with Bacillus Calmette-Guérin and chemotherapy is “relatively inexpensive compared to the checkpoint inhibitors, in part because the chemotherapy agents are available as generics.”
Urothelial carcinoma treatment can vary based on factors such as the stage of the tumor, its size, whether it has metastasized and the overall health of the patient, says Tegenu, noting that regimens can consist of chemotherapy, immunotherapy, radiation and surgery. That said, “standard first-line therapy is usually a cisplatin-based combination chemotherapy regimen when systemic therapy is required. For patients who are ineligible for cisplatin, alternative regimens like carboplatin plus gemcitabine can be used.”
“The Padcev/Keytruda combination is definitely now the first line of treatment of platinum-ineligible patients, along with pembrolizumab as a single agent or other chemotherapy; however, given the significant positive clinical OS and PFS benefit, the Padcev/Keytruda combination would be hard to rationalize against,” says Wong.
In the second-line setting, immune checkpoint inhibitors such as Keytruda, Bavencio (avelumab) from Merck KGaA division EMD Serono and Opdivo (nivolumab) from Bristol Myers Squibb are usually used in people with disease progression during or after platinum-based chemotherapy, he states. “For patients with an FGFR3 [fibroblast growth factor receptor 3] genetic alteration, Balversa [(erdafitinib) from Johnson & Johnson Innovative Medicine] is approved as a second-line or later treatment. Additionally, Padcev and Trodelvy [(sacituzumab govitecan-hziy) from Gilead Sciences, Inc.] are typically utilized as later-line therapies for advanced disease, often after patients have progressed on platinum-based chemotherapy and immune checkpoint inhibitors.”
“As we move into the advanced or metastatic disease, cost becomes more of a concern; however, these stages of cancer are also less able to be managed, as treatment options are fewer,” he points out. And if people stop responding to Padcev plus Keytruda, what is their next step?
“We already know Keytruda by itself is expensive; however, now there is even a greater cost with this antibody/drug conjugate combination,” says Wong. “This is what will keep payers up at night. The cost should also be a question taken into consideration for the patient share as well, especially in the Medicare population.”
Drugs.com lists the price of one single-dose 20 mg vial of Padcev as $2,909. The list price of every-three-weeks Keytruda is $11,115; for every-six-weeks dosing, it is $22,230. Assuming treatment lasts one year, the annual per-person cost could be more than half a million dollars, according to one estimate.
Both Wong and Tegenu say they agree that that estimate seems accurate. In addition, says Wong, “these agents are rarely rebated, simply because they do not need to be. The approved regimens are so niche that one cannot across the board start preferring checkpoint inhibitors. The closest to UM [utilization management] will be to the approved indication.
“What strengthens this position are legislative regulations mandating payers to cover cancer drugs for either their approved indications or what is documented in the compendia,” he continues. “In a recent discussion with an oncologist, he stated that almost all new indications for a targeted agent/regimen almost have to be treated as orphan/rare diseases because the advancement in technology is refining the treatment of cancers to so many different subpopulations.”
But with the cost of the new regimen, rebates may need to be part of the equation, says Tegenu. “Because this combination is notably more expensive than platinum-based chemotherapy regimens, which have long been the standard of care in first-line treatment, there may need to be significant payer rebate opportunities to secure coverage on a medical policy. Payers may also consider value-based agreements to manage costs. Lastly, because Padcev plus Keytruda was previously granted priority review and breakthrough therapy designation, payers may want to wait until additional real-world evidence is available to see the impact.”
However, he notes, “unlike pharmacy benefit products, where influencing and tracking formulary placement is a major driver for extensive payer/manufacturer contracting and rebates, it's more challenging for manufacturers to monitor if payers meet all contract requirements for medical benefit drugs. Because Keytruda is one of the three checkpoint inhibitors approved for use in bladder cancer, there may be more contracting opportunities with Keytruda. Furthermore, the other checkpoint inhibitor manufacturers may position themselves more competitively after the recent approval of Keytruda/Padcev.”
“I think payers will ultimately be managing to the approved indication,” says Wong. “What will certainly drive the positioning, or regimen sequencing per se, will be the placement by the professional organizations like NCCN [National Comprehensive Cancer Network] or ASCO [American Society of Clinical Oncology] in their treatment guidelines.”
For more information on the Zitter Insights data, contact Jill Brown Kettler at jkettler@mmitnetwork.com. Contact Tegenu at Mesfin.Tegenu@rxparadigm.com and Wong at w2sqgroup@gmail.com.
]]>Feb. 9: The FDA approved Takeda Pharmaceuticals U.S.A., Inc.’s Eohilia (budesonide) for the treatment of people at least 11 years old with eosinophilic esophagitis. The corticosteroid is the first and only FDA-approved oral treatment for the indication. Recommended dosing is 2 mg twice daily for 12 weeks; the agent is available in 2 mg/10 mL single-dose stick packs. Its monthly wholesale acquisition cost is $1,875.
]]>Feb. 9: The FDA approved Takeda Pharmaceuticals U.S.A., Inc.’s Eohilia (budesonide) for the treatment of people at least 11 years old with eosinophilic esophagitis. The corticosteroid is the first and only FDA-approved oral treatment for the indication. Recommended dosing is 2 mg twice daily for 12 weeks; the agent is available in 2 mg/10 mL single-dose stick packs. Its monthly wholesale acquisition cost is $1,875.
Feb. 13: The FDA gave an additional indication to Ipsen Biopharmaceuticals, Inc.’s Onivyde (irinotecan liposome) in combination with oxaliplatin, fluorouracil and leucovorin for the first-line treatment of metastatic pancreatic adenocarcinoma. The agency first approved the topoisomerase inhibitor on Oct. 22, 2015. The newest use had orphan drug designation. Dosing is 50 mg/m2 via a 90-minute intravenous infusion every two weeks. Drugs.com lists the price of a 43 mg/10 mL (4.3 mg/mL) single-dose vial as more than $2,922.
Feb. 15: The FDA granted traditional approval to Merck KGaA division EMD Serono, Inc.’s Tepmetko (tepotinib) for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. The agency gave the kinase inhibitor accelerated approval for the indication on Feb. 3, 2021. The FDA granted the application breakthrough therapy and orphan drug designations, and it used the Assessment Aid in its review. Dosing for the newest use of the tablet is 450 mg once daily. Drugs.com lists the price of 30 225 mg tablets as more than $12,868.
Feb. 16: The FDA gave another indication to AstraZeneca’s Tagrisso (osimertinib) in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adults with locally advanced or metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. The agency first approved the tyrosine kinase inhibitor on Nov. 13, 2015. The FDA granted the application priority review, as well as orphan drug, regenerative medicine advanced therapy and fast track designations. It conducted its review under Project Orbis in collaboration with the Australian Therapeutic Goods Administration, Health Canada and Switzerland’s Swissmedic, and it used the Assessment Aid. Dosing for the tablet’s newest use is 80 mg once daily. Drugs.com lists the price of 30 tablets of both the 40 mg and 80 mg formulations as more than $17,508.
Feb. 16: The FDA gave accelerated approval to Iovance Biotherapeutics, Inc.’s Amtagvi (lifileucel) for the treatment of adults with unresectable or metastatic melanoma previously treated with a programmed death receptor-1 (PD-1) inhibitor and, if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. The agency gave the therapy orphan drug, regenerative medicine advanced therapy, fast track and priority review designations. The tumor infiltrating lymphocyte (TIL) therapy, which is created from a patient’s T cells from their tumor, is the first and only one-time individualized T cell therapy with FDA approval for a solid tumor cancer. More than 30 authorized treatment centers are available to collect and ship tumor tissue, which is sent to Iovance’s Philadelphia Iovance Cell Therapy Center for manufacturing and then returned to an ATC for administration. The cost of a one-time intravenous infusion is $515,000.
Feb. 16: The FDA gave an additional indication to Roche Group member Genentech USA, Inc. and Novartis Pharmaceuticals Corp.’s Xolair (omalizumab), in combination with food allergen avoidance, for the reduction of allergic reactions, including anaphylaxis, that may occur following accidental exposure to one or more foods in people at least 1 year old with immunoglobulin E (IgE)-mediated food allergy. The agency first approved the anti-IgE antibody on June 20, 2003. Dosing via subcutaneous injection ranges from 75 mg to 600 mg every two or four weeks and is based on serum total IgE level before the start of treatment and body weight. Drugs.com lists the price of 150 mg of lyophilized powder in a single-dose vial as more than $1,467.
Feb. 20: The FDA approved a reduced dosing frequency for Johnson & Johnson Innovative Medicine’s Tecvayli (teclistamab-cqyv) of 1.5 mg/kg every two weeks for the treatment of adults with relapsed or refractory multiple myeloma who have achieved and maintained a complete response or better for at least six months. The agency first gave the bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager accelerated approval on Oct. 25, 2022, for once-weekly dosing in people who had received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody. A health care provider administers the agent via subcutaneous injection. Drugs.com lists the price of a 153 mg/1.7 mL (90 mg/mL) single-dose vial as more than $9,990.
Feb. 23: The FDA approved and granted interchangeable status to Alvotech and Teva Pharmaceutical Industries Ltd. affiliate Teva Pharmaceuticals’ Simlandi (adalimumab-ryvk) for the treatment of (1) adults with moderately to severely active rheumatoid arthritis; (2) people at least 2 years old with moderately to severely active polyarticular juvenile idiopathic arthritis; (3) adults with active psoriatic arthritis; (4) adults with active ankylosing spondylitis; (5) people at least 6 years old with Crohn’s disease; (6) adults with moderately to severely active ulcerative colitis; (7) adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, when other systemic therapies are medically less appropriate; (8) adults with moderate to severe hidradenitis suppurativa; and (9) adults with noninfectious intermediate and posterior uveitis and panuveitis. The tumor necrosis factor (TNF) inhibitor is the 10th biosimilar of AbbVie Inc.’s Humira (adalimumab) that the FDA has approved and the first citrate-free, high-concentration biosimilar with interchangeability status. Dosing is via subcutaneous injection and varies due to the indication. The product is available in a 40 mg/0.4 mL single-dose autoinjector.
Feb. 23: The FDA granted another indication to Gilead Sciences, Inc.’s Biktarvy (bictegravir/emtricitabine and tenofovir alafenamide) for the treatment of people with HIV who have suppressed viral loads with known or suspected M184V/I resistance. The agent is the first and only integrase strand transfer inhibitor (INSTI)-based single-tablet regimen that is FDA approved for this indication. The FDA initially approved it on Feb. 7, 2018. The recommended dosage for people weighing at least 25 kg is one 50 mg/200 mg and 25 mg tablet once daily; for people at least 14 kg and less than 25 kg, the dosage is one 30 mg/120 mg and 15 mg tablet once daily. Drugs.com lists the price of 30 tablets of both strengths as more than $4,201.
Feb. 28: The FDA gave an additional indication to Sandoz Inc.’s Ziextenzo (pegfilgrastim-bmez) to increase survival in people acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome or H-ARS). The agency initially approved the granulocyte colony-stimulating factor (G-CSF), a biosimilar of Amgen Inc.’s Neulasta (pegfilgrastim), on Nov. 4, 2019. Dosing for the newest use in people weighing at least 45 kg is two 6 mg doses administered via subcutaneous injection one week apart, with the first dose administered as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy). For those weighing less than 45 kg, dosing is based on weight. Drugs.com lists the price of one 6 mg/0.6 mL single-dose vial as more than $4,143.
Feb. 29: The FDA approved a new delivery device for Mallinckrodt plc’s Acthar Gel (corticotropin) as a single-dose prefilled SelfJect injector for subcutaneous administration by adults to administer single doses of either 40 units or 80 units for the treatment of chronic and acute inflammatory and autoimmune conditions. The agency first approved the product on April 29, 1952. The agent remains available as an injection with a vial and syringe. Dosing is based on indication. The drug’s list price for an 80 u/mL injection is $43,984.
March 1: The FDA expanded the label of the Janssen Pharmaceutical Companies of Johnson & Johnson’s Rybrevant (amivantamab-vmjw) to include, in combination with carboplatin and pemetrexed, the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. The agency also granted traditional approval to the bispecific EGF receptor-directed and MET receptor-directed antibody for the treatment of adults with locally advanced or metastatic NSCLC with exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy; that indication — also the drug’s first — gained accelerated approval on May 21, 2021. The FDA granted the newest application priority review and conducted the review under Project Orbis in collaboration with the Brazilian Health Regulatory Agency and Health Canada. The review also used the Real-Time Oncology Review pilot program and the Assessment Aid. Dosing via intravenous infusion is based on baseline body weight and indication. For the newest use, the recommended dosing is 1,400 mg weekly in weeks one through four for people weighing less than 80 kg and then 1,750 mg weekly from week seven onward. For people weighing at least 80 kg, dosing for weeks one through four is 1,750 mg weekly and then 2,100 mg weekly from week seven onward. The agent should be administered in combination with chemotherapy weekly for four weeks, with the initial dose as a split infusion in week one on day one and day two, then every three weeks starting at week seven. Drugs.com lists the price of one 350 mg/7 mL (50 mg/mL) single-dose vial of Rybrevant as more than $3,676.
March 5: The FDA approved Fresenius Kabi’s Tyenne (tocilizumab-aazg) for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to at least one disease-modifying anti-rheumatic drug (DMARD), adults with giant cell arteritis, people at least 2 years old with active polyarticular juvenile idiopathic arthritis and people at least 2 years old with active systemic juvenile idiopathic arthritis. This is the second biosimilar of Roche Group member Genentech USA, Inc.’s Actemra (tocilizumab) that the FDA has approved, and the first approved in both intravenous and subcutaneous formulations. Dosing of the interleukin-6 inhibitor is based on indication. Fresenius Kabi entered into a settlement agreement in October 2022 with Genentech that allows the company to market Tyenne on license dates that are confidential.
March 5: The FDA approved Sandoz’s Wyost (denosumab-bbdz) and Jubbonti (denosumab-bbdz) as biosimilar to and interchangeable with Amgen Inc.’s Xgeva (denosumab) and Prolia (denosumab). Wyost is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors; the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity; and the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. Jubbonti is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture; to increase bone mass in men with osteoporosis at high risk for fracture; the treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture; to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer; and to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. They are the first FDA-approved biosimilars of the RANK ligand (RANKL) inhibitor. Both are administered via subcutaneous injection, and Jubbonti should be administered by a health care professional. Dosing varies based on indication. Sandoz says that due to ongoing patent litigation, the company “will not comment on anticipated launch timing or other launch details at this time.”
March 6: The FDA approved another indication for Bristol Myers Squibb’s Opdivo (nivolumab) in combination with cisplatin and gemcitabine for the first-line treatment of adults with unresectable or metastatic urothelial carcinoma. The agency first approved the PD-1 inhibitor on Dec. 22, 2014; it gave the newest use priority review. The FDA conducted its review under Project Orbis in collaboration with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada and Switzerland’s Swissmedic. It also used the Real-Time Oncology Review program and the Assessment Aid. Dosing for the newest use is 360 mg via intravenous infusion every three weeks with cisplatin and gemcitabine on the same day for up to six cycles, followed by 240 mg every two weeks or 480 mg every four weeks. For people receiving 240 mg every two weeks, the list price is $7,194. For those receiving 480 mg every four weeks, the list price is $14,389.
March 6: The FDA broadened the label of Pfizer Inc.’s Besponsa (inotuzumab ozogamicin) to include the treatment of pediatric patients at least 1 year old with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia. The agency first approved the CD22-directed antibody-drug conjugate on Aug. 17, 2017. The newest indication was given priority review and orphan drug designation. Dosing via intravenous infusion is 0.8 mg/m2 on day one, 0.5 mg/m2 on day eight and 0.5 mg/m2 on day 15 of a 21-day cycle. Subsequent dosing is based on response to treatment. Drugs.com lists the price of one 0.9 mg of lyophilized powder in a single-dose vial as more than $23,423.
March 7: The FDA gave accelerated approval to BeiGene Ltd.’s Brukinsa (zanubrutinib) in combination with obinutuzumab (available as Genentech’s Gazyva) for relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. The agency first approved the kinase inhibitor on Nov. 14, 2019. The application had fast track and orphan drug designations, and its review used the Assessment Aid. The recommended dosing of the capsule is 160 mg twice daily or 320 mg once daily. Drugs.com lists the price of 120 80 mg capsules as more than $15,874.
March 7: The FDA approved a new liquid-filled soft gelatin capsule formulation for Pfizer’s Talzenna (talazoparib) for the treatment of adults with deleterious or suspected deleterious germline BRCA-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer and in combination with enzalutamide for the treatment of adults with homologous recombination repair (HRR) gene mutated metastatic castration-resistant prostate cancer. The FDA initially approved the poly (ADP-ribose) polymerase (PARP) inhibitor on Oct. 16, 2018. Dosing is based on indication. Drugs.com lists the price of 30 0.1 mg capsules as more than $19,005.
March 8: The FDA expanded the use of Regeneron Pharmaceuticals, Inc.’s Praluent (alirocumab) to include, as an adjunct to diet and other low-density lipoprotein cholesterol-lowering therapies, the treatment of pediatric patients at least 8 years old with heterozygous familial hypercholesterolemia. The agency first approved the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor on July 24, 2015. The recommended dosing for the newest use in people with a body weight less than 50 kg is 150 mg via subcutaneous injection once every four weeks; for people weighing at least 50 kg, dosing is 300 mg once every four weeks. Drugs.com lists the price of both a 75 mg/mL and a 150 mg/mL single-dose prefilled pen as more than $542.
]]>Catalyst Pharmaceuticals, Inc.’s Agamree (vamorolone) is now available in the U.S., the company said March 13. The FDA approved the first-in-class corticosteroid on Oct. 26 for the treatment of Duchenne muscular dystrophy in people at least 2 years old. The company is offering the comprehensive support program Catalyst Pathways Patient Assistance Program for Agamree for eligible patients. Drugs.com lists the price of 40 mg/mL oral suspension as more than $10,013.
]]>Catalyst Pharmaceuticals, Inc.’s Agamree (vamorolone) is now available in the U.S., the company said March 13. The FDA approved the first-in-class corticosteroid on Oct. 26 for the treatment of Duchenne muscular dystrophy in people at least 2 years old. The company is offering the comprehensive support program Catalyst Pathways Patient Assistance Program for Agamree for eligible patients. Drugs.com lists the price of 40 mg/mL oral suspension as more than $10,013.
The FDA has made the decision to withdraw the approval for Oncopeptides AB’s Pepaxto (melphalan flufenamide), the agency revealed on Feb. 23. It is the first time that the FDA has used the process for withdrawing a drug granted accelerated approval that was enacted as part of the Food and Drug Omnibus Report Act of 2022 (FDORA). The FDA initially gave the therapy accelerated approval on Feb. 26, 2021, in combination with dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent and one CD38-directed monoclonal antibody. But then on Oct. 22, 2021, the company requested voluntary withdrawal of the peptide-drug conjugate’s New Drug Application (NDA). That was followed early in 2022 by Oncopeptides’ rescinding the letter requesting the NDA’s withdrawal based on “further review and analyses of the heterogenous Overall Survival data from the phase 3 OCEAN study and other relevant trials.” On Sept. 22, 2022, the FDA’s Oncologic Drugs Advisory Committee (ODAC) held a meeting to assess the drug’s risk/benefit profile; it voted 14-2 that the drug is not favorable for adults with relapsed or refractory multiple myeloma. In December 2023, the FDA requested that the company withdraw its U.S. marketing authorization for the drug. Oncopeptides is commercializing the therapy in Europe, where it is known as Pepaxti, following its full approval on Aug. 18, 2022.
The U.S. Department of Veterans Affairs selected Organon’s biosimilar Hadlima (adalimumab-bwwd) to replace AbbVie Inc.’s Humira (adalimumab) on the VA National Formulary, Organon said on Feb. 20. The tumor necrosis factor launched in July 2023 with a wholesale acquisition cost of $1,038, about 85% off Humira’s WAC. It is available in a citrate-free high-concentration formulation, as well as a citrate-containing low-concentration version, in a prefilled syringe and an autoinjector option.
]]>Health plans and PBMs several years ago began implementing copay accumulators — and then a new iteration known as copay maximizers that declare certain drugs non-essential health benefits to avoid covering them per the Affordable Care Act (ACA) — to counter manufacturer copay assistance programs. Before these tools, that assistance would count toward beneficiaries’ annual out-of-pocket expenses. When those out-of-pocket maximums were reached, health plans would cover the remainder of members’ costs for the year. With accumulators and maximizers, patients can still use that assistance, but it does not help reduce those out-of-pocket costs.
]]>Health plans and PBMs several years ago began implementing copay accumulators — and then a new iteration known as copay maximizers that declare certain drugs non-essential health benefits to avoid covering them per the Affordable Care Act (ACA) — to counter manufacturer copay assistance programs. Before these tools, that assistance would count toward beneficiaries’ annual out-of-pocket expenses. When those out-of-pocket maximums were reached, health plans would cover the remainder of members’ costs for the year. With accumulators and maximizers, patients can still use that assistance, but it does not help reduce their out-of-pocket costs.
Once the assistance is depleted — usually fairly early in the year with accumulators — beneficiaries must pay for often-costly drugs until they hit their out-of-pocket maximums, shifting payers’ financial responsibilities to their members and manufacturers.
At the crux of the lawsuit was the 2021 Notice of Benefit and Payment Parameters (NBPP). The 2020 NBPP stated that plans could exclude manufacturer assistance from counting toward patients’ out-of-pocket limit for only “specific prescription brand drugs that have an available and medically appropriate generic equivalent.” That excluded many costly specialty drugs that did not have a generic equivalent.
But in the 2021 NBPP, CMS said plans were not required to apply manufacturer assistance toward beneficiaries’ annual cost sharing, leaving members on the hook for numerous specialty medications once assistance ran out.
In August 2022, the HIV+Hepatitis Policy Institute, the Diabetes Patient Advocacy Coalition, the Diabetes Leadership Council and three people dependent on copay assistance whose health plans had copay accumulators in place filed a lawsuit (Case 1:22-cv-02604) against HHS, CMS and their respective leaders challenging the 2021 NBPP. The plaintiffs claimed that allowing the use of accumulators is at odds with how the ACA — as well as the agencies’ preexisting regulatory definition — defines “cost sharing” and charged that the 2021 NBPP is “arbitrary and capricious.”
On Sept. 29, 2023, U.S. District Judge John D. Bates of the U.S. District Court for the District of Columbia ruled in favor of the plaintiffs, ordering that the 2021 NBPP “must be set aside based on its contradictory reading of the same statutory and regulatory language and the fact that the agencies have yet to offer a definitive interpretation of this language that would support the rule.”
In response, on Nov. 27, HHS filed a conditional motion to clarify the scope of the court’s order. “Defendants do not understand this Court’s order to require HHS to take enforcement action,” it said. “The Court vacated the relevant portion of the 2021 NBPP but did not order any additional relief.…To ensure that they are not inadvertently running afoul of the Court’s Order, however, Defendants respectfully request clarification from the Court if their understanding of the scope of the Court’s Order is incorrect.”
In the motion, HHS revealed that the agency “intends to address, through rulemaking, the issues left open by the Court’s opinion, including whether financial assistance provided to patients by drug manufacturers qualifies as ‘cost sharing’ under the Affordable Care Act.”
HHS also said that until it issues a final rule, it has no intentions of taking “any enforcement action against issuers or plans based on their treatment of such manufacturer assistance.”
The following day, HHS filed a notice of appeal, which was followed on Dec. 11 by the plaintiffs’ filing of a notice of appeal, as well as a brief outlining why the court should deny HHS’s motion for clarification.
On Dec. 22, Bates responded to HHS’s motion for clarification, explaining that the 2020 NBPP is in effect.
Less than a month later, on Jan. 16, the U.S. Department of Justice filed a motion to dismiss the government’s appeal. That was followed on Feb. 1 by the plaintiffs’ filing to dismiss their cross-appeal.
As for enforcing the ruling that manufacturer assistance must be counted toward patients’ out-of-pocket responsibility unless a brand-name drug has a medically appropriate generic equivalent, the government’s role is to issue guidance for health plans and PBMs saying exactly that, says Carl Schmid, executive director of the HIV+Hepatitis Policy Institute.
CMS did not respond to a request from AIS Health, a division of MMIT, for comment on whether it will do so.
AIS Health reached out to the National Association of Insurance Commissioners about whether the NAIC is taking any kind of action in response to the lawsuit. A spokesperson says that CMS would be the entity taking enforcement action. “The NAIC is not a regulator, so we will not be taking action,” they clarify.
That enforcement, says Schmid, would fall mainly to state insurance commissioners, who “can enforce this [ruling]. Actually, they should be doing it now.”
Similarly, he says, the U.S. Department of Labor can enforce the ruling under the Employee Retirement Income Security Act (ERISA), although “it may take filing additional complaints with DOL, class-action suits and other legal action. We are speaking to lawyers now.”
Schmid says that he has already heard of people “this year who are being stuck with thousands of dollars in costs for their drugs even though they have copay assistance from the drug manufacturer. One father told me that he received a $4,000 bill for his child’s infusion that he must get monthly. Another woman is putting thousands of dollars on her credit card. And a man with HIV recently learned his copay assistance did not count.”
He says that he expects insurers and PBMs to turn to alternate funding methods, such as copay maximizers.
While CMS did not comment on whether it would still issue a rule addressing copay assistance, Schmid says that “there really is no need to, but guidance would be useful. We will just have to wait and see. I can’t imagine the Biden administration would issue a rule that said copay assistance would not count. That would substantially increase patient cost sharing. People are already having trouble paying for their drugs due to insurance benefit design.”
He points to IQVIA data showing that in 2022, copay assistance totaled almost $19 billion. “That is a lot of money patients would have to come up [with] for them to afford the drugs their provider prescribes.”
