FDA Grants Interchangeable Status to Humira Biosimilar, but Certain Factors May