“Because the 2020 Accumulator Rule is currently in effect per the Court’s decision, hubs, copay vendors, and drug manufacturers should prepare to comply with the rule and only utilize Accumulator Adjustment Programs, where allowed by state law, for branded drugs with a generic equivalent,” recommend attorneys from Bass, Berry & Sims PLC. in a Feb. 5 publication.
As of press time, 20 states have enacted legislation banning the use of copay accumulators for state-regulated health plans, including individual, fully insured large-group and small-group plans.
“While this decision may not have a direct impact on pharmacy operations, it may affect the ability of a pharmacy’s patients to afford expensive prescription drugs and purchase from the pharmacy, indirectly affecting the pharmacy’s bottom line,” they continue. “We recommend monitoring for future rulemaking to gain additional clarification on the use of Accumulator Adjustment Programs and for any action taken on the plaintiff’s appeal.”
Contact Schmid at cschmid@hivhep.org.
]]>AIS Health: What are some specialty pharmacy issues to keep an eye on in 2024, and why?
]]>While the FDA approved a large number of specialty drugs in 2023, payers shouldn’t let their attention wander in 2024. Multiple potential blockbusters are slated for decisions by the agency this year, as are several biosimilars and generic versions of specialty medications. Gene therapies will continue to garner headlines — and payer dollars. All of these trends and more point to an active year ahead within the specialty pharmacy space. AIS Health, a division of MMIT, spoke with some industry experts about what’s on board.
AIS Health: What are some specialty pharmacy issues to keep an eye on in 2024, and why?
Stefani Papazaharias, trade relations executive for Reliance Rx, the specialty drug company affiliated with the not-for-profit health plan Independent Health:
Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth: One of the key specialty pharmacy issues is the continuing affordability of specialty drug products. While specialty drugs are costly, they can also provide life-changing options to physicians and patients. Current pharmaceutical spending now exceeds $600 billion, with specialty products accounting for over 50% of the prescription drug benefit. The latest IQVIA estimates state that over 55% of all drug spending is on specialty drugs and has continued to increase year-over-year and is up from 28% in 2011.
The FDA has approved over 30 cell and gene therapy products, and the product pipeline has approximately 365 investigational therapies, with more than half of these in Phase II clinical trials. Oncology and rare diseases remain the top areas targeted by gene therapies from preclinical through preregistration. Approximately 1,604 clinical trials are under investigation for various cell and gene therapies in the U.S. The FDA approved more than 50 novel specialty drugs in 2023, and this trend is expected to continue. Newly approved and marketed therapies continue to be expensive, with one source indicating that the median cost of a newly approved therapy in 2022 was over $220,000, a 23% increase over 2021 ($180,000). This is expected to continue due to the [ongoing] development of orphan and new cancer therapies, with more than 80% of all specialty drug development for orphan conditions and cancer. This will increase the emphasis to ensure proper use and monitoring of these new and very expensive therapies, with specialty pharmacies at the forefront.
Due to these ultra-expensive therapies, there will be continued emphasis towards value-based and outcome-based agreements to link the cost of therapies to the real-world performance of the product and gaining the desired patient outcomes. With the increasing availability of cell and gene therapies, there will be increased pressure on pharmaceutical manufacturers to ensure that their therapies are producing the expected results, with pharmaceutical manufacturers bearing risk in the outcome.
Another continuing trend is the expanding role of specialty pharmacy to manage specialty drugs traditionally covered under the medical benefit. Specialty pharmacies are able to provide cost-effective options for payers to see savings with these products while ensuring the quality and care of the patient. Part of this may also include the potential movement of the site of administration of the specialty drug products from a hospital setting, either inpatient or outpatient, to clinically equivalent alternative settings such as infusion centers, provider offices or even home administration. Specialty pharmacies will be able to be on the forefront in assisting and directing patients to the best option for their unique medical condition and benefit coverage.
Mesfin Tegenu, CEO and chairman of RxParadigm, Inc.: The rise of cell and gene therapies is a key specialty pharmacy issue to watch for in 2024. In 2023, the FDA approved seven new cell and gene therapies, with several more expected to receive approval in 2024. Among the treatments approved last year, four were listed at over $2 million per treatment. It is anticipated that a number of therapies currently in the pipeline will be similarly priced. With the growing number of cell and gene therapy approvals, managing the high costs of these therapies while improving patient access will be a top priority for payers. Payers will increasingly adopt innovative payment models such as value-based and outcome-based contracts and explore other financial strategies to help improve the affordability and access of these therapies.
AIS Health: What do you expect we’ll see within the biosimilars landscape this year?
Papazaharias: Some of the most significant biosimilar launches for 2024 are Xgeva, Actemra, Eylea, Neulasta Onpro and additional biosimilars for Humira. Looking forward to biosimilars for Stelara and Prolia for 2025.
Nationally, slow-paced adoption as PBM-owned specialty pharmacies are still incentivized to dispense brand (i.e., due to rebates), and 340B entities will prefer brand over biosimilar.
Regional and independent plans will outpace nationals on biosimilar adoption if integrated well enough with a specialty pharmacy partner.
Providers and patients are becoming more comfortable with biosimilars clinically, especially when the path to prescribing is easy and transparent.
Szczotka: While this year does not have the punch of the initial introduction of adalimumab biosimilars, there will be some products that will further drive use and savings. Less expensive biosimilars will likely play a key role in controlling drug spend, as biologics continue to be a leading driver of increasing health care costs, with a recent survey identifying that 65% of health plans ranked biosimilars coming to market among their top cost deflator options.
The availability of biosimilars is decreasing the average sales prices (ASPs) of both reference products and the corresponding biosimilar products. Certain reference products have experienced dramatic decreases in ASPs, including Herceptin (25%), Neulasta Onpro (66%) and Remicade (60%). These decreases should assist in helping drive continued biosimilar adoption.
It is expected that biosimilar manufacturers will continue to offer various pricing strategies and approaches for their products. Some manufacturers have launched high- and low-WAC [wholesale acquisition cost] versions of their biosimilars while other manufacturers have opted to launch their high- and low-cost products using a branded and unbranded biosimilar approach. Some manufacturers opted to launch high-WAC biosimilar products only while others launched with a low-WAC-only strategy. The numerous strategies taken by various manufacturers will undoubtedly influence the tactics biosimilar manufacturers select in the future as $200 billion of biologic exclusivity is set to expire by 2028. Biosimilars are now regularly included on various payers’ medication formularies, with manufacturers jockeying for preferred formulary placement. The various cost scenarios and available discounts will continue to motivate payers to increase use of prior authorization, step therapy requirements and formulary tiering in order to optimize the savings available with the multiple biosimilar options.
Tegenu: The biosimilar landscape is expected to continue growing this year. Last year, the FDA approved five biosimilars, including three of which were the first for their reference products. Moreover, there are several biosimilars currently in the pipeline, with approvals expected within the year. The growing number of biosimilar approvals and launches will increase biosimilar utilization and contribute to savings. Payers will likely increase utilization management strategies, such as prior authorization and step therapy, and employ formulary tiering or switching to maximize savings. Given that biologics are a leading driver of prescription drug spending, biosimilars hold significant potential to reduce health care costs.
AIS Health: Are there any big specialty drugs expected to see patent expiration — and potentially generic or biosimilar competition — in 2024?
Papazaharias:
Szczotka: Some key biosimilars are anticipated in 2024. There are additional adalimumab interchangeable high-concentration biosimilars likely to be approved. These new additions will directly compete with the market-leading Humira high-concentration product for market share. Along with the continued introduction of low-cost product options, the competitive landscape for adalimumab products will continue to evolve.
The approval of the Udenyca Onbody biosimilar late in 2023 will likely provide an alternative to the market-leading Neulasta Onpro. This will provide a biosimilar on-body injector version of Udenyca, providing a self-administration version of pegfilgrastim for patients post-chemotherapy.
Another anticipated product will be eculizumab, the biosimilar to Soliris. If approved, this would be the first biosimilar available to treat paroxysmal nocturnal hemoglobinuria (PNH). While the introduction and conversion to Ultomiris by Alexion has impacted the utilization of Soliris, this should provide a potential cost-savings opportunity.
Tegenu: Several specialty drugs, including Cimzia, Neulasta Onpro, Simponi, Sprycel and Tasigna are set to lose their patents this year. Among them, Neulasta Onpro is the only biologic anticipating biosimilar competition this year. Udenyca Onbody, the biosimilar to Neulasta Onpro, is scheduled for launch in the first quarter of this year. Additionally, both Sprycel and Tasigna may potentially face generic competition this year, while biosimilars for Cimzia and Simponi are currently in development.
AIS Health: In terms of the specialty drug pipeline, are there particular drugs and/or therapeutic categories that should be on payers’ radar, and why?
Papazaharias: Yes, extremely high-cost cell/gene therapies for sickle cell and hemophilia, as well as treatments for NASH [non-alcoholic steatohepatitis] and Alzheimer’s.
Ensuring 2023 launches of generic oral oncology drugs have transitioned to generic and are reviewed for preferable formulary placement and/or step edit.
Outlook Therapeutics is seeking approval and will market a competitor to compounded Avastin for retina use. This could offset any savings from the Eylea biosimilar launch. Payers should continue to intensely manage the VEGF [vascular endothelial growth factor inhibitor] ocular category to ensure patients are managed with the lowest cost therapy and to minimize transition to more expensive, newer agents such as Vabysmo and Eylea HD.
Current volume restrictions on Revlimid generic allocations will end in first-quarter 2026, and plans may recognize significant savings at that point.
Szczotka: There are some key pipeline products that payers should be keeping an eye on for 2024. Some of these products would include:
Tegenu: Oncology, immunology and neurology are quickly growing areas with numerous drugs in the pipeline and thus warrant close attention. Similarly, payers should monitor orphan drugs, as the approvals for orphan drugs have consistently risen in recent years. The introduction of new drugs may lead to changes in treatment guidelines and standards of care, which may have financial implications for payers. Staying well-informed about these therapeutic categories is essential for payers, as they represent significant potential costs, and strategies need to be developed to manage these potential costs effectively.
AIS Health: Is there anything I’ve neglected to ask about that you’d like to add?
Papazaharias: To control costs of GLP1s [glucagon-like peptide-1s], health plans are implementing utilization management, such as prior authorization, step therapy and quantity limits, to ensure payment only for FDA-approved indications and to address off-label prescribing concerns. Moreover, there is a consideration for the inclusion of wellness or weight-loss programs within GLP1-coverage to promote a comprehensive approach to health.
Given the anticipated growth in the prescription weight-loss category, expanding the definition of specialty drugs may be necessary, and health plans may adopt more aggressive criteria to manage utilization and costs, including longer waiting periods, prescription coaching, wellness requirements and restrictions on prescribing.
According to a 2023 pipeline review, the highest-cost items, each with annual sales exceeding $500 million, include xanomeline-trospium, tirzepatide, sotatercept, donanemab, datopotamab deruxtecan, blarcamesine and aficamten. These pharmaceutical products represent significant contributors to the overall sales landscape based on their substantial revenue.
Contact Papazaharias via Frank Sava at Frank.Sava@independenthealth.com, Szczotka via Caroline Chambers at cchambers@cpronline.com and Tegenu at Mesfin.Tegenu@rxparadigm.com.
]]>A Walgreens spokesperson told AIS Health, a division of MMIT, that the company has no comment.
]]>A Walgreens spokesperson told AIS Health, a division of MMIT, that the company has no comment.
Shields — which partners with health systems to help them create and grow a hospital-owned specialty pharmacy program — has more than 80 health system partners consisting of academic medical centers and community-based hospitals across 47 states.
Shields’ first-quarter 2024 (ending Nov. 30, 2023,) sales rose 27.2% to $133 million from the year-ago quarter, “driven by recent contract wins and further expansion of existing partnerships,” Walgreens said in its Form 10-Q, filed Jan. 4 with the U.S. Securities and Exchange Commission. “We expect Shields to continue to leverage and benefit from the rapid growth in the broader specialty market and our intense focus on accelerating hospital-owned specialty pharmacy programs,” said Walgreens CEO Tim Wentworth during a Jan. 4 call to discuss first-quarter earnings.
In a Nov. 7, 2023, Drug Channels blog, longtime industry expert Adam J. Fein, Ph.D., CEO of Drug Channels Institute, noted that “hospitals and health systems have emerged as significant participants in the specialty pharmacy industry.…Vertical integration among insurers, PBMs, specialty pharmacies, and providers within U.S. drug channels gets most of the attention. But a parallel vertical integration has been occurring among hospitals, specialty pharmacies, and physicians. Manufacturers and payers must adapt to the growing power and market tactics of hospital-owned specialty pharmacies.”
According to Fein, of the more than 1,600 accredited specialty pharmacy locations, almost one-fourth are owned by hospitals. Of those, “more than one-third rely on an external company for specialty pharmacy services and/or to provide specialty medications,” with Shields and Trellis Rx, which is owned by CPS Solutions, being the largest of those companies.
Walgreens’ interest in Shields played out over several years. It initially made a minority investment of 23% in Shields in July 2019, followed by a $970 million investment in September 2021 that upped its stake to 71% ownership. Then in 2022, Walgreens purchased the remaining 30% for approximately $1.37 billion.
That 2021 investment followed Shields’ purchase earlier in 2021 of ExceleraRx Corp., which is a network of specialty pharmacies among its members, which are integrated delivery networks and academic medical centers. Created by Minneapolis-based Fairview Health Services a decade ago, Excelera consisted of almost 30 members at the time of the purchase.
Those deals were made under ex-CEO Roz Brewer, who stepped down on Aug. 31, 2023. On Oct. 23, 2023, the company named Wentworth, former CEO of The Cigna Group’s Evernorth division, its new CEO.
“Strategically, this would be an interesting move for Walgreens as under the prior management team Shields had been viewed as one of the drivers of growth in the Healthcare business, and also a helpful offset to Walgreens’ 340B exposure,” wrote Evercore ISI research analysts in a Jan. 23 note. “But, with the new regime, we are not surprised to see assets (e.g. a potential Boots sale) come up as part of Tim Wentworth’s broader portfolio review.”
Still, some analysts expressed a bit of skepticism over the speculation.
“While WBA's new CEO has been clear all options are on the table, we're not sure of the strategic logic of a Shields sale, given the increasing importance of specialty and the need then to recast expectations of US HC [health care] breakeven,” said research analysts from TD Cowen, a division of TD Securities, in a Jan. 23 note. “We think other options like a potential sale of Boots would make more sense than a sale of Shields.”
According to the TD Cowen note, Walgreens is “well-positioned to participate in the broader specialty market through Shields’ unique hospital-owned specialty pharmacy model, in addition to its existing significant specialty business.” Combined with Shields, Walgreens’ “specialty pharmacy assets represent $34B in gross sales,” wrote the analysts. That said, “Shields is likely the more sellable asset currently. At the end of the day, however, we would find selling Shields a strange move and would look to better understand the rationale if the decision to sell is ultimately made.”
Analysts at BofA Securities expressed similar sentiments: “We would be somewhat surprised to see Shields sold given it represents a significant growth driver for the US Healthcare business though it is unclear how many synergies this hospital focused specialty pharmacy has with Walgreens’ core specialty pharmacy business. A potential sale of the Shields business would provide incremental cash to Walgreens which could be used to manage the debt and the dividend.”
Specialty pharmacy accelerators such as Shields make their income first by consulting to start up operations and then charging a management fee for the day-to-day operations of that service, observes longtime industry expert Bill Sullivan in a Jan. 26 Anton Rx Report. This, however, can be a problem because while “the income may be good for a time,” it may not provide the return on investment (ROI) to justify Walgreens’ hanging onto Shields.
In addition, “Once you build the man a boat and then [teach him] how to fish, the fisherman no longer needs to pay someone else for doing what he/she can now do themselves,” he continues.
Shields, Sullivan tells AIS Health, “has a limited customer base, so any competitors will make it even harder for them to bring in profits to ‘mother’ Walgreens. Also, many key management pharmacists — or even consultants — now in specialty pharmacy would love to jump ship and work for a big hospital system and build their own specialty pharmacy, non-competes aside.”
Jeff DelVerne, senior vice president of market access with digital health company CCS, tells AIS Health that Walgreens may be motivated to expand the provider-focused health care business that currently consists of VillageMD and Summit Health. “Although Shields is growing 27%, it is a small business in terms of top-line revenue at an estimated $525 million ($133 million in the last quarter) in a business unit that is about $7 billion to $8 billion in annual revenue.”
CEO Wentworth, he says, may be looking to “clean up the balance sheet to get back to investment grade.” In addition, Walgreens may be undergoing a “change in strategy”: While Shields “works inside the hospital, most of their [Walgreens’] recent acquisitions are focused on moving care out of the hospital and into urgent care or the home.”
The income that Walgreens would make from selling Shields “would far and away be greater than yearly earnings could ever match,” contends Sullivan. “Walgreens also seems to need cash to shore up some of its other subsidiaries, especially when lending rates are not attractive.” The sale of Shields would give Walgreens “lots of free cash to invest in other higher ROI subsidiaries that are clearly aligned with their health services strategy,” he says. The company may “return to its roots and shore up its own specialty pharmacy, which has been overshadowed by the hospital-focused strategy Walgreens had embraced.”
“Specialty pharmacy is a very hot space for the largest insurance companies that own a PBM,” declares DelVerne, pointing to Elevance Health, Inc.’s deals for Paragon Healthcare, Inc. and BioPlus. “They might find this asset very attractive as a way to control inpatient spend on some of the infused J code drugs” such as chemotherapy, immune globulins, antivirals, growth factors and monoclonal antibodies.
“Cigna/Express Scripts could be a potential buyer along with a competitor in the space,” he says. “I think you will see some interest from a couple of the larger health plans that own a PBM trying to build out their services divisions, a specialty pharmacy with a large footprint, private-equity firm or one of the competitors.”
“It is hard to believe that anyone would pay $4 billion,” says Sullivan, “but there are lots of people with big money and are willing to put it at high risk.” Could those include “a dumb hedge fund? A PBM with way too much cash on hand [that] is willing to roll the dice on a hospital partnership strategy — which is what WAGS was trying — because their health plan partnerships are dying on the vine?”
Down the road, if Walgreens’ “health services investments take off, as they clearly hope,” the company “will look more like an ambulatory health services one-stop-shop and…also pharmacy services and toothpaste.”
Asked about the company’s identity five to 10 years from now, DelVerne replies, “this is a difficult question, as the new CEO may shift away from growing the U.S. health care business into selling some assets to help build the business back to the core of pharmacy.”
Over the past year and a half, the pharmacy channel has been under pressure “as many of the high-margin generic drugs are being removed from the medication basket they dispense to be moved into Amazon, Mark Cuban Cost Plus and the PBM mail order channel,” he says. High-margin generic drugs — those with gross margins of 35% to 40% — “would offset the low margin (3% to 5%) branded medications, and many retail pharmacies like Walgreens and Rite Aid are having financial trouble.”
Contact DelVerne at jeffdelverne@gmail.com and Sullivan at bsullivan0011@gmail.com.
]]>In late November, the FDA revealed that it was investigating the risks of CAR-T therapies following reports of T cell malignancies in people who had undergone treatment with the agents. Less than two months later, the agency issued safety labeling change notification letters to the six available B cell maturation antigen (BCMA)-directed or CD-19 directed autologous CAR-Ts, which cover a range of hematologic cancers:
]]>In late November, the FDA revealed that it was investigating the risks of CAR-T therapies following reports of T cell malignancies in people who had undergone treatment with the agents. Less than two months later, the agency issued safety labeling change notification letters to the six available B cell maturation antigen (BCMA)-directed or CD-19 directed autologous CAR-Ts, which cover a range of hematologic cancers:
The FDA initially sent the letters on Jan. 19, and the updated language was essentially the same for all of them: “T cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including [product name].”
However, on Jan. 23, the agency issued an updated letter to Kite for Tecartus, requiring a warning that “T cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies” without mentioning Tecartus specifically.
A spokesperson for the FDA’s Center for Biologics Evaluation and Research (CBER) told the Pink Sheet that officials held teleconferences with each sponsor to discuss the labeling changes, but they did not disclose any details on the conversations. The initial Tecartus letter “was removed from FDA’s website to incorporate updates consistent with the required class labeling changes,” said CBER.
AIS Health and the Pink Sheet are part of the same parent company, Norstella.
“This revised letter may seem to indicate that even though the FDA views secondary T-cell cancers as a class effect, Tecartus itself has not seen such cases reported,” observes Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth.
In a Jan. 24 article in the New England Journal of Medicine, Nicole Verdun, M.D., director of the FDA’s CBER Office of Therapeutic Products, and Peter Marks, M.D., Ph.D., director of CBER, explained that as of the end of 2023, the FDA was aware of 22 cases of T cell cancers that happened after treatment with CAR-T therapies. Of those, among the 14 with adequate data, secondary cancers have occurred within two years of CAR-T treatment, and cases have been reported for five of the six available agents — presumably not for Tecartus.
Verdun and Marks noted that the CAR-T agents have “well-described safety concerns” such as cytokine release syndrome that already are included in the products’ labels.
Kymriah was the first CAR-T therapy to receive FDA approval, which was granted Aug. 30, 2017.
“In three cases for which genetic sequencing has been performed to date, the CAR transgene has been detected in the malignant clone, which indicates that the CAR-T product was most likely involved in the development of the T-cell cancer,” wrote Verdun and Marks. “With more than 27,000 doses of the six approved products having been administered in the United States, the overall rate of T-cell cancers among people receiving CAR-T therapies appears to be quite low, even if all reported cases are assumed to be related to treatment. But relying on postmarketing reporting may lead to underestimates of such cases.”
The FDA is trying to gather as much information as possible but has inadequate samples for many of the lymphomas. They request that providers caring for people who have received CAR-T cells report any new cancers to the therapies’ manufacturers and the FDA.
“The FDA has stated that the overall benefits of the CAR-T therapies continue to outweigh their potential risks,” says Szczotka. “The initial approvals of each of these products included postmarketing requirements to conduct 15-year long-term follow-up observational studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment. Patients should be monitored life-long for new malignancies.”
Research analysts from Cantor Fitzgerald, however, shared a different take on the secondary malignancies. “We theorize that these ‘T cell lymphomas’ seen after CAR-T therapy were misdiagnosed and were actually part of the original malignancy!” they wrote in a Jan. 3 research note. “While unique surface markers of B cells, plasma cells and T cells are very helpful in identifying specific cell types, they are not always reliable in the setting of malignancies, where B cells and plasma cells can start to look like T cells.”
In addition, they said, T cell receptor (TCR) and B cell receptor (BCR) sequencing are not always reliable “due to the potential expression of TCR by B cells and myeloma cells in the context of malignancy (an important and surprising finding). Therefore, we suspect many T-cell lymphoma cases found in the context of CAR-T therapy are misdiagnosed — relying on inaccurate markers and TCR sequencing.”
Also lending credence to their hypothesis, they asserted, is the low incidence rate of T cell lymphoma cases.
All of the current therapies are autologous, meaning that they are manufactured from a patient’s own immune cells, but allogeneic — or off-the-shelf — CAR-T therapies are in development. Both kinds of CAR-T agents are under investigation for the treatment of not only cancerous indications but also noncancerous conditions such as autoimmune diseases like lupus. Indeed, data reported at the recent American Society of Hematology annual meeting showed promising results in those conditions.
However, the Cantor Fitzgerald analysts claimed that if their hypothesis is correct, “it would generally exonerate the autoimmune CAR-T programs, as these patients do not have any malignant clones to begin with! Therefore, we believe that ‘T-cell lymphoma’ is not a potential risk for the autoimmune CAR-T programs.”
In light of the safety warnings, could the use of CAR-Ts be negatively impacted?
“The FDA has not stated that every one of the reported cases [of secondary malignancies] has been shown that CAR-T therapy led to the malignancies, but rather that this is a safety signal,” points out Szczotka. “The FDA has stated that the benefits of CAR-T therapies continue to outweigh the risks, and this will likely continue to guide therapy choices.”
He tells AIS Health, a division of MMIT, that people who require CAR-Ts “often have a high chance of mortality from their current cancer type, and CAR-T therapies offer hope of a potential greater response rate and response durability after failure of initial therapies. From the currently available data, the risk of developing treatment-induced T-cell lymphoma appears to be extremely low. The proposed label changes will help support clinician discussion with patients on the risks associated with therapy and enhance the clinical decision-making process, but it would be anticipated that current utilization of these therapies for appropriate patients will continue.”
The fact that the FDA is allowing the CAR-Ts to remain on the market supports their favorable benefit/risk profile and use as treatment options, asserts Szczotka. That said, as the agents move into earlier lines of therapy, the perceived risk of secondary malignancies could impact that profile.
According to Szczotka, “the FDA will likely have a higher level of scrutiny and add additional time for the approval process for more detailed reviews. Both Legend Biotech and Bristol Myers Squibb have disclosed that the FDA will convene the Oncologic Drugs Advisory Committee to review their respective applications for earlier line treatments of their CAR-T therapies (i.e., Carvykti use in a second-line multiple myeloma setting and Abecma for earlier lines of triple-class exposed relapsed or refractory multiple myeloma).
“The impact of this revised safety warning is that this will likely push CAR-T manufacturers to develop more safe versions and conduct further and more detailed safety reviews of clinical studies and monitoring for future applications and indications,” he states.
For now, though, with CAR-Ts’ current indications in later line settings, “health plans and payers will continue to ensure that the appropriate patients will continue to have access to these treatments as later lines of therapies,” maintains Szczotka. “Product positioning by payers will likely not significantly impact current product positioning. Payers will continue to monitor the available clinical information and FDA guidance to ensure that the products remain safe and clinically effective, and the proper patient monitoring is being conducted.”
Contact Szczotka via Caroline Chambers at cchambers@cpronline.com.
]]>“AI-enabled solutions have transformed the specialty pharmacy and home infusion industries,” contends Mesfin Tegenu, CEO and chairman of RxParadigm, Inc. He notes that AI’s subset of machine learning (ML) uses algorithms to find patterns and make predictions, leading to streamlined operations, better patient care and optimized resource allocations, all of which have the potential to result in cost savings.
]]>“AI-enabled solutions have transformed the specialty pharmacy and home infusion industries,” contends Mesfin Tegenu, CEO and chairman of RxParadigm, Inc. He notes that AI’s subset of machine learning (ML) uses algorithms to find patterns and make predictions, leading to streamlined operations, better patient care and optimized resource allocations, all of which have the potential to result in cost savings.
“There is no doubt that AI can be used to increase operational efficiency,” agrees Winston Wong, Pharm.D., president of W-Squared Group. “However, the logic of AI is only as good as its programmers teaching the system. We still need the human intervention, if only to ensure that AI is used ethically and responsibly.”
“In specialty pharmacy, automation through AI facilitates tasks like prior authorization, benefit contract reviews and claim submissions,” Tegenu points out. “AI can also analyze data to help identify fraud and abuse.”
PBMs also are using AI to review contracts and their amendments to “reduce review time, identify key elements within the contract language and index them appropriately, and organize contracts for mining,” notes Haita Makanji, Pharm.D., vice president of clinical strategy and innovation for Prime/Magellan Rx.
But AI’s use in the administration of authorization programs also may pose challenges, says Wong, who points to the class action lawsuit that UnitedHealth Group is facing alleging that an algorithm is incorrectly denying seniors coverage for care under Medicare Advantage plans. Groups also have made similar charges against The Cigna Group.
Makanji echoes that point. “The adoption of AI in health care has been met with mixed feedback. While AI-enabled solutions might be helpful in decision making around diagnosis and treatment or in patient logistics, there has already been negative publicity and legal action related to the use of AI in utilization management.”
“In the home infusion industry, technology automates manual processes, saving time and resources,” Tegenu tells AIS Health, a division of MMIT. “AI-powered tools can also enable remote monitoring of patients’ vital signs, medication adherence and adverse effects, which can allow for timely interventions if an issue arises. AI algorithms can also analyze vast amounts of data to create personalized treatment plans, which can lead to improved patient outcomes. AI is evolving rapidly and has great potential to improve patient outcomes and reduce health care costs.”
According to Makanji, ML “can maximize infusion center capacity, and this may translate to the home infusion site of service as well.”
For the Managed Care Biologics & Injectables Index: Q3 2023, from Aug. 13, 2023, to Sept. 29, 2023, Zitter Insights polled 35 commercial payers covering 117.7 million lives, 103 physicians and 83 practice managers about their familiarity with Open AI’s ChatGPT and AI tools in general.
Among the respondents, 33 payers with 115.9 million commercial lives, 77 physicians and 59 practice managers said that they are familiar with ChatGPT/AI. Those respondents ranked data retrieval and prior authorization as the top potentially useful areas for them, while data privacy and data breaches were flagged as the areas of most concern (see chart).
Zitter Insights also is a division of MMIT.
Among the three stakeholder groups, payers reported having the most familiarity with ChatGPT, with physicians having the least amount. And while almost two-thirds of commercial payers said they are having preliminary discussions about implementing ChatGPT or similar AI tools, less than one-quarter said they are actively researching and implementing them.
AI-enabled solutions can assess large amounts of patients and help providers identify potential issues with patient care, notes Andy Szczotka, Pharm.D, chief pharmacy officer at AscellaHealth. “The key is that AI products provide another tool for the specialty and home infusion care team to provide enhanced patient care and a better health care experience for the patient and physician. Potential time savings for the care team can be directed towards the patient and helping ensure a positive health outcome. AI is not a replacement for a clinician but rather an additional decision aid and tool to enhance the patient care experience and positively impact the desired results.”
Szczotka also agrees that medication management is a key area for AI.
“These clinician-driven algorithms can support specialty and home infusion pharmacists assist with the right drug and dosage, [and] avoid drug interactions and potential adverse events proactively,” he explains. “By assisting with the pharmacy workflow and patient compliance, this can assist with lowering administrative burden and frees the clinical care team on direct patient care activities and monitoring.”
Pharma companies, however, may be further along in their use of and comfortability with AI.
For many reasons, AI “is a game changer in pharma,” asserts Dinesh Kabaleeswaran, senior vice president of consulting and advisory services for MMIT. “In a recent survey conducted by MMIT, more than two-thirds of commercial market access personas have indicated that their organizations are leveraging AI for several use cases. From a commercial standpoint, [AstraZeneca’s] initiative to identify diseases risks through unstructured patient notes by employing AI and NLP [natural language processing] could pave the way for greater innovation and better survival rate outcomes. One of the more common developments that we continue to hear more about is integrating AI with patient communication and disease management strategies.”
Indeed, multiple respondents to the Zitter Insights survey cited disease and drug management as areas in which they are actively researching and/or implementing AI.
Even before the commercialization phase, AI is having an impact in earlier stages of pharma development. Over the past year, “we observed significant traction in the role of AI in advancing drug discovery and development,” says Namrita Negi, head of the Life Sciences Knowledge Center at Deloitte Consulting LLP. “Big Tech companies made significant inroads in this space through investing, collaborating and introducing services for generative AI-based drug discovery, advancing their AI-driven molecular modeling capabilities, hence promising breakthroughs in understanding disease pathways, drug design and genomics.”
Negi adds that “another key milestone for the industry in 2023 was when the first drug discovered and designed with generative AI entered Phase II trials”: Insilico Medicine’s INS018_055, which is being assessed in idiopathic pulmonary fibrosis.
AI has been a potent tool in “drug discovery, development, manufacturing, personalization of drug therapy and drug safety through implementation of AI tools throughout the discovery process and supplemented applications of AI in nanotechnology-based products,” points out Makanji.
Elaborates Rumiana Tenchov, Ph.D., D.Sc., an information scientist at CAS, a division of the American Chemical Society, “AI can predict structure-function relationships for small-molecule drugs, identify targets and screen candidates by conducting molecular dynamics simulations. Similarly, it can predict protein structure and function to identify new therapeutic candidates.”
This expertise, she says, can mean “more therapies at lower costs. Pharmaceutical and biotechnology companies make large investments in developing AI capabilities, and companies like Alphabet and Nvidia have expanded into drug research. Traditional drug discovery is a notoriously time-consuming and expensive process, but AI tools are revolutionizing virtually every step of the drug discovery process, offering substantial potential to reshape the pace and finances of the industry.”
When it comes to identifying potential targets, AI can be trained to use large datasets in order to “understand the biological mechanisms of diseases and to identify novel proteins and/or genes that can be targeted to counteract those diseases,” Tenchov tells AIS Health. “Combined with systems like AlphaFold, AI can proceed further by predicting the 3D structures of targets and speed up the design of appropriate drugs that bind to them.”
Researchers can also forgo traditional chemistry methods — and their costs — to physically test candidate drug compounds by instead using “high-fidelity molecular simulations that can be run entirely in silico,” she notes. In addition, certain systems can forecast important properties “such as toxicity, bioactivity and the physicochemical characteristics of molecules,” bypassing simulated testing of candidates.
“While traditional drug discovery has historically involved the screening of large libraries of candidate molecules, AI is shifting this paradigm,” declares Tenchov. “Some systems are capable of generating promising and novel drug molecules entirely afresh.”
Once a drug is available, companies have used algorithms that drive search engine optimization (SEO) “to influence website and ad rankings to generate additional market and mindshare with providers and patients that influence market position of specialty products,” explains Makanji.
And while she notes that AI-powered voice assistants and chatbots can “answer common member questions at scale” for payers, some areas have seen mixed results, according to two recent articles in JAMA Oncology.
The first assessed large language model (LLM) chatbots’ use in providing treatment recommendations for breast, prostate and lung cancer adhering to National Comprehensive Cancer Network (NCCN) guidelines. Researchers found that all of the outputs that had a recommendation had at least one NCCN-adherent treatment, but more than one-third of the outputs also recommended at least one treatment that did not adhere to NCCN guidelines.
Study authors concluded that “clinicians should advise patients that LLM chatbots are not a reliable source of treatment information. Language learning models can pass the US Medical Licensing Examination, encode clinical knowledge, and provide diagnoses better than laypeople. However, the chatbot did not perform well at providing accurate cancer treatment recommendations.”
For the second study, researchers examined the information provided by four AI chatbots about the top five search queries for skin, lung, breast, colorectal and prostate cancers. While researchers assessed the responses’ quality as good and did not detect misinformation, they found that understandability of the responses was moderate, and actionability was poor.
Researchers concluded that the chatbots “generally produce accurate information for the top cancer-related search queries, but the responses are not readily actionable and are written at a college reading level. These limitations suggest that AI chatbots should be used supplementarily and not as a primary source for medical information.”
For more information on the Zitter Insights data, contact Jill Brown Kettler at jkettler@mmitnetwork.com. Contact Kabaleeswaran at dkabaleeswaran@mmitnetwork.com, Makanji via Jenine Anderson at jenine.anderson@primetherapeutics.com, Negi via Julie Landmesser at jlandmesser@deloitte.com, Szczotka via Caroline Chambers at cchambers@cpronline.com, Tegenu at Mesfin.Tegenu@rxparadigm.com, Tenchov via Zornitsa Ivanova at ZIvanova@cas.org and Wong at w2sqgroup@gmail.com.
]]>Jan. 12: The FDA expanded the approval of Takeda Pharmaceuticals U.S.A., Inc.’s Hyqvia (immune globulin infusion 10% [human] with recombinant human hyaluronidase) to include the maintenance treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) to prevent the relapse of neuromuscular disability and impairment in adults. The agency first approved the agent on Sept. 12, 2014. Dosing via subcutaneous infusion when switching from immune globulin intravenous treatment is done when a person is on stable doses of IVIG. The starting dose is the same as the IVIG treatment, and the typical dosing frequency range is two to four weeks. The price of a 26.25 mL vial is more than $638.
Jan. 16: The FDA broadened the label of Vertex Pharmaceuticals Inc. and CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel; exa-cel) to include the treatment of people at least 12 years old with transfusion-dependent beta thalassemia (TDT). The agency initially approved the CRISPR/Cas9 genome-edited cell therapy on Dec. 8, 2023. The newest application had fast track and regenerative medicine advanced therapy designations. The therapy’s wholesale acquisition cost is $2.2 million for a one-time treatment. Vertex has nine authorized treatment centers in the U.S. that can provide Casgevy to people with TDT and sickle cell disease; the company says it expects to have additional ATCs activated in “the coming weeks.”
Jan. 19: The FDA converted the accelerated approval to full of Johnson & Johnson Innovative Medicine’s Balversa (erdafitinib) for the treatment of adults with locally advanced or metastatic urothelial carcinoma with susceptible fibroblast growth factor receptor 3 (FGFR3) genetic alterations whose disease has progressed on or after at least one line of systemic therapy. The kinase inhibitor is not recommended for people who are eligible for and have not received prior treatment with a PD-1 or programmed death-ligand 1 (PD-L1) inhibitor. The agency first approved the therapy on April 12, 2019. The newest application had priority review, and the review used the Assessment Aid. Recommended initial dosing of the tablet is 8 mg once daily, which can be increased to 9 mg daily. Drugs.com lists the price of 28 4 mg tablets as more than $13,235.
Jan. 25: The FDA broadened the patient population for Sanofi and Regeneron Pharmaceuticals, Inc.’s Dupixent (dupilumab) to include the treatment of eosinophilic esophagitis in children between 1 and 11 years old who weigh at least 15 kg. The agency first approved the interleukin-4 receptor alpha antagonist on March 28, 2017. The newest use had priority review. Dosing for people at least 1 year old weighing at least 15 kg and less than 30 kg is 200 mg every other week; for people weighing at least 30 kg and less than 40 kg, dosing is 300 mg every other week; for people at least 40 kg, dosing is 300 kg every week. The drug’s wholesale acquisition cost per carton, which consists of two 300 mg or 200 mg injections, is more than $3,803.
]]>Sandoz signed an agreement to acquire Cimerli (ranibizumab-eqrn) from Coherus BioSciences, Inc. for $170 million, the purchaser said Jan. 22. Sandoz said the deal is expected to close in the first half of this year. The vascular endothelial growth factor (VEGF) inhibitor is a biosimilar of and interchangeable with Lucentis (ranibizumab) from Genentech USA, Inc., a member of the Roche Group, for all of its indications: the treatment of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy and myopic choroidal neovascularization. The deal includes the biologics license application, product inventory, ophthalmology sales and field reimbursement talent and access to proprietary commercial software.
Celltrion USA launched an 80 mg/0.8 mL dosage strength of Yuflyma (adalimumab-aaty), the company said Jan. 17. The FDA first approved the high-concentration, citrate-free biosimilar of AbbVie Inc.’s Humira (adalimumab) on May 23, 2023, in a 40 mg formulation, and it approved 80 mg and 20 mg doses of the tumor necrosis factor (TNF) inhibitor on Sept. 29. Celltrion said that it expects the 20 mg dose to be available in pharmacies in late first-quarter 2024. The 80 mg and 40 mg formulations are available in single-dose prefilled auto-injectors and prefilled syringes with a safety guard, while all three strengths are available in single-dose prefilled syringes. The drugmaker said that the 80 mg dose is priced the same as the 40 mg one, which launched in early July at a wholesale acquisition cost of $6,576, which is 5% off Humira’s WAC.
Biogen Inc. is “reprioritizing resources” for Alzheimer's disease and will discontinue the development and commercialization of Aduhelm (aducanumab-avwa), the company said Jan. 31. The company had licensed the agent from Neurimmune, and Biogen terminated that license, which will revert to Neurimmune. Biogen received accelerated approval for the amyloid beta treatment on June 7, 2021. The firm also said that it is terminating Aduhelm’s Phase IV postmarketing ENVISION confirmatory trial and it will “redeploy” “a large portion of the resources” freed up from the Aduhelm program into its Alzheimer's franchise, which includes Leqembi (lecanemab-irmb), with which it is partnered with Eisai Inc. Biogen revealed that it recorded a one-time charge of about $60 million in fourth-quarter 2023 for the Aduhelm program’s close-out costs. The drugmaker told the Pink Sheet that the biologics license application for the drug will be withdrawn effective Nov. 1. AIS Health and Pink Sheet are part of the same parent company, Norstella.
Adstiladrin (nadofaragene firadenovec-vncg) is now fully available in the United States, manufacturer Ferring Pharmaceuticals said Jan. 16. The FDA approved the first gene therapy for bladder cancer on Dec. 16, 2022, and in September 2023, the company started the temporary Adstiladrin Early Experience Program in some clinical trial sites that had participated in the agent’s Phase III study and community clinics with the highest number of appropriate patients with non-muscle invasive bladder cancer. With full product availability ahead of schedule, the drugmaker has shut down the early experience program.
]]>While pharma manufacturers began offering the programs to help patients stay on costly therapies, payers have pushed back, saying they lead to higher-cost agents to be used over lower-cost ones. At the same time, similar programs, such as copay maximizers and alternate funding programs, have increased in use, to payers’ dismay.
]]>While pharma manufacturers began offering the programs to help patients stay on costly therapies, payers have pushed back, saying they lead to higher-cost agents to be used over lower-cost ones. At the same time, similar programs, such as copay maximizers and alternate funding programs, have increased in use.
The lawsuit in question concerns the 2020 Notice of Benefit and Payment Parameters (NBPP), in which CMS stated that plans could exclude manufacturer assistance from counting toward patients’ out-of-pocket limit for only “specific prescription brand drugs that have an available and medically appropriate generic equivalent.” That excluded many costly specialty drugs that did not have a generic.
But in the 2021 NBPP, which was finalized in 2020, CMS said plans were not required to apply manufacturer assistance toward beneficiaries’ annual cost sharing, leaving members on the hook for numerous specialty medications once assistance ran out.
That prompted the HIV+Hepatitis Policy Institute, the Diabetes Patient Advocacy Coalition, the Diabetes Leadership Council and three people dependent on copay assistance whose health plans had accumulators in place to file a lawsuit (Case 1:22-cv-02604) in August 2022 against HHS, CMS and their respective leaders challenging the 2021 NBPP. The lawsuit claimed that allowing the use of accumulators is at odds with how the Affordable Care Act (ACA) — as well as the agencies’ preexisting regulatory definition — defines “cost sharing,” charging that the 2021 NBPP is “arbitrary and capricious.”
U.S. District Judge John D. Bates of the U.S. District Court for the District of Columbia ruled in favor of the plaintiffs on Sept. 29, 2023, ordering that the 2021 NBPP “must be set aside based on its contradictory reading of the same statutory and regulatory language and the fact that the agencies have yet to offer a definitive interpretation of this language that would support the rule.”
In response, on Nov. 27, HHS filed a conditional motion to clarify the scope of the court’s order. “Defendants do not understand this Court’s order to require HHS to take enforcement action,” it said. “The Court vacated the relevant portion of the 2021 NBPP but did not order any additional relief.…To ensure that they are not inadvertently running afoul of the Court’s Order, however, Defendants respectfully request clarification from the Court if their understanding of the scope of the Court’s Order is incorrect.”
In the motion, HHS revealed that the agency “intends to address, through rulemaking, the issues left open by the Court’s opinion, including whether financial assistance provided to patients by drug manufacturers qualifies as ‘cost sharing’ under the Affordable Care Act.”
HHS also said that until it issues a final rule, it has no intentions of taking “any enforcement action against issuers or plans based on their treatment of such manufacturer assistance.”
The following day, HHS filed a notice of appeal. A CMS spokesperson clarified to AIS Health, a division of MMIT, that its filing was actually a “protective notice of appeal, which preserves its right to appeal. The decision whether to appeal will be made at a later date.”
On Dec. 11, the plaintiffs responded, filing a notice of appeal, as well as a brief outlining why the court should deny HHS’s motion for clarification.
On Dec. 22, Bates responded to HHS’s motion for clarification, noting that the motion “is not a formal creature of civil procedure.…Such motions ‘have a limited role,’ and are not a proper vehicle for ‘seek[ing] to alter or modify the result’ of the prior ruling.”
“The effect of vacatur is to ‘reinstate the rules previously in force,’” he wrote. “The prior (and thus reinstated) rule is the ‘2020 NBPP.’” Bates explained that his “prior decision vacated the 2021 NBPP” but did not interpret the 2020 NBPP or rule on whether nonenforcement was legal, as “these issues were not before the Court.”
“This is a victory for patients,” says Carl Schmid, executive director of the HIV+Hepatitis Policy Institute. “It really clarifies what we’ve been saying all along.” The judge, he tells AIS Health, ruled that the 2020 NBPP “regarding copay assistance is now in effect. And he didn’t say what that is. But…you can read the rule, and you can read the preamble, [and] it says that copay assistance must count for brand name drugs without a generic equivalent. And so that is in effect, and that is what we’ve been saying, and that’s what insurers need to follow right now.”
“We’re hoping now with this clarification that HHS will enforce the law. That’s their job, that’s their responsibility, and that’s our request now,” he says. HHS “should issue guidance” explaining that the 2020 NBPP is in effect, states Schmid. “Now if they don’t, I think it’s pretty hard for them not to do, to say, anything at this point. I think they have to say something because everyone’s looking toward them.”
A CMS spokesperson tells AIS Health that “CMS generally does not comment on matters in litigation.”
Asked about reaching out to patient advocacy groups, Schmid replies that “I think we need to regroup because people are asking, ‘Well, are there copay accumulators in effect right now, and what should we do?’ And so I think we’re just starting…that process.”
He clarifies that the plaintiffs’ appeal also was a protective one and that “we didn’t win on everything. And so we have a right to appeal as well. And that’s what we are thinking about.” That said, “I’m not saying that’s what we’re going to do.”
Even if the government follows through with its appeal, the 2020 NBPP is in effect, he notes. “No stay [was] requested.”
However, says Schmid, if the government were to issue a new rule like it has said it intends to do, and that rule says that “manufacturer copay assistance is not included in the definition of cost sharing,…that would be catastrophic for patients.”
He points to IQVIA data showing that in 2022, copay assistance totaled almost $19 billion. “The American people would have to come up with that money. And manufacturers may not offer copay assistance if that happens.”
“And why would the Biden administration do something that would increase the costs for patients, for prescription drugs? Why would they do something to allow the insurers to collect more money?” he asks. “The judge was very clear in the decision that copay accumulators increase patient costs, increase revenues to insurers and increase drug manufacturer costs as well. So I can’t imagine that the Biden administration would do that.…They don’t need a new rule,…but that’s what they said they would do. And I hope they’re going to reevaluate that.”
In the absence of administration enforcement of the 2020 NBPP, Schmid says that state insurance commissioners “can take action, and they should.” In addition, “under ERISA [i.e., the Employee Retirement Income Security Act], there is a private right of action” that allows individuals who are under copay accumulators to take legal action with their employers and insurers.
AIS Health reached out to the National Association of Insurance Commissioners for reaction to the most recent ruling, as well as whether the NAIC is taking any kind of action in response and what potential enforcement action may look like. Although the NAIC does not comment on litigation, a spokesperson tells AIS Health that the association is seeking additional guidance from CMS and declines to share a statement at this time.
But even though state insurance boards and/or other entities can take some kind of enforcement action, “will they, and, if they do, will the penalty amount to a slap on the wrist?” asks Madelaine A. Feldman, M.D., a clinical assistant professor of medicine at Tulane University School of Medicine and provider with The Rheumatology Group in New Orleans. “I have been disappointed with the lack of teeth in many states’ penalties if insurance companies break the law. ERISA plans are also affected by this, so I would hope that the plan beneficiaries (employees) would be able to file legal action if this is not enforced.”
Only two days before the Dec. 22 ruling, a bipartisan group of senators led by Sens. Tim Kaine (D-Va.) and Roger Marshall, M.D., (R-Kan.) sent a letter to the heads of HHS and the departments of Labor and the Treasury in support of the decision vacating the 2021 NBPP:
“This decision is an important step in the right direction for low-income and other eligible patients who rely on manufacturer and nonprofit copay assistance programs to alleviate affordability and access challenges for their medicines,” they wrote. “We are disappointed in HHS’s decision to file a notice of appeal of the decision and HHS’s articulated intention to not take any enforcement action against health insurance issuers or health plans that fail to count copay assistance toward the patient’s maximum annual limitation on cost-sharing. Instead of appealing the court’s ruling, we urge you to adopt policies from the 2020 NBPP that strike the right balance of preserving a plan’s ability to control costs while also putting the patient first.”
The administration’s stance on allowing accumulators would seem to be at odds with HHS’s 2025 NBPP (88 Fed. Reg. 82510, Nov. 24), which seeks to do away with the ACA's non-essential health benefit (NEHB) loophole that allows copay maximizers to exclude covering certain drugs so beneficiaries could be considered uninsured for those drugs and qualify for manufacturer assistance.
It also would seem to be in conflict with the Office of Personnel Management’s (OPM) March 2023 request for proposal (RFP) for federal employee health plans that noted the agency would not consider “any proposals that manipulate the prescription drug benefit design, or incorporate copay maximizer or optimizer programs, or other similar programs to capture such savings.”
“I am disappointed that HHS is taking a nonenforcement stance, considering that the federal employee health plans are not allowing copay accumulators because they are harmful to beneficiaries,” says Feldman, who is also immediate past president and current vice president of advocacy and government affairs of the Coalition of State Rheumatology Organizations. OPM, she says, “will not consider plans that allow copay accumulator nor maximizer programs. It states that these programs ‘are not in the best interest of the enrollee or the federal government.’ And yet it is just fine for the American people?”
Seth Friedman, pharmacy & health plan services practice leader at Arthur J. Gallagher & Co., tells AIS Health that “as of now,” the company’s clients are not taking a closer look at accumulators and maximizers due to the accumulator lawsuit and attention on maximizers. “Most clients are not even aware of the suit unless brought up by their consultant. We have not seen the PBMs be proactive about communicating this with them, along with the ramifications to their plan design and savings if this was to go through.”
Asked what these moves against accumulators and maximizers mean for plan sponsors and their ability to provide health insurance coverage, Friedman responds, “while I don’t think this impacts their ability to provide health insurance coverage, it will have an impact on their overall savings. If the proposed rule is finalized, plans in scope of the regulation would generally not be able to classify covered drugs as non-EHB. As a result, all covered drugs would be subject to EHB requirements, including the annual limitation on cost sharing and the restriction on annual and lifetime dollar limits.” This, he says, would affect plans’ ability to offer programs like SaveOnSP, which works with The Cigna Group’s Express Scripts, and CVS Caremark’s PrudentRx.
“For plans that utilize these types of programs to offset the costs of specialty pharmaceuticals, it can have a significant impact to their overall health care budgeting and premium setting in the future,” he concludes. “Like squeezing a balloon, these costs will be passed on somewhere else.”
Contact Feldman at nolarheum@gmail.com, Friedman at Seth_Friedman@ajg.com and Schmid at cschmid@hivhep.org.
]]>Haita Makanji, Pharm.D., vice president of clinical strategy and innovation for Prime/Magellan Rx: Notable FDA approvals in 2023 must include gene therapies and some highly anticipated biosimilars. Specifically, Roctavian [(valoctocogene roxaparvovec-rvox) from BioMarin Pharmaceuticals Inc.] was the first gene therapy approved for hemophilia A. Most recently, two separate gene therapies were approved in December for sickle cell disease, Casgevy [(exagamglogene autotemcel; exa-cel) from Vertex Pharmaceuticals Inc. and CRISPR Therapeutics] and Lyfgenia [(lovotibeglogene autotemcel; lovo-cel) from bluebird bio, Inc.]. These approvals are important because the products not only present potential curative treatment options for patients but, depending on the durability of each product’s effect, could at least present a long-term cost benefit by reducing the need for current standard-of-care treatment options, which are also costly.
The approval of Elevidys [(delandistrogene moxeparvovec-rokl) from Sarepta Therapeutics, Inc.] for a rare condition such as Duchenne muscular dystrophy was controversial due to concerns over its benefits vs. risks and $3.2 million price tag. Elevidys was the first gene therapy approved based on a surrogate biomarker, dystrophin protein, which was believed to predict likelihood of clinical benefit.
Leqembi [(lecanemab-irmb) from Eisai Co., Ltd. and Biogen Inc.] for Alzheimer’s disease created controversy due to its modest slowing of the progression of cognitive and functional decline in people with Alzheimer’s disease and amyloid-related imaging abnormalities (ARIA), such as brain swelling and/or bleeding. There are about 6.7 million Americans diagnosed with Alzheimer’s, and this approval had the potential to reach a significant amount of people.
In terms of biosimilars, most of the interest was in biosimilars for Humira [(adalimumab) from AbbVie Inc.]. There have been multiple approvals [and launches] for Humira biosimilars in 2023. In addition, there were biosimilars for other biologics approved, including [Bio-Thera and Biogen’s] Tofidence (tocilizumab-bavi), a biosimilar to Actemra [(tocilizumab) from Genentech USA, Inc., a member of the Roche Group]; [Celltrion USA’s] Zymfentra (infliximab-dyyb) a subcutaneous version of Inflectra, which is a biosimilar to [the Janssen Pharmaceutical Companies of Johnson & Johnson’s] Remicade (infliximab), and has the potential to shift patients from long infusions to self-administered subcutaneous injections; [Polypharma Biologics and Sandoz Inc.’s] Tyruko (natalizumab-sztn), a biosimilar to [Biogen’s] Tysabri (natalizumab); and [Amgen Inc.’s] Wezlana ((ustekinumab-auub), an interchangeable biosimilar to [the Janssen Pharmaceutical Companies of Johnson & Johnson’s] Stelara (ustekinumab). Biologics that treat autoimmune inflammatory conditions are among the most frequently prescribed specialty drugs, so the presence of biosimilars in the market brings the potential for improved affordability and accessibility to critical treatments.
In addition, on Dec. 22, 2023, the FDA approved [Coherus BioSciences, Inc.’s] Udenyca Onbody (pegfilgrastim-cbqv), which is the first biosimilar of the Neulasta Onpro (pegfilgrastim) on-body injector [from Amgen]. Approval may increase the slow biosimilar utilization and adoption seen with long-acting colony stimulating factors.
In April, the FDA approved [Astellas Pharma Inc. and Seagen Inc.’s] Padcev (enfortumab vedotin-ejfv) in combination with [Merck & Co., Inc.’s] Keytruda (pembrolizumab) as first line for the treatment of patients with locally advanced or metastatic bladder cancer not eligible for cisplatin-containing chemotherapy. Almost 50% of patients with metastatic bladder cancer are cisplatin-ineligible. Then in December, the FDA approved the same combination as first line for patients with locally advanced or metastatic urothelial cancer. For the first time, a nonplatinum-based combination therapy received approval as a first-line therapy. Due to the high price of these two agents, the cost of therapy increases significantly, as does the projected budget impact.
The FDA approved three new combination therapies for metastatic castration-resistant prostate cancer.
Six new FDA indication expansions for Keytruda and use earlier in lines of therapy grow pembrolizumab’s market share as one of the most highly utilized drugs in cancer therapy.
Andy Szczotka, Pharm.D, chief pharmacy officer at AscellaHealth: [Last year’s] approvals across the various drug classes represent new therapeutic options for clinicians to use in treatment of the related medical conditions.
Some notable approvals include Leqembi, which is the first of a new class of medications to be converted from an accelerated FDA approval to a traditional approval for the treatment of early-stage Alzheimer’s disease. AD causes cognitive, functional and behavioral impairments and accounts for 60%-80% of all dementia cases. The disease is thought to be caused by the accumulation of amyloid beta plaques in the brain. Leqembi works by removing these plaques. It has been shown to modestly slow the progression of the disease but has not been definitively shown to demonstrate a clinical benefit. Leqembi comes with a warning of the potential for small amounts of bleeding in the brain. The condition is usually asymptomatic, but serious brain hemorrhaging has occurred in patients treated with this class of medications. While Leqembi is not a cure for AD, it does provide hope for patients and their caregivers. The knowledge gained from real-world experience with Leqembi should contribute to the success of future medications that could prevent or reverse the memory problems and dementia associated with the disease.
Roctavian is the first approved single-dose gene therapy for the treatment of severe hemophilia A, a lifelong bleeding disorder. The disease is caused by a single genetic defect that reduces the production of a protein called clotting factor VIII. Patients living with hemophilia A typically require regular prophylactic treatment with clotting factor treatment to prevent bleeding episodes. Prophylactic intravenous infusions can cost over $500,000 annually. Roctavian uses a nonharmful virus to deliver a functional gene to liver cells that will enable the body to produce factor VIII on its own. As a result, patients treated with Roctavian need very little, if any, prophylactic therapy. In fact, in the most recent study at the end of year three, 92% of patients remained off prophylactic therapy. To date, a single dose of Roctavian has been well tolerated with no delayed-onset treatment-related adverse events. Roctavian has the potential to dramatically change the way severe hemophilia A patients are treated and improve their quality of life.
Altuviiio [(antihemophilic factor [recombinant], Fc-VWF-XTEN fusion protein-ehtl) from Sanofi and Sobi] is a new class of factor VIII therapy for hemophilia A. It is the first treatment that delivers near-normal factor activity levels for most of the week, allowing for once-weekly dosing. It also significantly reduces bleeds compared to prior factor VIII prophylaxis. [Its weekly infusions] significantly improve the quality of life for many individuals and their families whose schedules currently revolve around multiple necessary prophylactic infusions each week.
Casgevy and Lyfgenia are the first cell-based gene therapies for the treatment of sickle-cell disease (SCD) in patients 12 years and older. Casgevy also becomes the first FDA-approved therapy that uses CRISPR gene-editing technology. SCD is an inherited blood disorder caused by a defective gene that affects hemoglobin, the protein that helps red blood cells transport oxygen throughout the body. The faulty gene causes some red blood cells to be rigid, sticky and shaped like sickles or crescent moons. This results in restricted blood flow, and the lack of oxygen causes significant acute pain. Current treatments aim to manage symptoms, lower the frequency of acute pain and reduce the risk of complications.
Both treatments are administered as one-time infusions and are made from a patient’s own blood stem cells, which are modified and returned to the patient. In clinical trials, a single dose with either Casgevy or Lyfgenia enabled patients to make healthy hemoglobin-producing blood cells and prevented acute pain events for more than two years. By reducing or eliminating the debilitating pain often associated with the disease, both Casgevy and Lyfgenia have the potential to significantly improve the quality of life and life expectancy of SCD patients. In addition, Casgevy represents an important medical advance using new gene editing techniques that will likely be applicable for other diseases in the future.
Mesfin Tegenu, CEO and chairman of RxParadigm, Inc.: Notable FDA approvals in 2023 include Tyruko, Tofidence and Wezlana, which are biosimilars of Tysabri, Actemra and Stelara, respectively. These biosimilars are the first biosimilars to get approved for their respective reference products. Notably, before Wezlana received FDA approval, Stelara was chosen as one of the 10 drugs slated for price negotiations under the Inflation Reduction Act (IRA). According to new guidance from CMS on the IRA’s drug price negotiation program, CMS can reevaluate a drug's eligibility for price negotiations if a generic or biosimilar competitor gets approved based on the availability and “bona fide marketing” of the drug. This suggests that Stelara could potentially be excluded from the list of drugs subject to price negotiations. It will be interesting to see what the outcome is; CMS’s decision may impact the value of future biosimilars entering the market with high Medicare utilization.
Drew Walk, CEO of Soleo Health: Soleo Health deems the approval of Leqembi in July 2023 as among — if not, the most — important advancement in 2023 due to the role it plays in the ongoing fight against AD. Leqembi marks a major breakthrough in the AD drug class. It holds enormous potential since the addressable market for Leqembi is large, as an estimated 6.7 million Americans aged 65 and older, or about 11% of the population, were living with AD in 2023. The number of those afflicted is growing fast.
Leqembi shows promise as it demonstrates a reduction of amyloid beta plaque, a marker of AD in patients with mild cognitive impairment or mild dementia stage of the disease. This reduction may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to AD, thereby enhancing quality of life.
In early 2023, Soleo Health was selected by Eisai Inc., a developer of pharmaceuticals including Leqembi, as the sole specialty pharmacy distribution partner of this treatment. To this end, Soleo Health offers Leqembi to patients across multiple sites of care including in their homes, at one of the company’s 35+ ambulatory infusion centers or in provider offices.
Winston Wong, Pharm.D., president of W-Squared Group: 2023 will stand as a year of notable FDA approvals representing major advancements in several therapeutic areas, ranging from vaccines to gene therapy. Fifty-five new molecular entities were approved, not including vaccines, allergenic products, blood and blood products, plasma derivatives, and cellular and gene therapy products. On the vaccine front, three vaccines were approved for RSV [respiratory syncytial virus], as well as the full approval for Paxlovid for mild to moderate COVID-19. We also have full approval of the first clinically proven monoclonal antibody to slow the progression of Alzheimer’s disease, a step forward from the previously similar medication receiving accelerated approval in 2021, but [it] still fails to show clinical benefit. We finish the 2023 year in review with several gene therapies, used for the treatment of hemophilia A and sickle cell disease. However, as with all technological advances, come the rather expensive costs, and our challenge still remains on how to keep health care affordable.
Contact Makanji via Jenine Anderson at jenine.anderson@primetherapeutics.com, Szczotka via Caroline Chambers at cchambers@cpronline.com, Tegenu at Mesfin.Tegenu@rxparadigm.com, Walk via Susan Turkell at sturkell@pairelations.com and Wong at w2sqgroup@gmail.com.
]]>Dec. 8 saw the newest approvals, both for the treatment of sickle cell disease in people at least 12 years old: bluebird bio, Inc’s Lyfgenia (lovotibeglogene autotemcel; lovo-cel) and Vertex Pharmaceuticals Inc. and CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel; exa-cel). The latter agent is the first CRISPR/Cas9 genome-edited cell therapy that the FDA has approved. The FDA gave both applications priority review, orphan drug, fast track and regenerative medicine advanced therapy designations. It also gave Lyfgenia rare pediatric disease designation.
]]>Dec. 8 saw the newest approvals, both for the treatment of sickle cell disease in people at least 12 years old: bluebird bio, Inc’s Lyfgenia (lovotibeglogene autotemcel; lovo-cel) and Vertex Pharmaceuticals Inc. and CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel; exa-cel). The latter agent is the first CRISPR/Cas9 genome-edited cell therapy that the FDA has approved. The FDA gave both applications priority review, orphan drug, fast track and regenerative medicine advanced therapy designations. It also gave Lyfgenia rare pediatric disease designation.
The one-time treatments come with hefty price tags: Lyfgenia is priced at $3.1 million and Casgevy at $2.2 million.
Each agent is available through its manufacturer’s national network of treatment centers.
For the Managed Care Biologics & Injectables Index: Q3 2023, from Aug. 13, 2023, to Sept. 21, 2023, Zitter Insights polled 35 commercial payers covering 117.8 million lives and 28 Medicare payers representing 43.6 million lives about their management of gene therapies. Slightly less than half of payers — 49% — said that managing branded products is a very high priority for them. About half of the respondents expressed average satisfaction with current gene therapies.
Both AIS Health and Zitter Insights are divisions of MMIT.
Almost three-quarters of all payers said that their organization allows for coverage of an FDA-approved gene therapy that is not on formulary through a medical exception request. Among the reimbursement models that survey respondents reported using, outcomes-based contracts were most common (see chart).
Payers told Zitter Insights that they take a variety of steps to increase their level of aggression in managing gene therapies. The top approach is mandating submission of genetic testing results for initial authorization, done by 69% of respondents, followed by engaging with manufacturers in alternative methods of contracting, such as outcomes-based contracts, which 60% of respondents reported doing. Other common approaches include requiring patients to step through agents with different mechanisms of action before they can access gene therapies, managing the agents separately from others within a therapeutic area, placing them at higher cost-sharing tiers and requiring genetic testing results for continued access.
“First, we have to view solving high-cost gene therapy as a societal issue as much as it is the payer’s responsibility,” contends Mesfin Tegenu, CEO and chairman of RxParadigm, Inc. “Substantial upfront costs” and questions around the therapies’ long-term durability and effectiveness “can impede payer coverage and strain payer budgets.”
Payers, he says, have turned to risk-pooling strategies, which involve “the collective sharing of gene therapy costs among multiple payers to alleviate the financial burden on individual payers”; “establishing separate budgets for gene therapies”; entering into outcomes-based contracts with pharma manufacturers that link “payment to specified patient outcomes and either sharing or shifting the risk from payer to manufacturer”; and setting up installment payments, which are spread out over several years.
Installment payments, however, says Winston Wong, Pharm.D., president of W-Squared Group, are “highly dependent upon the plan’s ability to track the patient should the patient change to a different payer. The primary focus is finding the appropriate patient to receive the treatment, which, in my mind, will require a greater amount of collaboration between the plan and the provider.” Another approach is demonstrated by payers such as CVS Health Corp.'s Aetna, for example, which has implemented a Centers-of-Excellence-type model where designated providers can administer the agents.
Outcomes-based models and some similar approaches can help address the issue of uncertainty around gene therapies’ long-term efficacy and durability. The lack of long-term data “may give rise to concerns about their long-term value and cost-effectiveness,” observes Tegenu, but innovative reimbursement models may assuage such concerns. “Additionally, payers can assess real-world evidence and long-term follow-up studies to help address uncertainties related to the long-term impacts of gene therapies.”
The two new sickle cell agents “are significant milestones in the treatment of sickle cell disease,” a “rare, debilitating disease with limited treatment options and a significant disease burden,” declares Tegenu. In addition, both therapies “also have the potential to provide a cure”; they “address a significant unmet need and represent a major advancement in both sickle cell disease treatment and gene therapy,” he tells AIS Health.
The therapies “represent technological breakthroughs” in the treatment of the disease, as they are the first cell-based gene therapies for it, asserts Wong. Long-term studies will assess the treatments’ safety and efficacy. While both “work at the gene level, their mechanisms of action differ,” he explains. “Casgevy exerts its clinical action through gene editing, while Lyfgenia exerts its action through vector modification.”
Wong tells AIS Health that “maybe more important than the approval for the treatment of sickle cell disease is that Casgevy is the first approved treatment utilizing CRISPR, an innovative gene editing technology. CRISPR has been in research and development for a while, leading to the 2020 Nobel Prize in Chemistry” for Emmanuelle Charpentier, Ph.D., and Jennifer Doudna, Ph.D.
“It is great to see CRISPR has finally made it to the clinical realm,” he says.
Asked what Casgevy’s approval in particular says about the FDA, he replies, “the FDA realizes the urgent unmet need in the sickle cell disease arena. At the same time, they are embracing the new technology. Given some of the backlash in the past year, the FDA made a statement of thoroughly examining and reviewing the clinical efficacy and safety data to grant the accelerated approval. Hence, the FDA is not being ‘gun shy’ in their embrace of new technology and is being more thorough in the review process.”
Tegenu agrees. “This approval demonstrates the FDA’s recognition of the potential of gene therapies and its commitment to fostering the development and approval of innovative treatments, especially through revolutionary technology like CRISPR.”
Cost is the major roadblock to payer coverage of these agents, both sources maintain. A report published in August by the Institute for Clinical and Economic Review (ICER) determined that “in order to be cost effective, a cost of $1.35 million to $2.05 million for each therapy is needed,” points out Wong. “Thus, the bioethical question for payers is the balance between access to these medications vs. the cost.”
Wong points out that single-arm trials of the agents have demonstrated that they work. But “the question is how to pay for them. While Casgevy in the single-arm trial appears to be well tolerated, Lyfgenia has a black box warning due to a link to hematologic malignancy, which I suspect will push the utilization of these medications towards the relatively lower cost Casgevy.” Lyfgenia’s black box warning recommends complete blood counts every six months to monitor for evidence of malignancy.
“Given that both medications were approved based upon a single arm trial, payers will still be concerned of the long-term safety of these products,” states Wong. “The true long-term effects of these medications are still unknown. Also in question is the durability of the clinical benefit,” as patients were followed 12 to 18 months post administration.
Ultimately, when it comes to payer management of cell and gene therapies overall, payers “must consider various critical factors,” asserts Tegenu, including their budget impact and various reimbursement models. When entering into outcomes-based models, “the outcomes should be clearly defined and easily measurable over time to offer any advantage to payers.”
In addition, the use of “scalable data-tracking methods that can ensure the ability to track patient outcomes and clinical data, while also evaluating the appropriateness, safety and efficacy of therapies…is crucial for efficient management of high-cost therapies. Payers should also account for the implications of patients switching insurance plans, recognizing that the clinical benefits/cost offsets of gene therapy may not directly benefit the plan that funded the treatment.”
And it’s not only the upfront costs that can pose an issue, Tegenu says. It’s essential for payers to take into account costs for follow-up care. “The continued supportive care and monitoring required following gene therapy will likely represent a significant cost to payers.”
For more information on the Zitter Insights data, contact Jill Brown Kettler at jkettler@mmitnetwork.com. Contact Tegenu at Mesfin.Tegenu@rxparadigm.com and Wong at w2sqgroup@gmail.com.
]]>In September, InformedDNA — which provides genomic solutions to an array of health care stakeholders to improve outcomes — acquired gWell Health, a digital health, genomics and wellness company. As part of the deal, gWell founder and CEO Surya Singh, M.D., transitioned to CEO of InformedDNA. Singh has worked in various health care organizations in more than 20 years, including serving as corporate vice president and chief medical officer at CVS Health Specialty.
]]>In September, InformedDNA — which provides genomic solutions to an array of health care stakeholders to improve outcomes — acquired gWell Health, a digital health, genomics and wellness company. As part of the deal, gWell founder and CEO Surya Singh, M.D., transitioned to CEO of InformedDNA. Singh has worked in various health care organizations over more than 20 years, including serving as corporate vice president and chief medical officer at CVS Health Specialty.
He recently spoke with AIS Health, a division of MMIT, about making genomic data more accessible and actionable across the health care industry.
Singh says that three factors are standing in the way of optimizing and accelerating preventive screenings and diagnoses. First, “the guidelines that are set out for prevention are just not updated quickly enough. The interval is too long between reviews of new data, new evidence of new data that’s generated, [and] unlike many other areas, it just takes several years to get those various bodies to review things.”
The second barrier is tied to the way screenings are currently done. “We’ve closed the gap with some of the work of integrating screening into quality metrics because by the very nature of them being quality metrics and being reported, you get some uptick.…Tying payment to them and value-based care models has worked as well” for screenings for certain cancers such as colon and breast, he says. “So we’ve made improvements, but it still leaves something to be desired. There’s a lot of room to move on that front.”
Finally, while a push for novel methods of screening and generating evidence exists, these do not appear in industry guidelines, Singh states. In addition, “we really have not done a great job of being able to use population health programs and targeting through population health programs to find those sectors that will benefit from more novel techniques earlier.”
But payer-sponsored population health programs can help with integrating “newer techniques with very good evidence behind them” in order to identify populations for better screening.
In addition, such programs can be helpful to reach “patients who either have been lost to follow-up after a referral is made for screening or never got referred in the first place, even though they’re plugged into the health care system.…I think the targeting and outreach to that population [that never received a referral] and for a program to be graded essentially to be evaluated on how successful are you at (a) contacting those patients and (b) bringing them in for screening is essential.”
He continues: “Just as a broad bucket of what needs to be done, I think that’s where the lowest hanging fruit is because those are things that are already well accepted, that are in this quality scorecard, to try and push the percentage of people [who] get those screenings up.”
Unfortunately, he notes, a “huge chunk” of people with a family history of cancer — about two-thirds — “don’t go on to get even considered for quote-unquote germline genetic testing,” says Singh. “Then in the roughly third of people at the top end who do get screened, we just don’t do a great job of being able to get the testing done for those patients in a streamlined fashion. So even if the clinician thinks to order it, there’s no guidance for that clinician decision support, so to speak.”
However, “we have made inroads on doing that” and having a “medical process in place for us to do a pretest when the order comes in” that determines what type of testing is most appropriate for that patient — a “kind of pretest genetic counseling,” he explains. He clarifies that this is not an effort to stop tests from being done but rather to get the right test or the right panel done.
Several states have biomarker mandates in place, and those will be important for the uptake of pharmacogenomic testing, he asserts. Also significant is the FDA’s table of pharmacogenomic biomarkers on drug labels, which included almost 600 agents as of August 2023.
The definition of precision health has undergone a transformation, Singh explains, starting with personalized medicine, specifically targeted therapies such as monoclonal antibodies, about 15 or 20 years ago. But now precision health is a broader umbrella term that encompasses “both the diagnostics and then the upstream screenings that really are going to result in this use of those targeted therapies and even cell and gene therapy downstream.”
But this has been an issue for health plans’ and PBMs’ approaches to precision health, he maintains, and the “paradigm for doing health technology assessment just did not lend itself well to looking at diagnostics, frankly, to start off with. The same similar processes have been used for imaging and for other things, but it’s most tried and true for therapeutics.”
There has been “such an overwhelming volume” of “new therapies being approved and needing assessment to try to figure out should this be covered and if so at what level” by plans and PBMs. This means that “we continue to have just limited capacity to be able to adapt the paradigm and manage care,…to do a more rigorous job and adapt it in a way that is the most appropriate for these types of screening and diagnostic approaches that we’re talking about here as part of the precision medicine to health expansion.”
That is changing, though, says Singh, driven in large part by self-insured employers, which tend to keep their members for longer and have been advocates for earlier diagnosis and screening.
However, misunderstandings around precision health persist, he states, with one of the main ones being that the field is focused on only individual therapies when it is much more than that.
In addition, “the companies that have really grown up in the diagnostic space, the molecular diagnostic space, the ones that are most well-known and most mature at this point have done some, but maybe not as much as I would like to see it, aggressively moving into the world of value-based contracting and value-based care.” Diagnostics manufacturers “have still been very transactional focused, if you will, where getting the most utilization of their particular product is priority No. 1, rather than trying to figure out how to make sure it gets used effectively to drive the most value in a very real way.”
So a “thoughtful approach” to improving the implementation of precision health, of diagnostics and screening, is needed, “and that’s workflow, that’s reimbursement, that’s coverage, all of those things,” he stresses.
Proactive screening of people who are at risk of complex and costly diseases should be done, and identifying those people can be accomplished in several ways:
Genetically targeted screenings and treatments may be quite accessible for some populations but not really at all for others, and much of that is due to implementation science, he observes. “There’s not been an organized approach to how do you try to make this an easy and integrated-into-the-workflow option for providers? If providers were presented with an easy and integrated workflow option for essentially offloading this from their plate, they would make these types of assessments. They would access them on behalf of their patients through referrals very frequently, but there’s just not been a great easy way to do that.”
Companies such as InformedDNA, explains Singh, can help create a streamlined way for community providers to incorporate assessments, as well as help interpret the results.
Contact Singh at inquiries@informeddna.com.
]]>Dec. 13: The FDA approved US WorldMeds’ Iwilfin (eflornithine) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy, including anti-disialoganglioside (anti-GD2) immunotherapy. Between 700 and 800 cases of neuroblastoma are diagnosed annually in the U.S., with 90% of those before age 5. About half of those cases in children are HRNB. The agency used the Real-Time Oncology Review pilot program and the Assessment Aid. It also granted the application priority review and breakthrough drug and orphan drug designations. The recommended dosing of the tablet is based on body surface area.
]]>Dec. 13: The FDA approved US WorldMeds’ Iwilfin (eflornithine) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy, including anti-disialoganglioside (anti-GD2) immunotherapy. Between 700 and 800 cases of neuroblastoma are diagnosed annually in the U.S., with 90% of those before age 5. About half of those cases in children are HRNB. The agency used the Real-Time Oncology Review pilot program and the Assessment Aid. It also granted the application priority review and breakthrough drug and orphan drug designations. The recommended dosing of the tablet is based on body surface area.
Dec. 14: The FDA expanded the patient population for LEO Pharma Inc.’s Adbry (tralokinumab-ldrm) to include the treatment of people at least 12 years old with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription drugs or when those products are not advisable. The agency initially approved the interleukin-13 (IL-13) antagonist on Dec. 27, 2021. Dosing for the newest use is an initial 300 mg dose via two 150 mg subcutaneous injections followed by a 150 mg dose every other week. Drugs.com lists the price of one 150 mg/mL single-dose prefilled syringe as more than $1,916.
Dec. 14: The FDA approved Merck & Co., Inc.’s Welireg (belzutifan) for people with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). The agency first approved the treatment on Aug. 13, 2021. It granted the application priority review and used the Assessment Aid. The company says that the agent is the first hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor approved for adults with advanced RCC. Dosing for the tablet is 120 mg once daily. Drugs.com lists the price of 90 40 mg tablets as more than $29,754.
Dec. 15: The FDA approved a new formulation of Arcutis Biotherapeutics, Inc.’s Zoryve (roflumilast) as a foam for the topical treatment of seborrheic dermatitis in people at least 9 years old. The company says it is the first drug approved for seborrheic dermatitis — which affects more than 10 million people in the U.S. — with a new mechanism of action in more than two decades. The agency initially approved the first topical phosphodiesterase-4 (PDE4) inhibitor on July 29, 2022, as a cream. Dosing is once daily to affected areas. The wholesale acquisition cost of both the foam and the cream is $858 per tube.
Dec. 15: The FDA approved Pfizer Inc. and Astellas Pharma Inc.’s Padcev (enfortumab vedotin-ejfv) in combination with Merck & Co., Inc.’s Keytruda (pembrolizumab) for the treatment of people with locally advanced or metastatic urothelial cancer (la/mUC). The agency gave accelerated approval to this combination for people with la/mUC who are not eligible for cisplatin-containing chemotherapy on April 3, 2023. The newest approval converts that accelerated approval to full and expands the labeled indication to include the treatment of people eligible for cisplatin chemotherapy. The application had priority review and breakthrough therapy designation. The FDA conducted its review under Project Orbis in collaboration with the Australian Therapeutic Goods Administration and Health Canada. The review also used the Real-Time Oncology Review pilot program and the Assessment Aid. Dosing for Padcev, a Nectin-4-directed antibody and microtubule inhibitor conjugate, is 1.25 mg/kg via a 30-minute infusion on days one and eight of a 21-day cycle, and for Keytruda, a PD-1 inhibitor, dosing is 200 mg via a 30-minute infusion every three weeks or 400 mg every six weeks. Drugs.com lists the price of one single-dose 20 mg vial of Padcev as $2,909. The list price of every-three-weeks Keytruda is $11,115; for every-six-weeks dosing, it is $22,230.
Dec. 18: The FDA approved GC Biopharma Corp.’s Alyglo (immune globulin intravenous, human-stwk) for the treatment of primary humoral immunodeficiency in people at least 17 years old. The initial intravenous infusion rate is 1 mg/kg/minute for a dose of 300-800 mg/kg of body weight every 21 or 28 days, with the infusion rate doubled every 30 minutes if tolerated up to 8 mg/kg/minute. Starting with the second infusion, the infusion rate should be 2 mg/kg/minute for a dose of 300-800 mg/kg of body weight every 21 or 28 days, with the infusion rate doubling every 15 minutes if tolerated up to 8 mg/kg/minute.
Dec. 18: The FDA approved Chiesi Group unit Chiesi Global Rare Diseases’ Filsuvez (birch triterpenes) for the treatment of partial thickness wounds in people at least 6 months old with junctional epidermolysis bullosa (JEB) and dystrophic epidermolysis bullosa (DEB). The topical gel is the first FDA-approved agent for wounds associated with JEB, a moderate-to-severe form of EB with blisters beginning in infancy. Dosing is a 1 mm layer applied to the affected wound surface and then covered with wound dressing.
Dec. 20: The FDA converted the accelerated approval of Calliditas Therapeutics AB’s Tarpeyo (budesonide) to full approval to reduce the loss of kidney function in adults with primary immunoglobulin A nephropathy (IgAN) — which is also known as Berger disease — at risk for disease progression. The agency granted the accelerated approval on Dec. 15, 2021. The company says it is the first fully FDA-approved treatment for IgAN based on a measure of kidney function. The recommended dose of the delayed-release capsules is 16 mg once daily, with a recommended duration of therapy of nine months. Drugs.com lists the price of 120 4 mg capsules as more than $15,934.
Dec. 21: The FDA approved AstraZeneca and Ionis Pharmaceuticals, Inc.’s Wainua (eplontersen) for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults (hATTR-PN or ATTRy-PN). The company says that the ligand-conjugated antisense oligonucleotide medicine is the only approved treatment for ATTRy-PN that can be self-administered using an auto-injector. The agency gave the therapy orphan drug designation. Dosing is 45 mg via subcutaneous injection once monthly.
Dec. 22: The FDA expanded the approval of Celltrion USA, Inc.’s Yuflyma (adalimumab-aaty) to include the treatment of adults with non-infectious intermediate and posterior uveitis and panuveitis. The agency first approved the biosimilar of AbbVie Inc.’s tumor necrosis factor (TNF) blocker Humira (adalimumab) on May 23, 2023. Dosing starts with 80 mg via subcutaneous injection, followed by 40 mg every other week starting one week after the initial dose. The price of two single-dose prefilled pens or two single-dose prefilled glass syringes is $6,576.
Dec. 22: The FDA granted an additional presentation of Coherus BioSciences, Inc.’s Udenyca (pegfilgrastim-cbqv) as an on-body injector (OBI) known as Udenyca Onbody to decrease the incidence of infection, as manifested by febrile neutropenia, in people with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Udenyca was first approved Nov. 2, 2018, and the leukocyte growth factor is one of six biosimilars of Amgen Inc.’s Neulasta (pegfilgrastim) that the agency has greenlighted. A health care provider must fill the OBI with the co-packaged syringe and apply it to the patient’s abdomen or back of the arm. About 27 hours after the OBI is applied to the skin, it will deliver a 6 mg/0.6 mL dose of Udenyca over about five minutes. The company says it will be available in first-quarter 2024.
]]>Hizentra (immune globulin subcutaneous [human] 20% liquid) is now available in a 10 g prefilled syringe, manufacturer CSL Behring disclosed Jan. 3. The agent is the first and only subcutaneous immune globulin treatment approved for the maintenance of chronic inflammatory demyelinating polyneuropathy in the U.S. It also is approved for primary immunodeficiency in people at least 2 years old. In addition to the new size, the drug also is available in 1 g, 2 g and 4 g prefilled syringes.
]]>Hizentra (immune globulin subcutaneous [human] 20% liquid) is now available in a 10 g prefilled syringe, manufacturer CSL Behring disclosed Jan. 3. The agent is the first and only subcutaneous immune globulin treatment approved for the maintenance of chronic inflammatory demyelinating polyneuropathy in the U.S. It also is approved for primary immunodeficiency in people at least 2 years old. In addition to the new size, the drug also is available in 1 g, 2 g and 4 g prefilled syringes.
Shorla Oncology and EVERSANA launched Jylamvo (methotrexate) in the U.S., the companies revealed Dec. 19. EVERSANA is partnering with the specialty pharmaceutical company on the commercialization of the therapy, including providing launch support. The FDA approved the drug — which is the first FDA-approved oral methotrexate solution — on Nov. 29, 2022, when it belonged to Therakind Ltd., which did not make the therapy available in the U.S. On Oct. 31, Shorla and Therakind revealed that Shorla had acquired the agent. The folate analog metabolic inhibitor is approved to treat adults with acute lymphoblastic leukemia as part of a combination chemotherapy maintenance regimen; mycosis fungoides (cutaneous T-cell lymphoma) as a single agent or as part of a combination chemotherapy regimen; relapsed or refractory non-Hodgkin lymphomas as part of a metronomic combination chemotherapy regimen; rheumatoid arthritis; and severe psoriasis.
PEOPLE ON THE MOVE: BioMatrix Specialty Pharmacy promoted President and Chief Clinical Officer Kathee Kramm to CEO. She succeeds Nick Karalis, who is assuming the role of executive chairman.
]]>To help patients pay for pricy therapies — usually specialty drugs — pharmaceutical manufacturers offer assistance that can help cover their out-of-pocket costs. Companies claim that the assistance helps improve patient adherence to medications that often treat rare and deadly conditions. But critics of them say such programs incentivize drugmakers to raise prices of these agents.
]]>To help patients pay for pricy therapies — usually specialty drugs — pharmaceutical manufacturers offer assistance that can help cover their out-of-pocket costs. Companies claim that the assistance helps improve patient adherence to medications that often treat rare and deadly conditions. But critics of them say such programs incentivize drugmakers to raise prices of these agents.
Health plans and PBMs began implementing copay accumulators — and then a new iteration known as copay maximizers that declare certain drugs non-essential health benefits to avoid covering them per the Affordable Care Act (ACA) — several years ago to counter these copay assistance programs. Before these tools, manufacturer assistance would count toward beneficiaries’ annual out-of-pocket expenses. When those were reached, health plans would cover the remainder of members’ costs for the year. With accumulators and maximizers, patients can still use that assistance, but it does not help reduce those out-of-pocket costs.
Once the assistance is depleted — usually fairly early in the year with accumulators — beneficiaries must pay for often-costly drugs until they hit their out-of-pocket maximums, shifting payers’ financial responsibilities to their members and manufacturers.
While the programs began less than 10 years ago, their use is growing and will likely continue to grow for the time being. In an online poll of 2,200 adults conducted Oct. 28 and 29 by Morning Consult on behalf of the PAN Foundation, a group that provides financial assistance to people with life-threatening and rare diseases, 25% of the 215 commercially insured respondents said their health insurer told them their specialty drug is considered a non-essential health benefit. In addition, 28% responded that their insurer said the financial aid they receive for a specialty therapy will not count toward their deductible or out-of-pocket maximum.
In the 2020 Notice of Benefit and Payment Parameters (NBPP), CMS stated that plans could exclude manufacturer assistance from counting toward patients’ out-of-pocket limit for only “specific prescription brand drugs that have an available and medically appropriate generic equivalent.” That excluded many costly specialty drugs that did not have a generic equivalent.
But in the 2021 NBPP, which was finalized in 2020, CMS said plans were not required to apply manufacturer assistance toward beneficiaries’ annual cost sharing, leaving members on the hook for numerous specialty medications once assistance ran out.
That prompted the HIV + Hepatitis Policy Institute, the Diabetes Patient Advocacy Coalition, the Diabetes Leadership Council and three people dependent on copay assistance whose health plans had accumulators in place to file a lawsuit (Case 1:22-cv-02604) in August 2022 against HHS, CMS and their respective leaders challenging the 2021 NBPP. The lawsuit claimed that allowing the use of accumulators is at odds with how the ACA — as well as the agencies’ preexisting regulatory definition — defines “cost sharing,” charging that the 2021 NBPP is “arbitrary and capricious.”
U.S. District Judge John D. Bates of the U.S. District Court for the District of Columbia ruled in favor of the plaintiffs on Sept. 29, ordering that the 2021 NBPP “must be set aside based on its contradictory reading of the same statutory and regulatory language and the fact that the agencies have yet to offer a definitive interpretation of this language that would support the rule.”
But on Nov. 27, HHS filed a conditional motion to clarify the scope of the court’s order. “Defendants do not understand this Court’s order to require HHS to take enforcement action,” it said. “The Court vacated the relevant portion of the 2021 NBPP but did not order any additional relief.…To ensure that they are not inadvertently running afoul of the Court’s Order, however, Defendants respectfully request clarification from the Court if their understanding of the scope of the Court’s Order is incorrect.”
In the motion, HHS revealed that the agency “intends to address, through rulemaking, the issues left open by the Court’s opinion, including whether financial assistance provided to patients by drug manufacturers qualifies as ‘cost sharing’ under the Affordable Care Act.”
HHS also said that until it issues a final rule, it has no intentions of taking “any enforcement action against issuers or plans based on their treatment of such manufacturer assistance.”
The following day, HHS filed a notice of appeal.
Asked about the government’s actions, a CMS spokesperson tells AIS Health, a division of MMIT, that “CMS does not comment on matters in litigation.” That said, “We continue to consider the court’s ruling and have filed a conditional motion for clarification.” In addition, they explain, “The government has not yet decided whether to appeal the district court’s decision. The government has filed a protective notice of appeal, which preserves its right to appeal. The decision whether to appeal will be made at a later date.”
On Dec. 11, the plaintiffs responded, filing a notice of appeal, as well as a brief outlining why the court should deny HHS’s motion for clarification.
The government’s moves came as a bit of a surprise considering that HHS’s 2025 NBPP (88 Fed. Reg. 82510, Nov. 24), which was published just a few days before the government’s filings, seeks to do away with the non-essential health benefit loophole that allows copay maximizers to exclude covering certain drugs so beneficiaries could be considered uninsured for those drugs and qualify for manufacturer assistance.
It also would seem to be in conflict with the Office of Personnel Management’s March 2023 request for proposal (RFP) for federal employee health plans that noted the agency would not consider “any proposals that manipulate the prescription drug benefit design, or incorporate copay maximizer or optimizer programs, or other similar programs to capture such savings.”
“It most definitely seems contradictory” that the government is both for such programs and against them, says Madelaine A. Feldman, M.D., a clinical assistant professor of medicine at Tulane University School of Medicine and provider with The Rheumatology Group in New Orleans. Elan Rubinstein, Pharm. D., principal at EB Rubinstein Associates, says he agrees with the contradictory assessment but adds that “only a small fraction of Americans are subject to” the ACA’s essential health benefit mandate.
HHS’s pushback was “certainly disappointing,” says Feldman, who is also president of the Coalition of State Rheumatology Organizations, which was among provider and patient groups that sent a letter to HHS after the September ruling asking the agency not to appeal the decision. “I have been pointing out the ‘do as I say, but not as I do’ aspect of the Office of Personnel Management RFP for federal employee health plans, which will not consider plans that allow copay accumulator nor maximizer programs. It states that these programs ’are not in the best interest of the enrollee or the federal government.’ And yet it is just fine for the American people?”
The RFP, she says, “is frustrating because it creates the impression that federal employees are allowing insurer behavior in other markets that they would never tolerate for their own coverage.”
Feldman tells AIS Health that she does not agree with the administration’s approach in the motion to clarify. “With the 2021 regulation vacated, the administration is left with the 2020 regulation’s approach to this issue, which was that only manufacturer assistance used for a brand drug with a generic equivalent did not count toward the annual limit on cost-sharing,” she says. “That was a balanced approach, in that it would still fully credit manufacturer assistance for patients in need of expensive brand drugs without lower-cost equivalents. The 2020 regulation also made its approach subject to state law, which meant that a state could require that all manufacturer assistance count, regardless of whether a drug had a lower-cost therapeutic equivalent or not. In other words, it established a ‘floor’ but left states free to enact more expansive approaches to manufacturer assistance.
“That paradigm is what I had assumed the Administration would have to default back to, after the September court ruling. It’s my hope that the judge assumed the same, but we won’t know until he responds to that motion to clarify.”
Shortly after CMS’s filings, Sen. Marsha Blackburn (R-Tenn.), a member of the Senate Finance Committee, penned a letter to the HHS and CMS secretaries expressing “profound disappointment in your decision to double down on the flawed 2021” NBPP following the September ruling and urged them to “reconsider and reverse course as expeditiously as possible.”
“Prioritizing the interests of large health plans over patients runs counter to the Biden Administration’s expressed commitment to drive down prescription drug costs. Appealing an even-handed, commonsense legal opinion, in this context, risks rubber-stamping one of the most pernicious and pervasive tools deployed by pharmacy benefit managers (PBMs) and their insurer clients. As working families across the country continue to wrestle with rising costs, the Administration’s posture sends a strident and saddening signal to patients and their families losing out on copay assistance copay through accumulators and other inflationary insurance policy levers.”
One of the arguments in the government’s March motion is that insurance companies do not “‘collect’ the value of manufacturer coupons through their accumulator adjustment programs.” Instead, “accumulator adjustment programs allow issuers and plans to delay incurring coverage liability until after the enrollee has satisfied the amount of the required cost sharing without including the amount of the manufacturer assistance.”
That argument, says Rubinstein, is a logical fallacy — a distinction without a difference: “the assertion that a position is different from another position based on the language when, in fact, both positions are the same — at least in practice or practical terms.”
According to Feldman, “We need to understand that there is some entity in the drug supply chain that is collecting the manufacturers’ assistance money and some entity collecting the patient’s deductible money. I suppose it depends on your definition of the ‘health insurance company’ as to who is collecting the money.” She points to all of the vertical integration with insurers and PBMs, “who then contract with and/or own maximizer programs, allowing them to make money on these programs.”
Specialty pharmacies also are involved, she points out, and they collect “the copay assistance from the manufacturer, and then they also collect the patient cost share — and with maximizers they can sometimes triple dip the actual amount of what the patient owes. Let’s not be fooled by incessant finger-pointing of who is really making the money.”
According to Feldman, “The absurdity of an accumulator becomes easier to see when you replace the drug company with someone else. What if my sister pays my coinsurances for me? By the logic of an accumulator, the insurance company could refuse to credit her money towards my deductible. I think most people intuitively grasp the unfairness of that.”
One of the other arguments in favor of accumulators that the government and others cite is that they incentivize providers and patients to favor an expensive medication over “a medically appropriate generic drug.” But, says Feldman, “for many patients who need specialty biologics, there is no lower-cost alternative. For those patients, copay assistance makes the difference between being treated or not. Studies have shown a significant loss of adherence to needed medications when copay accumulators are implemented in an employer health plan when compared to prior implementation of accumulators. I think it is important to remember that these policies predominantly affect patients with chronic illness, who can’t afford a low deductible plan.
“Clearly it is a discriminatory policy, which disproportionately affects people who have little disposable income and have chronic illnesses, usually with multiple comorbidities, and need expensive medicines for which there are no lower cost alternatives,” she adds.
“The pharmaceutical market for complex and serious diseases is unique in that the ultimate consumer — the patient — cannot choose whether or not they need the product, but the consequences of not being able to afford the product can be devastating. That seems to get lost in a lot of these debates,” asserts Feldman, who points to the government’s March RFP, which says that assistance programs “decouple demand for a drug from the drug’s price.”
“That’s a depressing sentence for its implication that patients want these medications because they don’t have to pay for them,” she says. “Using rheumatoid arthritis as an example, ‘demand’ for the medication exists because the patient suffers crippling pain and joint damage without it. How much the patient has to pay out-of-pocket for the medication will affect whether they’re able to fill the prescription — but it has no bearing on their need for it.”
What happens next is anyone’s guess, but a Dec. 4 article by attorneys at law firm Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C. says that prior actions and statements by HHS “indicate that the agency plans to use the tools at its disposal to protect copay accumulators. The most direct way to do so would be to amend the definition of ‘cost sharing’ to outright exclude manufacturer copay assistance. While HHS would likely prefer to give plans discretion over how to treat the manufacturer copay assistance rather than outright exclude it — as it did in the 2021 NBPP — it was this discretion that the District Court primarily took issue with.”
In addition, they said, as HHS “made clear in prior guidance, it believes that manufacturer copay assistance ‘can add significant long-term costs to the health care system that may outweigh the short-term benefits of allowing [it],’ a point it has reiterated throughout the government’s filings in the current litigation.”
“If anything is certain at this moment, it’s that the issue of how copay accumulators can be implemented is far from settled,” they contended. “There will likely be challenges to HHS’s future rulemaking on either substantive or procedural grounds.” And while notice-and-comment rulemaking takes time, “rushing out a regulatory fix to address the District Court’s ruling, or using a faster method of implementing a change (e.g. Interim Final Rule), could also make future rulemaking vulnerable to invalidation by a court.”
So for now, plans and PBMs are free to use copay accumulators without any changes to their policies or procedures.
In a Dec. 8 article, though, attorneys with law firm Ballard Spahr LLP recommend that plan sponsors watch out for HHS guidance related to accumulators. “The non-enforcement policy provides welcome — albeit temporary — relief for employers weighing their options following the court’s decision,” they said. “Although the filing provides only HHS’ views on the subject, plan sponsors with copay accumulator programs will likely welcome the news as an indication that those programs do not need to be abandoned, pending further agency guidance on the subject.”
Contact Feldman at nolarheum@gmail.com and Rubinstein at elan.b.rubinstein@gmail.com.
]]>Based on the initial list prices, though, it seems like perhaps competition cannot do that, at least not in this case, or at least not yet. Bluebird bio’s Lyfgenia has a wholesale acquisition cost of $3.1m, while the WAC for Vertex and CRISPR’s Casgevy is $2.2m, which might be a significant handicap for bluebird in securing reimbursement.
]]>Based on the initial list prices, though, it seems like perhaps competition cannot do that, at least not in this case, or at least not yet. Bluebird bio’s Lyfgenia has a wholesale acquisition cost of $3.1m, while the WAC for Vertex and CRISPR’s Casgevy is $2.2m, which might be a significant handicap for bluebird in securing reimbursement.
The two are the first gene therapies for sickle cell disease to be approved in the US and are positioned as one-time treatments for patients with recurrent vaso-occlusive events, a hallmark of serious disease. Their indications are very similar but slightly different.
Bluebird’s Lyfgenia (lovotibeglogene autotemcel) is a lentiviral vector-based gene therapy, while Vertex’s Casgevy (exagamglogene autotemcel) is a CRISPR/Cas9 gene-edited therapy developed using CRISPR Therapeutics’s gene editing technology. Vertex said it is launching Casgevy immediately and bluebird plans to introduce Lyfgenia in early 2024.
The nearly $1m price differential between the two treatments, which have comparable efficacy, hands payers substantial leverage in contracting negotiations with bluebird. As a result, the company may need to concede big discounts in order to secure coverage for Lyfgenia. In the pivotal clinical trial on Casgevy, 93.5% of patients had no severe vaso-occlusive crises (VOCs) for at least 12 consecutive months after treatment and research on Lyfgenia found 88% of treated patients had complete resolution of VOCs after six to 18 months.
Increasing pharmaceutical competition as a way to reduce prices has been a hallmark of policy rhetoric in Republican and Democratic administrations alike for some time. Indeed, the Biden administration’s most recent Rx pricing push, unveiled the day before the gene therapy approvals, emphasizes the need for competition – albeit through increased enforcement rather an unfettering of the market that a conservative policy approach might favor.
If the competition theory is correct, having two very similar products entering the market at the same time should theoretically keep prices in check. But what the sickle cell gene therapies may end of demonstrating – just as the launch of Humira biosimilars showed in a different way earlier this year – is that US pharmaceutical reimbursement is full of opaque systems and perverse incentives that in no way resemble the tidy supply and demand curves found in introductory economics textbooks.
So policymakers may find themselves fielding more calls for change instead of congratulating themselves on concepts well executed.
Vertex chose a price that is roughly in line with the Institute for Clinical and Economic Review’s estimate of a fair price for the two sickle cell treatments in a report issued in July.
It is close to the upper bound estimate in the report, ICER chief medical officer David Rind told the Pink Sheet. Nevertheless, “we note … the special obligation on all stakeholders, including public and private payers, health systems, and manufacturers to make these new therapies accessible to patients who need them. With that in mind, it would have been preferable to see a lower price for this therapy,” he said.
On the other hand, “the bluebird bio price is substantially higher than what ICER feels would be a fair price.”
It is unclear whether payer response to Lyfgenia relative to Casgevy may also be influenced by the fact that bluebird’s therapy has a black box warning for the possible development of blood cancer and Casgevy does not. Bluebird explained in a release on the approval that “two patients treated with an earlier version of Lygenia using a different manufacturing process and transplant procedure … developed acute myeloid leukemia.”
ICER’s Rind believes the warning will not be a reason for payers to prefer Casgevy over bluebird’s treatment. “There are necessarily uncertainties about the long-term safety of both therapies. There is not, currently, sufficient reason to prefer one therapy to the other based either on safety or efficacy, so it would be easy to imagine some payers preferring the less expensive therapy from Vertex,” he said.
Bluebird bio emphasized the unmet need in sickle cell disease and the heavy lifetime medical costs involved with serious illness in a release announcing its price. “Despite a median age of death of 45 years, it is estimated that US patients with frequent VOCs average $4m -$6m in direct lifetime medical costs, not including patient-incurred out-of-pocket costs or the impact on caregivers,” the company said.
In addition, “patients also forgo approximately $1.3m in lifetime earnings compared to their peers based on how their disease can limit academic and professional opportunities,” according to the company.
The price for Lyfgenia is also in line with the US pricing for Bluebird bio’s two marketed gene therapies, Zynteglo for beta thalassemia ($2.8m) and Skysona for cerebral adrenoleukodystrophy ($3m), the company pointed out.
Chief commercial and operating officer Tom Klima indicated that US acceptance of the prices for the existing treatments contributed to the thinking on Lyfgenia’s price.
“We feel very confident in our value-based approach for how we price all three of our gene therapies now,” he said during an 8 December call on the approval. “We ran a very similar process for Lyfgenia that we ran for both Zyntelgo and Skysona and obviously, looking at a potentially curative therapy for such a devastating disease like sickle cell disease becomes very important.”
He suggested the company’s proposed outcomes-based agreement with payers for the new treatment “will be a key part of the strategy to ensure rapid access.” The outcomes-based agreement is a risk sharing arrangement tied to measuring hospitalizations after treatment and involves a three-year patient follow-up.
Bluebird also said it is in “advanced discussions” about the arrangement with the largest commercial payers and is also talking with more than 15% of Medicaid agencies representing 80% of US patients with sickle cell disease. Medicaid will be the primary payer for the two treatments, covering 45% to 50% of patients, while commercial insurance plans are expected to cover 35% to 40%.
Another 10%-5% is expected to be covered by Medicare. The total number of patients eligible for treatments is 16,000 to 20,000, according to the companies.
Bluebird bio also said it is engaging with the Center for Medicare and Medicaid Innovation regarding a proposed demonstration project in which the Centers for Medicare and Medicaid Services could negotiate contracts for cell and gene therapies, likely including treatments for sickle cell disease, on behalf of a group of state Medicaid programs. The project is scheduled to begin in 2025.
This article originally appeared in Pink Sheet. AIS Health and Pink Sheet are part of the same parent company, Norstella.
]]>While no cure exists for the inflammatory bowel disease, the FDA has approved numerous agents to treat signs and symptoms of the condition. In addition to the nine biosimilars of AbbVie Inc.’s Humira (adalimumab) that have launched in the U.S. in 2023, a handful of other approvals happened from late September through late October. All of the agents offer maintenance dosing either through an oral or subcutaneous route of administration.
]]>While no cure exists for the inflammatory bowel disease, the FDA has approved numerous agents to treat signs and symptoms of the condition. In addition to the nine biosimilars of AbbVie Inc.’s Humira (adalimumab) that have launched in the U.S. in 2023, a handful of other approvals happened from late September through late October. All of the agents offer maintenance dosing either through an oral or subcutaneous route of administration.
On Sept. 27, the FDA approved a subcutaneous formulation of Takeda Pharmaceuticals U.S.A., Inc.’s Entyvio (vedolizumab) for the maintenance treatment of adults with moderately to severely active UC. The agency initially approved the integrin receptor antagonist on May 20, 2014, as an intravenous infusion, which remains available. Dosing for the drug starts with infusions, and then people can switch to subcutaneous injections.
On Oct. 13, the FDA approved Pfizer Inc.’s Velsipity (etrasimod) for the treatment of adults with moderately to severely active UC. The tablet is the second sphingosine 1-phosphate (S1P) receptor modulator approved for UC following Bristol Myers Squibb’s Zeposia (ozanimod), approved May 27, 2021.
On Oct. 23, the FDA approved Celltrion USA’s subcutaneous Zymfentra (infliximab-dyyb) for maintenance therapy in adults with moderately to severely active UC and Crohn’s disease following treatment with an intravenously administered infliximab product. The tumor necrosis factor (TNF) inhibitor is the first FDA-approved subcutaneous formulation of infliximab; it also is available as an intravenous infusion under the name Inflectra. The latter drug was initially approved April 5, 2016, as the first biosimilar of the Janssen Pharmaceutical Companies of Johnson & Johnson’s Remicade (infliximab), but the FDA approved Zymfentra as a novel drug.
Zymfentra is “a quite unique biologic,” observed Ivo Abraham, Ph.D., chief scientist of Matrix45, in an Oct. 30 column. It is “the first biobetter … of a biosimilar … of an originator product.”
On Oct. 26, the FDA approved Eli Lilly and Co.’s Omvoh (mirikizumab-mrkz) for the treatment of moderately to severely active UC in adults. The agent is the first interleukin-23p19 (IL-23p19) antagonist for this indication. It is approved both as an intravenous infusion and a subcutaneous injection. Dosing starts with infusions and then shifts to injections.
Then on Oct. 31, the FDA approved Amgen Inc.’s Wezlana (ustekinumab-auub) as a biosimilar to and interchangeable with Stelara (ustekinumab) from the Janssen Pharmaceutical Companies of Johnson & Johnson for the treatment of adults with moderately to severely active Crohn’s disease and moderately to severely active UC and the treatment of people at least 6 years old with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis. The human IL-12/-23 antagonist is approved for all of Stelara’s indications and for both intravenous and subcutaneous administration. It is the first biosimilar of that reference drug, with many others in development.
For the Managed Care Biologics & Injectables Index: Q3 2023, from Aug. 13, 2023, to Sept. 29, 2023, Zitter Insights polled 35 commercial payers covering 117.5 million lives, 27 Medicare payers representing 43.6 million lives and 53 gastroenterologists about their management and prescribing of UC therapies. More than half of payers said that managing branded UC drugs is a high priority for them and that they take an aggressive approach to management of the agents (see chart).
Both AIS Health and Zitter Insights are divisions of MMIT.
Payers with 55% of commercial lives, the same amount of Medicare beneficiaries and 49% of gastroenterologists expressed average satisfaction with current UC medications. Payers with 91% of commercial lives, 98% of Medicare lives and 75% of gastroenterologists said there was either moderate or high unmet need in the treatment of UC. More than half of both payers and gastroenterologists said that there is a high disease burden for people with UC.
“The treatment landscape of ulcerative colitis is becoming increasingly competitive, as seen with the recent approvals,” says Mesfin Tegenu, CEO and chairman of RxParadigm, Inc.
“The recent approvals represent an approach to treating UC from a multitude of perspectives,” observes Winston Wong, Pharm.D., president of W-Squared Group. The two biosimilars’ reference products “are highly utilized treatment options,” and both are from Janssen, but “by no means was Janssen caught off-guard.” Since 2016, the FDA has approved four biosimilars of Remicade, and the company has been aware of multiple Stelara biosimilars in development, filing patent infringement lawsuits against several companies and securing four settlements so far this year.
“Most significant for Wezlana is that it is approved as an interchangeable biosimilar, meaning that it may be substituted for the reference product without consulting the prescriber,” says Wong. “The implications of this are how will Janssen respond contractually to maintain their market share? What works in their favor is that nearly 100% of either Stelara or Wezlana will be dispensed by a specialty pharmacy; hence, even with the interchangeability, the specialty pharmacy will still be able to control utilization.”
Entyvio’s subcutaneous formulation means that people with UC have the option to self-administer every two weeks as opposed to going to a health care provider every eight weeks for a 30-minute infusion, points out Tegenu.
IL-23 inhibitor Omvoh “targets one of many interleukin pathways being studied,” Wong points out. “While it may not represent a true novel treatment option, especially since ustekinumab is a combined interleukin 12/23 inhibitor, it does represent an additional possible treatment option in a disease state that [can be] very heterogenous when seeking effective medications.” Tegenu adds that Omvoh “is the first UC treatment that selectively targets the p19 subunit of IL-23, which is known to play a large role in UC-related inflammation.”
The drug’s unique mechanism of action and its “significant efficacy in clinical trials,” he says, may make it the agent that has the biggest impact on the treatment of UC. “Omvoh is a promising treatment which may help relieve key feature symptoms of UC, such as stool frequency, rectal bleeding and bowel urgency, regardless of past use with biologics. In the clinical trials, improvements in symptoms like rectal bleeding and stool frequency were seen as early as three weeks in patients treated with Omvoh. Additionally, significant improvements in bowel urgency were reported by the patients.”
S1P receptor modulator Velsipity “represents a true novel approach,” asserts Wong. “Clinical trials showed Velsipity to be effective and well tolerated, and the true value is that Velsipity is an oral agent.” Tegenu contends that because S1P modulators do not have labeling requiring their use after a person has failed on a TNF inhibitor and do not have a black-box warning on their labels, this gives them an advantage over the oral Janus kinase (JAK) inhibitors.
“Clearly, the research appears to be moving in the direction of becoming more sensitive to disparities of health care, addressing the primary cause of health inequities being access to care,” says Wong. “With two new self-administered subcutaneous preparations and one oral regimen, patient access should be improved. The two biosimilar products will no doubt cause continued erosion on the cost of infliximab and start the price erosion of ustekinumab” — “be it by a lower biosimilar price, or deeper rebating by the innovator manufacturer to maintain market share” — “thus addressing the patient affordability disparity.”
With the move from provider-administered UC agents to self-administered ones, “payers will likely see a shift in UC drug spend from the medical benefit to the pharmacy benefit,” notes Tegenu. “UC drugs are a highly managed class by payers, and with the increasing competition from Remicade and Humira biosimilars that are already available, Stelara biosimilars anticipated to launch in 2025 and several self-administered drugs in the pipeline, payers may reevaluate their current management strategies for UC drugs to see which products provide the lowest net cost.”
The bump in self-administered treatments also “allows for tighter control of the utilization,” says Wong. “Not only is the utilization under tighter control, but it also allows for a contracting opportunity, as these medications can be sequenced via a pathway, especially as more practices and organizations are falling under performance reimbursement/model agreements. This presents…an opportunity to optimize clinical outcomes, balanced with total cost of care monitoring and trend blunting. Hopefully this is an opportunity that the vertically integrated organizations, e.g., PBMs/health plans, IDNs [integrated delivery networks], will seize.”
The class, he states, is “a significant cost driver; thus, there should be a significant ROI for the effort to more tightly manage” it. But to be successful, that management should be done in collaboration with providers. “In a different era, such an effort was put into motion in rheumatology with notable results. Such an effort here would require the buy-in of the rheumatologists, gastroenterologists and dermatologists in order to control all aspects of the immunology class. This is a different place and time compared to previous decades, and collaboration is the key today.”
Wong asserts that the biosimilars of AbbVie Inc.’s Humira — nine of which launched in 2023 — “can only lower costs” in UC. Tegenu agrees: They “will have a significant impact on the class. With the availability of aggressively priced Humira biosimilars, payers may reassess their management strategies, potentially leading to changes in formulary placement and implementing utilization management such as prior authorization and step therapy to prefer products with the lowest net cost as a cost-savings strategy.”
According to Tegenu, treatment of UC “is usually selected based on disease severity, location and dosing. Aminosalicylates are typically used as first-line agents in mild-to-moderate UC.” Several drug classes are available to manage moderate-to-severe UC, “including conventional therapies, such as corticosteroids and thiopurines, and advanced therapies, which include several classes of targeted immune modulators,” including TNF, JAK, interleukin and integrin inhibitors and S1P modulators.
Of those, the TNF inhibitors for the most part are the first-line agents, “due to their proven efficacy and tolerability,” declares Wong. “They are also the most deeply rebated, with additional net-price erosion due to the biosimilars.…Second line may also be driven by a combination of the label, contracting and the tolerability. Anything beyond that is simply based upon provider preference and consistency with the approved label. Unlike the oncology arena, pathways outlining the sequencing of medications are not as prevalent from a payer perspective, although they may be present within a practice or IDN.”
“There is not clear evidence of superiority of one treatment over another; therefore, the selection of therapy can depend on factors such as coexisting conditions and age,” Tegenu says. “In moderate-to-severe UC, most plans require failure with at least one conventional therapy prior to starting an advanced therapy. They will also generally have several preferred products and one or two nonpreferred products.”
Both Tegenu and Wong maintain that managing drugs for UC is a high priority for payers. “Many of the drugs used to manage moderate to severe UC are branded specialty drugs; thus, effectively controlling costs is a top priority,” observes Tegenu. “Furthermore, some patients don’t respond to treatments or lose response over time, so there’s a need for additional therapies for the management of moderate-to-severe UC. With the recent new approvals, managing this class will be a higher priority for payers so that costs can be managed effectively while ensuring patient access.”
Payers consider the UC drugs important to manage, agrees Wong, “however, in my opinion, not for the right reasons. They are a high priority because the medications are a high-cost class of medications with a high rebate potential. The medications within the immunology class are also used across multiple disease indications. There was a time when payers managed by indication (mostly the PBMs), but they really only managed the rebated drugs. Payers need to take the next step to manage the entire class across all indications and all medications.”
The newly approved agents, he asserts, provide an opportunity for this “because many of the medications can now shift to the pharmacy benefit. Maybe the pharmacy and medical benefits will finally integrate more to manage the entire patient and not in a siloed world with the focus of improving outcomes and controlling cost, either through rebates or appropriate utilization.”
For more information on the Zitter Insights data, contact Jill Brown Kettler at jkettler@mmitnetwork.com. Contact Tegenu at Mesfin.Tegenu@rxparadigm.com and Wong at w2sqgroup@gmail.com.
]]>The agency gave Aliqopa accelerated approval on Sept. 14, 2017, for the treatment of adults with relapsed follicular lymphoma (FL) who have received at least two systemic therapies. Approval was based on the CHRONOS-1 Phase II clinical trial. In the confirmatory study, CHRONOS-4, adding Aliqopa to standard immunochemotherapy regimens did not meet the primary endpoint of progression-free survival (PFS) vs. the standard immunochemotherapy control arm. Bayer says it will publish the trial results “in a timely manner.”
]]>The agency gave Aliqopa accelerated approval on Sept. 14, 2017, for the treatment of adults with relapsed follicular lymphoma (FL) who have received at least two systemic therapies. Approval was based on the CHRONOS-1 Phase II clinical trial. In the confirmatory study, CHRONOS-4, adding Aliqopa to standard immunochemotherapy regimens did not meet the primary endpoint of progression-free survival (PFS) vs. the standard immunochemotherapy control arm. Bayer says it will publish the trial results “in a timely manner.”
Other PI3K inhibitors given accelerated approval for hematologic malignancies have had their indications withdrawn from the U.S. market.
The first was Secura Bio, Inc.’s Copiktra (duvelisib), which was given accelerated approval on Sept. 24, 2018, for the treatment of adults with relapsed or refractory FL after at least two systemic therapies. On Dec. 3, 2021, the manufacturer disclosed that it was voluntary withdrawing the agent.
Then on Jan. 14, 2022, Gilead Sciences, Inc. revealed that it was voluntarily withdrawing two indications for Zydelig (idelalisib): for the treatment of relapsed FL and small lymphocytic leukemia (SLL), both of which were given accelerated approval on July 23, 2014.
Finally, on April 15, 2022, TG Therapeutics, Inc. said that it voluntarily withdrew its pending Biologics License Application (BLA)/supplemental NDA (sNDA) for the combination of ublituximab and Ukoniq (umbralisib) for the treatment of adults with chronic lymphocytic leukemia (CLL) and SLL. The company also said that it voluntarily withdrew Ukoniq from sale for two indications: (1) for adults with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen, and (2) for adults with FL who have received at least three prior systemic therapies. The FDA gave the drug accelerated approval for those indications on Feb. 5, 2021.
A couple of months before TG Therapeutics withdrew the pending BLA/supplemental NDA and approved indications, the FDA issued a drug safety communication about the possible increased risk of death with Ukoniq based on the agency’s review of the Phase III UNITY trial of people with CLL. “The results showed a possible increased risk of death in patients receiving the combination of Ukoniq and the monoclonal antibody compared to the control arm. Those receiving the combination of Ukoniq and the monoclonal antibody also experienced more serious adverse events than those in the control arm,” said the agency on Feb. 3, 2022. It noted that while the drug was not approved for CLL, “the FDA believes these findings have implications for” its MZL and FL indications.
A little more than two months later, the FDA’s Oncologic Drugs Advisory Committee (ODAC) held an April 21 meeting to discuss PI3K inhibitors in hematologic malignancies. The committee initially had scheduled a second meeting for April 22 to discuss the BLA/sNDA for ublituximab and Ukoniq and Ukoniq’s MZL and FL indications, but it canceled that meeting following TG Therapeutics’ move to withdraw those.
In its briefing document for the April 21 meeting, ODAC noted that “there are several central issues relating to the development of PI3K inhibitors in hematologic malignancies: concerning trends in overall survival (OS) in multiple randomized controlled trials (RCTs), toxicities of the PI3K inhibitor class, inadequate dose optimization, and trial design considerations regarding the limitations of single-arm trials.”
More specifically, “six randomized trials evaluating a PI3K inhibitor have demonstrated a higher rate of death or concerning OS results suggesting potential harm to patients. The randomized trials demonstrated or suggested a favorable effect on PFS and other efficacy parameters such as ORR [overall response rate]. Therefore, the adverse effect on OS is likely driven by PI3K inhibitor toxicity.
“The observation of a potential detriment in OS across this many randomized trials is unprecedented in oncology,” stated ODAC. “For each trial, there is a low number of observed OS events (as low as 3% to 20% of the planned sample size without a pre-specified plan for evaluating OS), leading to uncertainty of the specific OS estimate. However, based on the confidence intervals for the HRs, potential harm to patients cannot be ruled out. Taken together, these are not isolated observations, but rather repeated observations across multiple trials of different PI3K inhibitors in patients with indolent lymphoid malignancies.”
ODAC subsequently voted 16-0, with one abstention, in favor of requiring randomized controlled data to support the approval of PIK3 inhibitors given the observed toxicities with the class.
The committee did not discuss Novartis Pharmaceuticals Corp.’s PI3K inhibitor Piqray (alpelisib), which is approved for certain people with breast cancer.
“This class has shown a concerning trend in decrease in OS, a high rate of severe adverse events and subsequent patient discontinuation,” says Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth. Bayer’s withdrawal of Aliqopa’s NDA “will likely impact other PI3K inhibitors with additional review and caution, given these current safety and efficacy signals. Additionally, this will likely keep the available PI3K therapies as a later line option after exhausting other available therapies with more robust randomized clinical studies and more established safety profiles.”
He comments that “it is interesting to note that Bayer withdrew their marketing application [for Aliqopa] to the European Medicines Agency in December 2021.”
He tells AIS Health, a division of MMIT, that the issue with PI3K inhibitors is likely due to “a combination of factors.” In trials, the drugs have shown durable ORR and PFS improvements, he notes, but lower OS. “The single-arm trial design which led to the approvals was not supported by the subsequent randomized clinical trial data.…The randomized trials have shown higher rates of Grade 3 or higher fatal and serious adverse events (ADRs) than in the single arm studies. This may be a reflection of the drug itself, the toxicities inherent with the PI3K class, potential nonoptimal dose being identified that would assist with optimizing the efficacy and minimizing the ADRs of the drug and/or having nonrandomized trial design for the accelerated approval process.”
Asked about how developments within the class could impact PI3K inhibitors being developed, Szczotka points to the ODAC vote requiring randomized data. “Other PI3K inhibitors in development will need to submit data that includes this type of trial design and ensure that OS is demonstrated, in addition to having durable ORR and PFS, while minimizing the ADRs in comparison to the prior marketed PI3K inhibitors in larger patient populations. This will likely extend their clinical trials and delay submission to the FDA for approval.”
In addition, he says, because of the known toxicities, clinical trials for the drugs “will need to ensure that the proper optimal dosing regimen is identified that will minimize the ADR seen with this class of agents to a larger number of patients in the clinical trial. This would assist with addressing the known safety issues and OS.”
Moving forward, payers are likely to evaluate accelerated approvals for other drugs within the class “to ensure that randomized control trial design with [an] adequate number of study participants over a longer time period would be a cornerstone for payer review. Additionally, studies will need to have relevant standard-of-care therapies included in the placebo or control arm of the study, especially in those diseases with current multiple therapy options. While payers will evaluate the available approved clinical trials and their design, they can influence manufacturers to ensure that their submitted clinical trial designs will move towards these targets and have safe and effective therapy available at the time of FDA approval.”
Contact Szczotka via Caroline Chambers at cchambers@cpronline.com.
]]>The FDA established the accelerated approval pathway in 1992 to bring HIV/AIDS medicines onto the market sooner during the ongoing epidemic. Between that time and Dec. 31, 2020, the agency has granted more than 253 accelerated approvals, according to a 2021 report from the Institute for Clinical and Economic Review (ICER) examining the designation. Of those, 125 — 49.4% — later received full approval, with a median time of 3.2 years from accelerated approval to full. Sixteen — 6.3% — of the indications have been withdrawn, and the remaining 112 drugs have been on the market for a median of 1.9 years.
]]>The FDA established the accelerated approval pathway in 1992 to bring HIV/AIDS medicines onto the market sooner during the ongoing epidemic. Between that time and Dec. 31, 2020, the agency has granted more than 253 accelerated approvals, according to a 2021 report from the Institute for Clinical and Economic Review (ICER) examining the designation. Of those, 125 — 49.4% — later received full approval, with a median time of 3.2 years from accelerated approval to full. Sixteen — 6.3% — of the indications have been withdrawn, and the remaining 112 drugs have been on the market for a median of 1.9 years.
Some studies have examined the accelerated approval program, with many focusing on oncology, revealing some not-so-flattering findings. For instance, a study published in August 2022 on JAMA Health Forum revealed that of the oncology indications given accelerated approval between Jan. 1, 2007, and Dec. 31, 2021, only 36% were rated as having high added therapeutic value compared with 53.3% for noncancer indications. A study published in JAMA Oncology in June 2018 found that of the 93 new accelerated approval hematology and oncology indications from Dec. 11, 1992, to May 31, 2017, only slightly more than half — 55% — had completed confirmatory trials in a median of 3.4 years after approval, while 40% had not completed those trials. Another study published in BMJ in September 2021 showed that even after a negative confirmatory trial, one-third of indications remained on a cancer drug’s label, and half had the second-highest level of recommendation in National Comprehensive Cancer Network (NCCN) guidelines. Over the past few years, various industry experts have called for a variety of overhauls to the pathway.
As part of the Consolidated Appropriations Act, 2023 (H.R. 2617), passed Dec. 29, 2022, the Food and Drug Omnibus Reform Act of 2022 included several modifications to the accelerated approval process, including giving the FDA the ability to require that manufacturers have a postapproval study underway before the agency grants approval. And it looks like the agency may be taking advantage of that change.
Pink Sheet recently reported that Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence (OCE) and acting director of the Office of Oncologic Diseases, told attendees at the Nov. 14 Friends of Cancer Research Annual Meeting that if a company does not have an ongoing confirmatory study for an oncology agent, the drug will not receive accelerated approval. “We may have an application that has demonstrated safety and efficacy, but will we approve the drug if the confirmatory trial is not underway? And the answer to that is no,” he said.
AIS Health and Pink Sheet are part of the same parent company, Norstella.
“We really want to send a clear message that these trials need to be ongoing,” said Pazdur. “We’re writing guidance at the present time on what ongoing means, but let me tell you folks it’s not just one patient on the trial when the trial has been activated at sites.”
An OCE spokesperson declined to tell the publication when the guidance will be available.
Pazdur’s comments were made two days before the FDA’s Oncologic Drugs Advisory Committee (ODAC) Nov. 16 meeting to discuss the accelerated approval program in oncology and Acrotech Biopharma Inc.’s Folotyn (pralatrexate) and Beleodaq (belinostat). The FDA gave accelerated approval to Folotyn on Sept. 24, 2009, and to Beleodaq on July 3, 2014; however, confirmatory trials have been delayed, with completion not expected until 2030.
The meeting came two years after an April 27-28, 2021, ODAC meeting that scrutinized six indications for a handful of checkpoint inhibitors that target programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) and received accelerated approval to determine whether confirmatory trials verified the therapies’ clinical benefits.
According to the ODAC briefing document for the more recent meeting, the median time from accelerated approval to traditional approval is 3.1 years, and it is 4.1 years from accelerated approval to withdrawal. Out of 187 accelerated approvals for unique drug-indication anticancer pairings, confirmatory trial for slightly more than half — 96 — have verified their clinical benefit and resulted in traditional approval. Before 2020, only six oncolytics with the designation had been withdrawn. But since 2020, manufacturers have withdrawn or begun the process for more than 20 cancer indications and/or drugs. Most recently, Bayer said last month that it will work with the FDA to voluntarily withdraw the New Drug Application for its Aliqopa (copanlisib).
Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth, notes that if data from the ICER report were assessed for the period prior to 2016 — giving those older agents time to complete confirmatory trials — more than three-quarters of the drugs were granted traditional approval, 10% were withdrawn, and “13% were reported to be on the market for a median of almost 10 years without confirmatory evidence to warrant traditional approval. From this data, most of the accelerated approvals are confirmed and contributing positively to disease treatment paradigms.
“While a significant number of these accelerated approvals are ultimately receiving traditional approval, one of the main concerns with this process is the time it takes some companies to complete confirmatory studies and what happens when those studies fail or are not completed,” he tells AIS Health.
One of the FDA’s goals is to make sure that approved agents are safe and effective. “When non-traditional endpoints are used to gain approval, this raises the level of scrutiny for the product to ensure that it will be able to ultimately meet the overall objective, traditional endpoint(s),” says Szczotka. “While surrogate markers may be effective in certain situations, sometimes these are not the ultimate measure of a product’s safety and/or efficacy. Continued review of the accelerated approval process should be an essential element to ensure that the program is meeting the goal to expedite access to truly innovative products that provide new treatment options for serious medical conditions and remove products that are not timely completing their confirmatory trials or meeting agreed-upon clinical endpoints.”
When reviewing drugs with accelerated approval, pharmacy and therapeutics (P&T) committees usually follow the same process as that used for products with traditional approval, he says. “Unless there is an urgent medical need, the P&T review process allows for the time to properly gather the available safety and clinical information needed for evaluation. Since the currently available data has the vast majority of these accelerated approval products ultimately gaining traditional approval, it is unlikely that the review timing would be lengthened.”
That could be changing, though, if a small sample of payers is any indication. An MMIT Payer Event Primer conducted over a few days in September with 10 payer stakeholders found that six of them said they distinguish between drugs with traditional FDA approval and those that require postmarket confirmatory trials. Many of them said that they would place more rigorous prior authorization (PA) criteria on fast-tracked drugs than they would on ones with traditional approval.
AIS Health is a division of MMIT.
Still, accelerated approval means that people have access to novel therapies on a speeded-up time frame compared with the traditional approach, and it “has likely helped provide additional therapy options to patients and physicians, hopefully leading to enhanced patient outcomes,” Szczotka says. “One study looking at all malignant hematology and oncology accelerated approvals were available to patients an average of three to four years earlier than a traditional approval would have allowed. Given the additional market time of these accelerated approval products, it is likely that manufacturers will continue to seek accelerated approvals.”
But given all the scrutiny of the pathway, payers likely “will continue to question how the cost of the accelerated approval products correlates with value and/or unmet need given the typically limited clinical data,” says Szczotka. In addition, manufacturers will be pressured “to complete their confirmatory trials in a timelier manner and then take immediate action on their product in case the trials do not demonstrate a clinically meaningful benefit.” When drugs are shown to be ineffective but remain on the market, this “will lead to additional scrutiny and review of these products.”
Asked about the FDA’s requiring drugs to already be in confirmatory trials by the time of accelerated approval, Szczotka observes that such studies “are an essential part of the accelerated approval process and help demonstrate the continued safety and efficacy of the product for its intended use. From a payer’s perspective, the earlier the confirmatory trial is completed, the sooner the product’s place in therapy can be confirmed. By requiring the confirmatory trial to be started at the time of the accelerated approval, this will only assist in completing the trial in a shorter overall time period.” It also will give payers a better sense of when the FDA will make a decision on granting traditional approval.
“Ideally, contracting for products that have not been granted traditional approval should have the manufacturer be responsible for the cost of those ineffective therapies,” he recommends. “Unfortunately, that is not the case for drug use in the U.S. Traditional contracting approaches will likely continue, with potential application of value-based contracting initiatives in targeted, reportable therapeutic areas.”
Contact Szczotka via Caroline Chambers at cchambers@cpronline.com.
]]>Oct. 31: The FDA expanded the approval of Fresenius Kabi’s Idacio (adalimumab-aacf) for the treatment of adults with non-infectious intermediate and posterior uveitis and panuveitis. The agency first approved the biosimilar of AbbVie Inc.’s tumor necrosis factor (TNF) blocker Humira (adalimumab) on Dec. 13, 2022. Dosing starts with 80 mg via subcutaneous injection, followed by 40 mg every other week starting one week after the initial dose. The price of two single-dose prefilled pens or two single-dose prefilled glass syringes is $6,576.
]]>Oct. 31: The FDA expanded the approval of Fresenius Kabi’s Idacio (adalimumab-aacf) for the treatment of adults with non-infectious intermediate and posterior uveitis and panuveitis. The agency first approved the biosimilar of AbbVie Inc.’s tumor necrosis factor (TNF) blocker Humira (adalimumab) on Dec. 13, 2022. Dosing starts with 80 mg via subcutaneous injection, followed by 40 mg every other week starting one week after the initial dose. The price of two single-dose prefilled pens or two single-dose prefilled glass syringes is $6,576.
Nov. 7: The FDA amended Merck & Co., Inc’s Keytruda (pembrolizumab) accelerated approval in combination with trastuzumab, fluoropyrimidine and platinum-containing chemotherapy for the first-line treatment of people with locally advanced unresectable or metastatic human epidermal growth factor receptor-2 (HER2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma to restrict its use to people whose tumors express programmed death-ligand 1 (PD-L1) (CPS > 1) as determined by an FDA-approved test (see below brief). The agency first approved the programmed death receptor-1 (PD-1) inhibitor on Sept. 4, 2014. Dosing is 200 mg every three weeks via intravenous infusion or 400 mg every six weeks. The list price for every-three-weeks dosing is $11,115; for every-six-weeks dosing, it is $22,230.
Nov. 7: The FDA approved Agilent Technologies Inc.’s PD-L1 IHC 22C3 pharmDx as a companion diagnostic device to select people with gastric or GEJ adenocarcinoma whose tumors express PD-L1 and who may be candidates for Keytruda (see above brief). The in vitro diagnostic also is approved for five other indications of the PD-1 inhibitor.
Nov. 8: The FDA approved Takeda Pharmaceuticals U.S.A., Inc.’s Fruzaqla (fruquintinib) for the treatment of adults with metastatic colorectal cancer (mCRC) who have been treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy and, if Rat sarcoma (RAS) wild-type and medically appropriate, an anti-epidermal growth factor receptor (EGFR) therapy. The agent is the first FDA-approved selective inhibitor of all three VEGF receptor kinases for previously treated mCRC regardless of biomarker status. The agency gave the drug priority review. Dosing for the capsule is 5 mg once daily for the first 21 days of each 28-day cycle.
Nov. 9: The FDA approved Takeda’s Adzynma (ADAMTS13, recombinant-krhn) for prophylactic or on-demand treatment of adult and pediatric patients with congenital thrombotic thrombocytopenic purpura (cTTP). The company says it is the first FDA-approved recombinant A disintegrin and metalloproteinase with thrombospondin motifs 13 (rADAMTS13) protein designed to address an unmet medical need in people with the ultra-rare chronic blood clotting disorder cTTP by replacing the deficient ADAMTS13 enzyme. Untreated acute TTP events have a more than 90% mortality rate. The agency gave the application priority review, fast track and orphan drug designations, as well as a rare pediatric disease priority review voucher. Dosing as a prophylactic therapy is 40 IU/kg body weight once every other week intravenously at a rate of 2 to 4 mL per minute. For on-demand therapy, dosing is 40 IU/kg body weight on day one, 20 IU/kg body weight on day two and 15 IU/kg body weight on day three and beyond until two days after resolution of the acute event.
Nov. 15: The FDA approved Bristol Myers Squibb’s Augtyro (repotrectinib) for the treatment of adults with locally advanced or metastatic ROS proto-oncogene 1 (ROS1) non-small cell lung cancer. Dosing for the tyrosine kinase inhibitor (TKI) is 160 mg once daily for 14 days and then 160 mg twice daily.
Nov. 16: The FDA gave an additional indication to Astellas Pharma Inc. and Pfizer Inc.’s Xtandi (enzalutamide) for the treatment of people with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis. The agency first approved the androgen receptor signaling inhibitor as a capsule on Aug. 31, 2012; the medication also is available as a tablet. Both formulations are approved for the newest use. The FDA gave the most recent application priority review and fast track designations, as well as used the Real-Time Oncology Review program. Dosing is 160 mg once daily. Drugs.com lists the price of 120 40 mg capsules, 120 40 mg tablets and 60 80 mg tablets as more than $14,382.
Nov. 16: The FDA approved AstraZeneca’s Truqap (capivasertib) in combination with fulvestrant for adults with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with at least one PIK3CA/AKT1/PTEN alteration, as detected by an FDA-approved test (see below brief), following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. The review of the first-in-class AKT inhibitor was conducted under Project Orbis in collaboration with the Australian Therapeutic Goods Administration, Health Canada, Israel’s Ministry of Health, Singapore’s Health Sciences Authority, Switzerland’s Swissmedic and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency, and it used the Assessment Aid. The application was given priority review. Dosing for the tablet is 400 mg twice daily for four days, followed by three days off.
Nov. 16: The FDA expanded the approval of Foundation Medicine, Inc.’s FoundationOne CDx assay to include its use as a companion diagnostic to identify people with breast cancer who have certain alterations and are candidates for treatment with Truqap and fulvestrant (see above brief). It is the first FDA-approved test to identify this new subset of breast cancer patients. The tissue-based test analyzes more than 300 cancer-related genes for genomic alterations in a tumor. It has more than 35 companion diagnostic indications, and five of those are in breast cancer.
Nov. 16: The FDA approved Yifan Pharmaceutical Co. Ltd. subsidiary Evive Biotechnology Singapore PTE. Ltd.’s Ryzneuta (efbemalenograstim alfa-vuxw) to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Acrotech Biopharma, a subsidiary of Aurobindo Pharma USA Inc., will commercialize the leukocyte growth factor in the U.S. The recommended dose is 20 mg via subcutaneous injection approximately 24 hours after cytotoxic chemotherapy.
Nov. 16: The FDA gave an additional approval to Merck’s Keytruda in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma. The review was conducted under Project Orbis in collaboration with the Australian Therapeutic Goods Administration, Health Canada and Switzerland’s Swissmedic, and it used the Assessment Aid. The FDA granted orphan drug designation to the application. Dosing for the PD-1 inhibitor is 200 mg every three weeks via intravenous infusion or 400 mg every six weeks. The list price for dosing every three weeks is $11,115; for every six weeks, it is $22,230.
Nov. 27: The FDA approved SpringWorks Therapeutics, Inc.’s Ogsiveo (nirogacestat) for the treatment of adults with progressing desmoid tumors who require systemic treatment. The gamma secretase inhibitor is the first FDA-approved treatment for the tumors, which are locally aggressive and invasive soft-tissue tumors that in some cases may be life-threatening. The agency gave the application priority review, as well as breakthrough therapy, fast track and orphan drug designations. The FDA used the Real-Time Oncology Review program and the Assessment Aid. Dosing is 150 mg via three 50 mg tablets twice daily. The price of a 30-day supply is $29,000.
Nov. 29: The FDA approved Teva Pharmaceuticals USA, Inc.’s Alvaiz (eltrombopag) for the treatment of three indications: (1) thrombocytopenia in people at least 6 years old with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy; (2) thrombocytopenia in adults with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy; and (3) adults with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. It was approved via the 505(b)(2) pathway and is not substitutable with other eltrombopag products on a milligram per milligram basis. Dosing of the tablet for persistent or chronic ITP and for refractory severe aplastic anemia is 36 mg once daily; for chronic hepatitis C-associated thrombocytopenia, dosing is 18 mg once daily.
Dec. 1: The FDA gave accelerated approval to Eli Lilly and Co.’s Jaypirca (pirtobrutinib) for the treatment of adults with chronic lymphocytic leukemia or small lymphocytic leukemia who have received at least two lines of therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor and a B-cell leukemia/lymphoma-2 (BCL-2) inhibitor. The agency initially approved the non-covalent (reversible) BTK inhibitor on Jan. 27, 2023. Dosing for the tablet is 200 mg once daily. Drugs.com lists the price of 60 100 mg tablets as more than $22,122.
Dec. 1: The FDA expanded the use of Octapharma USA’s Wilate (von Willebrand factor/coagulation factor VIII complex [human]) to include its use as routine prophylaxis to reduce the frequency of bleeding episodes in people at least 6 years old with any type of von Willebrand disease. The agency first approved the therapy on Dec. 4, 2009. Recommended dosing of the intravenous infusion for the newest use is 20 to 40 IU/kg two or three times per week for people at least 6 years old and 20 to 40 IU/kg body weight every two to three days for adolescents and adults.
Dec. 5: The FDA approved Nanocopoeia, LLC’s Phyrago (dasatinib) for the treatment of adults with (1) newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase; (2) chronic, accelerated or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib; and (3) Ph+ acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. The tyrosine kinase inhibitor was approved via the 505(b)(2) pathway. Dosing of the tablet for chronic phase CML is 100 mg once daily; for accelerated phase CML, myeloid or lymphoid blast phase CML or Ph+ ALL, dosing is 140 mg once daily. In May 2022, Bristol Myers Squibb, manufacturer of Sprycel (dasatinib), filed a patent infringement lawsuit against Nanocopoeia. On Oct. 10, 2023, the companies entered into a confidential settlement agreement.
Dec. 5: The FDA approved Novartis Pharmaceuticals Corp.’s Fabhalta (iptacopan) for the treatment of adults with paroxysmal nocturnal hemoglobinuria. The complement factor B inhibitor is the first oral monotherapy for the indication. Dosing of the capsule is 200 mg twice daily. The drug’s annual wholesale acquisition cost is $550,000, and the company says it expects the drug to be available in the U.S. in December.
Dec. 6: The FDA approved Bio-Thera Solutions, Ltd.’s Avzivi (bevacizumab-tnjn) for the treatment of (1) metastatic colorectal cancer in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment; (2) metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in people who have progressed on a first-line bevacizumab product-containing regimen; (3) unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment; (4) recurrent glioblastoma in adults; (5) metastatic renal cell carcinoma in combination with interferon alfa; (6) persistent, recurrent or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan; and (7) epithelial ovarian, fallopian tube or primary peritoneal cancer in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan for platinum-resistant recurrent disease who received no more than two prior chemotherapy regimens. The VEGF inhibitor is the fifth FDA-approved biosimilar of Roche Group member Genentech USA, Inc.’s Avastin (bevacizumab). Sandoz will commercialize the agent.
Dec. 8: The FDA approved bluebird bio, Inc’s Lyfgenia (lovotibeglogene autotemcel; lovo-cel) for the treatment of sickle cell disease in people at least 12 years old who have a history of vaso-occlusive events. The autologous hematopoietic stem cell-based gene therapy is the company’s third FDA-approved ex vivo gene therapy for a rare genetic disease and second approval for an inherited hemoglobin disorder. The FDA gave the application priority review, orphan drug, fast track, regenerative medicine advanced therapy and rare pediatric disease designations. The therapy’s wholesale acquisition cost is $3.1 million for a one-time treatment, and bluebird will offer outcomes-based contracts to both commercial payers and Medicaid. Lyfgenia will be available through the manufacturer’s national network of qualified treatment centers starting in first-quarter 2024. The network now consists of 27 centers, with more expected to be activated by the end of the first quarter.
Dec. 8: The FDA approved Vertex Pharmaceuticals Inc. and CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel; exa-cel) for the treatment of sickle cell disease in people at least 12 years old with recurrent vaso-occlusive crises. The CRISPR/Cas9 genome-edited cell therapy is the first of its kind approved by the agency. The FDA gave the application priority review, orphan drug, fast track and regenerative medicine advanced therapy designations. The therapy’s wholesale acquisition cost is $2.2 million for a one-time treatment. Casgevy will be available through the manufacturer’s national network of authorized treatment centers. The network now consists of 10 centers, with more expected to be activated in the coming weeks.
]]>Samsung Bioepis Co., Ltd. settled all pending U.S. patent litigation with Johnson & Johnson over the latter’s Stelara (ustekinumab) and the former’s SB17, a biosimilar of the human interleukin-12 and -23 antagonist, Samsung Bioepis said Nov. 30. The company’s license period will begin Feb. 22, 2025; other terms of the agreement are confidential. SB17, which will be commercialized by Sandoz in the U.S., as well as other countries, is currently under FDA review. Three other companies also have revealed agreements with Johnson & Johnson for ustekinumab biosimilars. In May, Amgen said that it would be allowed to launch ABP 654 “no later than January 1st, 2025.” Then in June, Alvotech and Teva said that their AVT04 has a license entry date “no later than February 21, 2025.” And in August, Fresenius Kabi and Formycon revealed that they can launch FYB202 “no later than April 15, 2025.” According to the Nov. 1 edition of the U.S. Biosimilars Report from Cencora (formerly known as AmerisourceBergen), there are seven ustekinumab biosimilars in various stages of development. On Oct. 31, the FDA approved the first of them, Amgen’s ABP 654, known as Wezlana (ustekinumab-auub), as a biosimilar to and interchangeable with Stelara for both intravenous and subcutaneous administration and for all of its indications: the treatment of adults with moderately to severely active Crohn’s disease and moderately to severely active ulcerative colitis and the treatment of people at least 6 years old with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis.
Bayer issued a voluntary recall of one lot of Vitrakvi (larotrectinib) due to microbial contamination by Penicillium brevicompactum detected during stability testing, the company said Nov. 17. The recall impacts only Vitrakvi oral solution 20 mg/mL in 100 mL glass bottles with NDC No. 50419-392-01 and is identified with Lot No. 2114228 and an expiration date of February 29, 2024. That lot was distributed in the U.S. to wholesale distributors and specialty pharmacies between Jan. 3, 2023, and Feb. 13, 2023. The manufacturer said it had not gotten any information about adverse events tied to the recall.
Novartis Pharmaceuticals Corp. issued a voluntary recall of two lots of Sandimmune (cyclosporine) due to crystal formation in some bottles that could cause incorrect dosing, the company said Nov. 24. The recall impacts only the Sandimmune oral solution 100 mg/mL in 50 mL bottles with lot numbers FX001500, with an expiration date of September 2024, and FX001582, with an expiration date of September 2024, NDC No. 0078-0110-22. The lots were distributed in the U.S. to wholesalers beginning in January 2022 and September 2022, respectively.
]]>In contrast to the EU, whose European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) clarified in September 2022 that all biosimilars approved in the EU are interchangeable, the FDA has created two levels of biosimilars: biosimilars and interchangeable biosimilars.
]]>In contrast to the EU, whose European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) clarified in September 2022 that all biosimilars approved in the EU are interchangeable, the FDA has created two levels of biosimilars: biosimilars and interchangeable biosimilars.
The BPCIA requires that biosimilar manufacturers demonstrate that their drugs are “highly similar to the reference product notwithstanding minor differences in clinically inactive components,” safe, pure and potent. To be granted interchangeable status, drugmakers must demonstrate not only biosimilarity but also that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” Manufacturers must specifically apply for the interchangeable designation and provide data from these switching studies.
The FDA has granted the designation to only seven biosimilars so far: Biocon Biologics Inc.’s Semglee (insulin glargine-yfgn) and Eli Lilly and Co.’s Rezvoglar (insulin glargine-aglr), both of which reference Lantus (insulin glargine) from Sanofi US; Boehringer Ingelheim Pharmaceuticals, Inc.’s Cyltezo (adalimumab-adbm) and Pfizer Inc.’s Abrilada (adalimumab-afzb), both of which reference AbbVie Inc.’s Humira (adalimumab); Coherus BioSciences, Inc.’s Cimerli (ranibizumab-eqrn) and Biogen Inc. and Samsung Bioepis Co., Ltd.’s Byooviz (ranibizumab-nuna), both of which reference Lucentis (ranibizumab) from Genentech USA, Inc., a member of the Roche Group; and Amgen Inc.’s Wezlana (ustekinumab-auub), which references Stelara (ustekinumab) from the Janssen Pharmaceutical Companies of Johnson & Johnson.
Physicians must specifically prescribe biosimilars without interchangeable status. But agents with that designation may be dispensed at the pharmacy level without provider intervention. All 50 states, as well as Washington, D.C. and Puerto Rico, have enacted laws around interchangeable biosimilar substitution, with policies such as informing patients and physicians when a biosimilar is substituted without a prescription for that product.
On Sept. 15, the FDA released the draft guidance “Labeling for Biosimilar and Interchangeable Biosimilar Products.” It proposes various changes to the July 19, 2018, guidance “Labeling for Biosimilar Products,” which the new guidance will replace when finalized.
In the Federal Register notice (88 Fed. Reg. 63957 Sept. 18, 2023), the FDA explains that it “has gained valuable experience about labeling considerations for biosimilar and interchangeable biosimilar products” since it approved the first biosimilar, Sandoz’s Zarxio (filgrastim-sndz), on March 6, 2015. That experience has revealed issues around labeling of biosimilars and interchangeable biosimilars: “Determining how to appropriately label such products and keep labeling up to date without causing undue confusion has proven challenging,” it says.
“A demonstration of biosimilarity or interchangeability means, among other things, that FDA has determined that there are no clinically meaningful differences between the proposed product and the reference product in terms of safety, purity, and potency,” says the guidance.
It questions whether information explaining interchangeability on a drug’s label is useful for providers, “who can prescribe both biosimilar and interchangeable biosimilar products in place of the reference product with equal confidence that they are as safe and effective as their reference products.” Rather, that information “is more appropriately located” in the Purple Book Database of Licensed Biological Products, known simply as the Purple Book, which “has evolved as a resource for patients, pharmacists, physicians, and other health care providers to easily identify approved biosimilar and interchangeable biosimilar products.”
In addition, the guidance supports having the same biosimilarity statement for both biosimilars and interchangeable biosimilars on their labels. In line with this, the FDA also published the draft guidance “Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act,” which replaces the Q&A guidance issued on Nov. 19, 2020. The documents are the same except the new guidance withdraws the final two Q&As — which were on interchangeability labeling — that appeared in the initial guidance.
Comments are due by Nov. 17.
The new guidance is “surprising,” says Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth. While the FDA asserts that interchangeable biosimilars may help boost patients’ access to biologics, “by removing this designation from the product labeling, this may hinder prescriber and pharmacist ready access to this information at the point of patient care. Having information regarding interchangeable status available in multiple locations, including the product labeling, would provide valuable information regarding the product’s effectiveness and safety at the point of patient care and provide additional treatment considerations for the prescriber and patient.”
The interchangeability designation means that a biosimilar has undergone “an additional level of clinical testing,” he explains. “Having this information available in multiple locations, including the product labeling, provides additional clarity and data to the prescriber that should aid in their decision process. Prescribers typically do not reference or may not have knowledge of the Purple Book at the time of prescribing, so having the interchangeable designation available in both the Purple Book and the product labeling would be optimal for all parties. Not including this in the prescribing information may minimize the designation’s significance.”
He tells AIS Health, a division of MMIT, that “physicians may already be prescribing non-interchangeable biosimilars in an interchangeable fashion, and that distinction between the two is potentially confusing to prescribers.” Education on the differences between biosimilars and interchangeable biosimilars, as well as offering that information in a variety of places, “would likely benefit all parties and likely encourage the further adoption of biosimilars.”
Karina Abdallah, Pharm.D., senior director of the access experience team at PRECISIONvalue, says she is not surprised that the FDA issued the guidance, because in the time since the 2018 guidance was released, “the FDA’s interchangeability designation for biosimilars caused numerous debates among industry stakeholders (e.g., manufacturers and prescribers). With five years’ time since the last guidance, the industry was due for further clarification from the FDA.” Through the new guidance, the FDA is “attempting to promote [the] overall use of biosimilars, and it will be very telling when stakeholders (prescribers and manufacturers) provide comments for us to gauge the industry’s alignment with the FDA’s reasoning.”
Data from the switching studies that interchangeable biosimilars undergo in order to gain that designation assists the FDA in evaluating the safety of a pharmacist substituting a drug, but it “does not mean that an interchangeable biosimilar is safer or more effective than other biosimilars,” says Szczotka. The FDA’s proposal to have the same biosimilarity statement for both biosimilars and interchangeable biosimilars “does not appear to reflect the additional effectiveness and safety information that was conducted and reviewed by the FDA” for interchangeable agents. “This appears to diminish the additional testing conducted and does not provide incentives to the pharmaceutical manufacturers to undergo this process if they are provided the same status in product labeling as other biosimilar products that did not conduct these testing and switching studies.”
Having the same biosimilarity statement, says Ryan Clements, managing director at KPMG US, “diminishes the advantage that those with interchangeable designations have over those that do not. This is in line with efforts and policy to encourage competition and create greater access within the biosimilars market. It allows for the availability of more biosimilars entering the market, which in turn reduces price. Additionally, it lowers the cost burden to develop biosimilars, which ultimately lowers the cost for patients.”
Some of those efforts to level the biosimilar playing field are taking place in Congress.
For example, in the Consolidated Appropriations Act of 2023, H.R.2617, which was enacted on Dec. 29, 2022, Congress amended the BPCIA to change the wording around one-year exclusivity granted to the first interchangeable biosimilar for a product to expand that exclusivity to include any other interchangeable biosimilar approved on the same day as the first.
In addition, in July, Sen. Mike Lee (R-Utah) reintroduced the Biosimilar Red Tape Elimination Act (S. 2305). The legislation is focused on increasing competition among biologics and lowering consumer costs for them.
He first introduced the bill on Nov. 17, 2022, with the initial version focused on doing away with the FDA requirement for switching studies for biosimilars seeking the interchangeability designation. In a press release when the bill was first introduced, Lee claimed that the process companies need to undergo to get that designation is “cumbersome and expensive.…Eliminating this barrier would increase access to lower-cost biosimilars and save payers and consumers billions over the next five years.”
The reintroduced legislation, however, seeks to simply “deem biosimilars as interchangeable with their branded equivalent upon their approval by the FDA.”
The legislation, which has bipartisan support, has been referred to the Senate Committee on Health, Education, Labor, and Pensions.
When the bill was first introduced, Sarfaraz Niazi, Ph.D., an adjunct professor of biopharmaceutical sciences at the College of Pharmacy at the University of Illinois Chicago, pointed out that “according to the FDA, ‘biosimilars have no clinically meaningful difference with their reference product,’ so if there is no difference, they should be interchangeable without the extensive and expensive switching and alternating studies in patients.…Creating two classes of biosimilars has weakened the trust in biosimilars.”
So might the FDA do away with the interchangeable label entirely?
The FDA did not respond to an AIS Health request for comment on this issue, as well as other questions about the guidance.
Discarding the label could help streamline providers’ decision making and prescribing, states Szczotka. However, it also “may add confusion to the dispensing process depending upon the respective state laws. This may add additional processes for the pharmacy to ensure compliance with respective state laws. Pharmaceutical manufacturers may benefit from not having to conduct the additional studies if this designation was removed and potentially pass along these savings to the health care system,” he says, but at the same time, it “would not allow for any potential points of differentiation among similar biosimilar products.”
“The interchangeability label beyond biosimilars is deeply ingrained in the ways products get to patients,” asserts Clements. “Doing away with the label entirely would represent a big shift in the ways stakeholders interact with each other.”
“Impact on stakeholders would vary significantly, including how manufacturers negotiate price, offer rebates, prioritize formulary placement and develop access and adherence strategies,” he contends. “Wholesalers and PBMs would have less advantage in negotiating rebates, and much of the PBMs’ profit levers would be threatened by their ability to leverage control of formulary placement for profit. This could lead to price discounts, which would help patients from an affordability perspective similar to classic generic small molecule products.”
Without the interchangeability designation, physicians “would likely see biosimilars as comparable,…and they may feel more comfortable prescribing them more broadly. This could create opportunity for more innovative contracting options.”
Abdallah has a different take. Removing the designation on labeling “may diminish confidence in some providers to prescribe and administer biosimilars or may discourage their use,” she maintains. “Any potential impact on the uptake of a product could also impact payers’ coverage and product preferencing positions, which may in turn also stifle manufacturers’ appetite for the biosimilar market.”
Clements says that with the large amount of professionally administered biosimilars in the pipeline, particularly in the immunology arena, the label change could have more of an impact on Part B agents.
However, says Szczotka, Part D biosimilars will experience more of an effect, as pharmacists may be incentivized to stick with the reference drug. “Products dispensed through a pharmacy distribution channel have a greater potential for substitution at the point of dispensing, and the lack of clarity of an interchangeable status for a product may increase the likelihood of the reference product being dispensed as opposed to the interchangeable biosimilar being substituted. This may result in the lack of opportunity to capitalize on potential cost savings to the health care system and added costs for the patient and payer.”
With biosimilars administered by a health care professional, interchangeability “has played less of a role, and institutions and medical policy decision makers have been more willing to embrace biosimilars because of their ability to reduce costs,” explains Abdallah.
Only one of the five biosimilars with the interchangeability designation falls under Part B.
Once the proposed draft is finalized, Abdallah says, “it may take some time to trickle down to individual state boards that regulate pharmacist substitution laws. Pharmacy benefit biosimilars would be dispensed most often by pharmacists at the point of sale for retail, specialty and home delivery pharmacies. An inability for a pharmacy to automatically substitute a biosimilar for a reference product at the point of sale on the pharmacy benefit may negatively impact anticipated share shift and continue to be a challenge for payers and prescribers.”
State laws regarding the substitution of interchangeable biosimilars are not likely to be impacted by the labeling change, Szczotka says, because that information would remain available via the Purple Book. Clements maintains that those state laws “will need to align with federal laws more closely in order for the policy to be impactful.”
Abdallah notes that when the draft guidance is finalized, it will reflect the FDA’s current thinking on the issue. However, she says, “it does not establish any rights for any person and is not binding on FDA or the public. Therefore, individual state boards that regulate pharmacist substitution laws may be tasked with making regulatory updates, and this may take significant time and lead to state-by-state differentiation.”
Some of that effort may fall to Prescription Drug Affordability Boards (PDABs), nongovernmental state-level entities tasked with finding affordability solutions for prescription drugs, she says. Seven states — Colorado, Maine, Maryland, New Hampshire, Ohio, Oregon and Washington — have enacted laws establishing PDABs, which “are state specific and differ in funding, authority and structure,” explains Abdallah. “These PDABs may also play a significant role in establishing state laws regarding the substitution of interchangeable biosimilars to align with their charters — to make prescription drugs more affordable.”
While the impact on pharma manufacturers may be somewhat clear, potential payer repercussions of a change to interchangeability labeling are a bit murkier.
If finalized, the proposed guidance update is not likely to have a direct impact on payers’ coverage of biosimilars, says Szczotka. Rather, they “will likely continue to cover and encourage the use of biosimilars, when clinically and medically appropriate, as an alternative to the reference product. The proposed modification would not affect the designation of interchangeability, just the locations on where this designation would be located.” That said, interchangeable biosimilars’ uptake “may be more difficult due to the lack of clarity of substitution opportunities at the pharmacy level.”
“Any obstacles to prescribers or manufacturers that may negatively impact anticipated share shift in a biosimilar (or interchangeable) product will continue to be a challenge for payers,” Abdallah tells AIS Health. “For payers to adequately revise budget modeling (inclusive of rebated reference products vs. biosimilar products), they need to predict market share shift with some degree of confidence. Therefore, any prescribing confusion due to labeling changes, or lack of manufacturer investment into a biosimilar product, could be predicted as unstable and may impact payer coverage decisions and product preferencing.”
“Ultimately, this guidance update appears to be an attempt to address confusion and perhaps increase biosimilar usage,” she says, citing the FDA’s reassurances about prescribing both biosimilars and interchangeable biosimilars “‘with equal confidence that they are as safe and effective as their reference products.’ The success, impact to the market and adoption of these suggestions will be something to watch as affordability continues to take main stage.”
Contact Abdallah through Andie Lunkenheimer at andie.lunkenheimer@gcihealth.com, Clements via Marissa Ross at marissaross@KPMG.com and Szczotka via Caroline Chambers at cchambers@cpronline.com.
]]>On Sept. 29, the FDA approved Bio-Thera and Biogen Inc.’s Tofidence (tocilizumab-bavi) intravenous formulation for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to at least one disease-modifying antirheumatic drug (DMARD), people at least 2 years old with active polyarticular juvenile idiopathic arthritis and people at least 2 years old with active systemic juvenile idiopathic arthritis. Dosing of the intravenous infusion is based on the indication.
]]>On Sept. 29, the FDA approved Bio-Thera and Biogen Inc.’s Tofidence (tocilizumab-bavi) intravenous formulation for the treatment of adults with moderately to severely active RA who have had an inadequate response to at least one disease-modifying antirheumatic drug (DMARD), people at least 2 years old with active polyarticular juvenile idiopathic arthritis and people at least 2 years old with active systemic juvenile idiopathic arthritis. Dosing of the intravenous infusion is based on the indication.
It is the first FDA-approved biosimilar of interleukin-6 inhibitor Actemra, which is approved in both intravenous and subcutaneous formulations. In addition, the reference drug has four other FDA-approved indications: (1) treating adults with giant cell arteritis, (2) slowing the rate of decline in pulmonary function in adults with systemic sclerosis-associated interstitial lung disease, (3) treating people at least 2 years old with chimeric antigen receptor T-cell (CAR-T)-induced severe or life-threatening cytokine release syndrome (CRS), and (4) treating hospitalized adults with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
Biogen will commercialize Tofidence in the U.S., and the company said it is “evaluating the potential launch timeline” for the agent. As of AIS Health deadline, Tofidence had yet to launch. During Roche’s Oct. 19 call to discuss third-quarter results, CEO Thomas Schinecker said the company expected U.S. biosimilar competition for Actemra next year.
The launch delay may be due to a patent infringement lawsuit (No. 1:23-cv-11573) that Roche, Genentech and Chugai Pharmaceutical filed against Biogen and Bio-Thera on July 13. Just over three months later, on Oct. 23, the companies settled the case but did not provide details of the settlement.
For the Managed Care Biologics & Injectables Index: Q2 2023, from May 24, 2023, to June 30, 2023, Zitter Insights polled 36 commercial payers covering 116.6 million lives, 29 Medicare payers representing 43.3 million lives and 50 rheumatologists about their management and prescribing of RA therapies, including the anticipated impact of Tofidence. Payers representing 87% of commercial lives and 72% of Medicare beneficiaries rated managing branded RA treatments as a high or very high priority.
Payers with approximately three-quarters of commercial and Medicare lives said that they were either somewhat or moderately aware of Tofidence, which is also known as BAT1806. That’s compared with 30% of rheumatologists who ranked their awareness at a similar level.
Both AIS Health and Zitter Insights are divisions of MMIT.
Payers varied on their estimations of the biosimilar’s impact on available RA drugs, although none said they expected it to have a very high impact (see chart). The majority of rheumatologists — 58% — said they expect that Tofidence will have some impact on their treatment approach for patients, meaning that they anticipate it will remain mostly unchanged, but they may alter it with select current patients.
Industry experts tell AIS Health that they also expect Tofidence to have an impact on payer management of the agent’s approved indications, but the drug’s single formulation may hamper its uptake.
The biosimilar, says Mesfin Tegenu, CEO and chairman of RxParadigm, Inc., “offers patients with chronic autoimmune conditions a new treatment option that has proven safety and efficacy to Actemra at a potentially more affordable cost. The increasing number of biosimilar approvals will help foster competition within the market, which can lead to increased patient access and affordability, improved adherence and reduced health care costs.”
As of late October, the FDA had approved 43 biosimilars. Tofidence’s approval came about one month after the approval of Polypharma Biologics and Sandoz Inc.’s Tyruko (natalizumab-sztn), the first biosimilar for Biogen’s Tysabri (natalizumab).
According to the Sept. 1 edition of the U.S. Biosimilars Report from Cencora (formerly known as AmerisourceBergen), two other Actemra biosimilars are in the pipeline: Fresenius Kabi’s MSB11456, which is awaiting an FDA decision, and Celltrion USA’s CT-P47, which is in Phase III trials with both subcutaneous and intravenous formulations.
In August 2022, Fresenius Kabi revealed that the FDA had accepted the company’s Biologics License Review (BLA) for MSB11456 for review in both subcutaneous and intravenous formulations. The company said it expects FDA approval this year. More recently, on Sept. 19, the company disclosed that the European Commission (EC) granted marketing authorization to the drug, which is known as Tyenne. It is indicated for the treatment of RA, systemic juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, giant cell arteritis, CAR-T cell-induced severe or life-threatening CRS and COVID-19.
Celltrion’s CT-P47 will seek approval for RA, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis and CRS.
According to Winston Wong, Pharm.D., president of W-Squared Group, spending on drugs for autoimmune conditions has been increasing per year by 10% to 25% over the past decade. The new biosimilar offers “a potential for price erosion. At an estimated cost of $5,300 for a single 162 mg injection, the annual cost per patient for Actemra could reach $275,000. Thus, aside from payers controlling the drug markup or shifting patients to more cost-efficient alternative sites of care, the cost of the drug can play a significant role in reducing the total cost of care, as well as having an impact for patients with co-insurance liability.”
The level of savings, he says, “will depend upon the price point of Tofidence vs. the level of aggressiveness Genentech wishes to discount the product to keep their market share. Whichever the case, the reduced price will result in cost savings.”
“As the first biosimilar of Actemra approved by FDA, Tofidence represents a significant opportunity to help generate more access for patients, more choice for doctors and more savings to support the health care systems,” a spokesperson for Biogen says.
Both Wong and Tegenu say that the lack of a subcutaneous version of the biosimilar could impact uptake of the drug. Tegenu points out that other biosimilars, such as those of AbbVie Inc.’s tumor necrosis factor (TNF) inhibitor Humira (adalimumab), are available as self-administered injections and have FDA approval for two of Tofidence’s three indications. “Many patients prefer subcutaneous administration for various reasons, such as convenience, flexibility and comfort,” he observes. “Furthermore, since Tofidence is an intravenous infusion that must be administered by a health care professional, it could come with higher overall treatment costs.”
Wong notes that there is a growing trend toward the use of subcutaneous over IV administration overall. In addition to a self-administered injection offering a lesser cost to payers, it “lends itself to tighter control of utilization and the ability to negotiate discounts, as it will be managed through the prescription benefit. In short, the transparency of billing through the prescription benefit enables easier adjudication and time-sensitive management of claims, as well as allowing for more accurate billing and better cost management.” He also observes that subcutaneous Actemra use appears to be higher than that of the IV formulation.
Asked if Biogen is developing a subcutaneous version of Tofidence, the spokesperson says the company “can’t comment on future development plans for Tofidence at the moment.”
Among all of Actemra’s indications, RA has the most use, says Tegenu. But as far as where Tofidence may have the most uptake, he points to systemic juvenile idiopathic arthritis because the agent is the only biosimilar with that indication on its label.
The Biogen spokesperson tells AIS Health that the indications on Tofidence’s label “are those we elected to seek approval at this time, and we can’t comment on” whether the company is planning to apply for approval in any of the other Actemra indications. Actemra’s label allows for IV dosing for giant cell arteritis, CRS and COVID-19.
Other IL-6 inhibitors are available, including Kevzara (sarilumab) from Sanofi and Regeneron Pharmaceuticals, Inc., which is a subcutaneous formulation approved for (1) adults with moderately to severely active RA who have had an inadequate response or intolerance to one or more DMARDs, and (2) adults with polymyalgia rheumatica who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.
Tegenu says that randomized controlled trials have found that IL-6 inhibitors are superior to TNFs “as monotherapy in biologic-naïve RA patients who had an inadequate response/intolerance to methotrexate.” However, among biologic-experienced people with RA, limited data exists comparing the two mechanisms of action. “Additionally, there have been no head-to-head trials comparing IL-6 inhibitors to Janus kinase inhibitors in RA patients, but IL-6 inhibitors are generally preferred over JAK inhibitors due to long-term safety concerns.”
Methotrexate is the first line of treatment for RA, and IL-6 inhibitors are an option in the second-line space, says Tegenu. He notes that the 2021 American College of Rheumatology guidelines recommend the addition of a DMARD such as a TNF or IL-6 inhibitor or a targeted systemic DMARD such as a JAK inhibitor to the treatment regimen “for patients who have taken maximally tolerated doses of methotrexate and are not at target. The guidelines do not specify one drug class over another.
“IL-6 inhibitors are generally on formularies; however, there may be variations in tiering,” he continues. “Utilization management strategies such as prior authorization and quantity limits are often implemented to ensure appropriate use with formulary placement in the specialty tier.” The agents also are dispensed via a specialty pharmacy, points out Wong.
For payers considering putting Tofidence on formulary, price is likely to be the top factor, says Tegenu. “Because formulary placement is heavily driven by rebates/costs, Tofidence would need to have significant rebate discounts or be priced aggressively lower than the reference product to ensure formulary placement.”
In addition to the lack of a subcutaneous formulation, Wong agrees that final cost will be a determining factor. “The question of cost will depend upon the initial price offering by Biogen, followed by the negotiations with both Biogen and Genentech to arrive at the final net cost. The real question is whether there would be a scenario where the subcutaneous formulation could stay with Genentech, and the infusion would move to the biosimilar. However, even under this scenario, Actemra has indications that were not carried over to Tofidence; hence, I would not be confident that even a split-line strategy will be successful either.”
For more information on the Zitter Insights data, contact Jill Brown Kettler at jkettler@mmitnetwork.com. Contact Tegenu at Mesfin.Tegenu@rxparadigm.com and Wong at w2sqgroup@gmail.com.
]]>“2023 was a banner year for the biosimilar market,” contends Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth. “The availability of biosimilars across multiple therapeutic areas provides opportunities for physicians, patients and payers to have additional clinical and cost-saving treatment choices.”
In a span of just more than two months in the second half of the year, the FDA approved Tysabri biosimilar Tyruko (natalizumab-sztn) from Sandoz and Polypharma Biologics, Actemra biosimilar Tofidence (tocilizumab-bavi) from Bio-Thera and Biogen and Stelara biosimilar Wezlana (ustekinumab-auub) from Amgen Inc.
Szczotka points to a recently published study that “found no differences in terms of major safety parameters such as death, significant adverse effect and discontinuation when patients were switched to or from a biosimilar and its reference product or not switched. It was interesting to note that this was found across multiple therapeutic areas and was independent of the reference product class, the direction of the switch or following one or multiple switches.” Such data should help ease any concerns around the drugs’ use and help boost uptake.
“As more biosimilars enter the U.S. market, we are seeing more uptake of biosimilar use,” observes Renee Rayburg, R.Ph., vice president of specialty clinical consulting at Pharmaceutical Strategies Group (PSG), an EPIC company. Citing data from Artemetrx, PSG’s proprietary integrated data platform, she says that “biosimilar optimization increased from 20.5% to 26.3% in 2021 and 2022, respectively,” with the biggest uptake occurring with biosimilars of Genentech and Biogen’s Rituxan (rituximab) and Genentech’s Herceptin (trastuzumab). “Overall, the highest utilization of biosimilars is for Herceptin at 85.8%, and the lowest is for Remicade at 12.6%,” she states, citing the most recent Artemetrx Specialty Spend & Trend Report, which was published this summer.
In addition, she tells AIS Health, a division of MMIT, the competition posed by biosimilars is driving down the average sales price (ASP) for some of the reference drugs, as seen with the Janssen Pharmaceutical Companies of Johnson & Johnson’s Remicade (infliximab) and Amgen’s Neulasta (pegfilgrastim).
Multiple manufacturers, particularly with the adalimumab biosimilars, are offering both low wholesale acquisition cost/low rebate and high WAC/high rebate products. However, says Rayburg, evidence does not yet exist that payers are selecting the low WAC/low rebate offerings. “There seems to be interest from the payer perspective in more transparency,” she says. “Consequently, there may be interest in upfront savings and avoiding the complexities of rebates in the future. This strategy can also benefit their members enrolled in high deductible plans where their cost share will be lower based on a lower list price.”
She notes that these companies also are under pressure to provide, “at a minimum, the same level of service as the brand manufacturers, including patient support services and even copay assistance programs on top of the lower pricing. This can be appealing to a payer to add to their savings. Which seems to be most effective? Manufacturers who can match sufficient supply to keep up with the demand, patient support services equivalent to that of the brand manufacturers and optimal pricing to deliver savings will have a much better chance.”
A variety of factors may differentiate biosimilars both from each other as well as the reference drug. For example, most of Humira’s use is for a high-concentration formulation, but not all of its biosimilars are approved for it, with most of them having only a low-concentration version. In addition, only two of the nine available adalimumabs have interchangeable status. With the exception of the seven Humira biosimilars that launched in the beginning of July, most of the available biosimilars have come onto the market at different times, sometimes years apart. Other factors include type of administration device and rebates. So what is most important to payers?
Rayburg points out that PBMs are the main decision maker due to their role in rebating and contracting. “While payers in this situation can ask questions and pressure the PBM, they have little say in the final decisions.”
While many factors play a role, she says, “the contracting/negotiating and decisions come down to the lowest net cost product, which is reliant on competition, more products entering the market and competing. That’s where those other elements could make some difference. The expectation, however, is that if members are expected to transition to a biosimilar, they will receive an equivalent product in efficacy, supply, ease of use (device), patient support services, etc. I am not sure the market entry timing impacted Amgen and Amjevita as the first to enter the [Humira] market.” With small molecule drugs, the first generic to launch usually has the most share, but “in this case, the biosimilars are also competing against the brand, and Humira brand’s continued coverage has widely limited the uptake of any Humira biosimilars. Amjevita has seen little to no advantage for being first in the market.”
Szczotka agrees that cost — both gross cost and net after rebates — is a main consideration. “Biosimilars, while offering a safe and clinically effective product, traditionally have offered a list cost that is a discount to the reference product but may or may not be the lowest net cost option for that product or class and/or provide enough incentive for all the costs and impacts involved with a product switch. Payers will continually need to align that products available are not only safe and clinically effective, but also provide a cost-effective option. As market dynamics change, payers will reevaluate coverage decisions to ensure alignment.”
While nine Humira biosimilars have launched in the U.S. so far, industry experts did not expect the agents to have an immediate impact on payer coverage. Looking ahead to 2024, Szczotka points out that additional adalimumabs are expected and “will provide additional options for the higher concentration product, along with potential interchangeable designations. Payers will continue to evaluate their options amongst the adalimumab products to align their coverage strategy to ensure choices of product selection and cost. The anticipated arrival of multiple FDA-approved interchangeable products will be welcomed by payers, as long as they continue to provide a cost-competitive option. In 2024, payers will likely continue coverage of both reference and biosimilar product(s) to ensure therapy continuation and options for physicians and patients.”
Rayburg says that it may be difficult to anticipate what will happen, but “I think many will be watching the new CVS arrangement with its new subsidiary Cordavis and the white labeling of Sandoz’s Humira biosimilar. Will this be the beginning of transitioning patients to secure savings? How will AbbVie compete in that scenario? CVS has promised savings for clients in 2024, so there is expectation around how they will make that happen.”
Perhaps other PBMs may require a step through a biosimilar before Humira, says Rayburg. That said, PSG does “not have any information to confirm that will happen, and as long as AbbVie keeps pricing competitive, this may not happen to a great extent. There is tremendous competition in pricing” among the adalimumabs, with some priced at a discount around 85% off Humira. “It may take more than just Mark Cuban’s Cost Plus company to move the needle and figure out the best ways to optimize the savings that the presence of these biosimilars is creating.”
Over the last few years, PSG’s State of Specialty Spend and Trend reports have found drugs for inflammatory conditions to be the No. 1 category of specialty spend for most payers, so biosimilars of any of these agents would be significant, including Tofidence and biosimilars of Stelara, says Rayburg. This year’s report had Stelara at No. 2 behind Humira in the list of the top 10 specialty drugs by spend. She also points to biosimilars for Simponi Aria (golimumab) from the Janssen Pharmaceutical Companies of Johnson & Johnson and UCB, Inc.’s Cimzia (certolizumab pegol), with anticipated approvals “in the next year or so.”
Szczotka agrees on the significance of Tofidence and the ustekinumab biosimilars. “Stelara has been Johnson & Johnson’s (J&J) top-selling drug since 2019, with global sales reaching $9.7 billion in 2022,” says Szczotka.
The FDA approved the first Stelara biosimilar shortly before AIS Health press time: On Oct. 31, the agency approved Amgen’s Wezlana (ustekinumab-auub) as biosimilar to and interchangeable with Stelara. In May, following the settlement of patent lawsuits with Johnson & Johnson, Amgen said that it would be allowed to launch the agent “no later than January 1st, 2025.”
According to the Sept. 1 edition of the U.S. Biosimilars Report from Cencora (formerly known as AmerisourceBergen), there are seven additional ustekinumab biosimilars in various stages of development. In addition, Celltrion and Rani Therapeutics said earlier this year that they are developing an oral formulation of ustekinumab for psoriasis, Crohn’s and ulcerative colitis known as RT-111 that utilizes the latter’s robotic RaniPill capsule.
Two other companies developing a ustekinumab biosimilar also have settled patent lawsuits. In June, Alvotech and Teva said that their AVT04 has a license entry date “no later than February 21, 2025.” Most recently, Fresenius Kabi and Formycon revealed that they can launch FYB202 “no later than April 15, 2025.”
“While J&J seems to be managing a staggered release of the biosimilars into the marketplace in 2025, the number of manufacturers available in a relatively short time frame has the potential to create a variety of pricing strategies similar to the scenarios created when numerous adalimumab products launched in July,” observes Szczotka. “This should ultimately increase competition and provide physicians and patients with additional ustekinumab treatment options.” He notes that information about delivery devices and product formulation components for the ustekinumab biosimilars are not yet known at this point, and those have the potential to impact how significant those launches are.
Tofidence was approved Sept. 29 in an intravenous formulation for three of the seven indications of Actemra, which is approved in both IV and subcutaneous formulations. Biogen is “evaluating the potential launch timeline” for the agent; as of AIS Health deadline, the biosimilar had yet to launch. During Roche’s Oct. 19 call to discuss third-quarter results, CEO Thomas Schinecker said the company expected U.S. biosimilar competition for Actemra next year.
The launch delay may be due to a patent infringement lawsuit (No. 1:23-cv-11573) that Roche, Genentech and Chugai Pharmaceutical filed against Biogen and Bio-Thera on July 13. Just over three months later, on Oct. 23, the companies settled the case but did not provide details of the settlement. “The outcome of this litigation will likely be a significant factor on the launch of Tofidence,” maintains Szczotka.
“In 2022, Actemra sales declined as compared to 2021, but still represented over $1.2 billion in sales,” he says. “The biosimilar will provide another infusible product option in the anti-inflammatory category when it finally becomes market available.”
Szczotka also points to Udenyca Onbody (pegfilgrastim-cbqv), an on-body injector from Coherus BioSciences, Inc. Udenyca is one of five available biosimilars of Neulasta. But because of the Neulasta Onpro on-body injector, the reference drug has “maintain[ed] significant market share,” states Szczotka. Pegfilgrastim is given the day after a person receives chemotherapy to decrease the incidence of infection, and Neulasta Onpro automatically delivers a dose 27 hours after it is applied to a patient’s skin.
“There are certain types of cancer patients — those who live far away, have an active lifestyle or who are supporting the needs of a busy family — for whom the Neulasta Onpro eliminates the need to return to the clinic the day after completing a chemotherapy cycle for a dose of pegfilgrastim,” Szczotka says. If Udenyca Onbody is approved, it “would offer providers the same highly desired alternative delivery system to Neulasta’s Onpro at a presumably lower price.”
“Biosimilar adoption continues to grow and expand across all available therapeutic areas, and this will continue to be seen as more biosimilars gain FDA approval and become market available in new products and therapeutic categories,” predicts Szczotka. “Cost savings achieved with biosimilars can be used to help stretch the health care dollar. While the future impact may not rival the adalimumab biosimilar opportunity, biosimilars will continue to bring cost-saving opportunities to payers and patients.”
Contact Rayburg via Monica Estrada at monica@gregoryfca.com and Szczotka via Caroline Chambers at cchambers@cpronline.com.
]]>The 85% of respondents whose PBMs provide both specialty and traditional pharmacy benefit management ranked formulary management of specialty drugs and financial reporting in the pharmacy benefit as the services they were most satisfied with, while they were least satisfied with management of specialty agents in the medical benefit and offering competitive discounts on specialty medications.
]]>The 85% of respondents whose PBMs provide both specialty and traditional pharmacy benefit management ranked formulary management of specialty drugs and financial reporting in the pharmacy benefit as the services they were most satisfied with, while they were least satisfied with management of specialty agents in the medical benefit and offering competitive discounts on specialty medications.
The survey was conducted in May and June of 2023 and included 229 benefits leaders representing employers, health plans, health systems, and unions/Taft-Hartley plans. The report reveals that satisfaction with PBMs is the lowest it’s been in almost a decade,
In 2022, 30% of respondents said that their PBM offered alternative funding programs, which rose to 38% in the most recent report. Similarly, 24% said last year that their PBM offered gene therapy financial protection programs, which increased to 34% in 2023.
Thirty-three percent of respondents this year said they use copay accumulators, 31% use copay maximizers, and 24% use medical benefit management programs. Sixteen percent use alternative funding programs. Satisfaction with all of these offerings varied, with 89% of people saying they were satisfied with accumulators.
AIS Health, a division of MMIT, spoke with Morgan Lee, Ph.D., senior director of Research & Strategy at PSG, about these and some of the report’s other findings.
AIS Health: Were there any particularly interesting and/or surprising findings in the report?
Lee: The continued declines in high-level measures of satisfaction such as overall satisfaction, likelihood to recommend and likelihood to renew the PBM contract were very interesting and show that factors like rising drug trend and negative public attention are likely having an impact on payers' perceptions of their PBMs. It was also interesting to note that employers were more satisfied with their PBMs than health plans nearly across the board on both high-level measures and more specific services and functions. Finally, we think it's notable that respondents showed substantial interest in carving out specialty pharmacy and rebate management.
AIS Health: When undergoing a competitive request for proposal (RFP) process for a PBM, what do payers need to know? Is there anything they may not understand/incorrectly focus on?
Lee: The competitive RFP process is critically important for payers. There are many things to consider, and it would be difficult to list them all. At the highest level, payers should view the RFP process as an opportunity to ensure that their pharmacy program fully aligns with their strategic priorities as an organization. For health plans, this may mean ensuring their PBM partner is fully aligned with their growth strategies. Employers may consider how the PBM’s business model aligns with…the organization’s desired member experience and ability to manage the benefit. The reason we evaluate so many parameters in this satisfaction report is that there is no perfect PBM. Each one has different strengths and weaknesses. Ensuring alignment with what is most important to your organization is the desired outcome of the RFP process.
AIS Health: Could you please comment on the finding that 15% of respondents carve out specialty drugs from their PBM and 26% were considering doing this?
Lee: Health care payers have been interested in and tested models where aspects of the PBM bundled services are carved out from the core PBM agreement. Often, specialty drugs are a primary consideration due to their cost and complexity, especially as it relates to the member experience. Recently, we saw one of the largest health plans in the country unbundle all PBM services. This survey took place before that announcement, so the numbers are not reflective of a market response to that news. However, this is a trend that we will continue to observe and anticipate continued interest and engagement in testing out carved out services, especially for health plans.
AIS Health: The report shows low awareness and use of gene therapy financial protection programs but high overall satisfaction with them. Could you comment on that, please?
Lee: Gene therapy financial protection products are relatively new to the market, and not all PBMs have such offerings at this time. Additionally, payers, especially employers, are just beginning to recognize the potential impact of gene therapies, so this may not yet be on the radar for some. High satisfaction with existing gene therapy financial protection programs is encouraging, but keep in mind that just 9% of respondents are using such a program, so this finding should be interpreted cautiously.
AIS Health: Could you please comment on the medical benefit management findings?
Lee: Medical benefit management is middle of the pack in terms of clinical and cost management programs satisfaction. Overall satisfaction with medical benefit management decreased slightly from 2022 to 2023, but satisfaction with clinical outcomes of medical benefit management increased slightly in the same time frame.
AIS Health: What are takeaways from this report for payers? For PBMs?
Lee: For payers, the takeaways are to carefully consider your priorities and needs when selecting a PBM and have open communication about concerns and areas of need once you are in a contract with a PBM. For PBMs, it's to recognize that payers are looking for proactive and transparent partnerships with their PBMs as they face challenges in drug benefit management, and they want more innovative approaches to addressing these challenges.
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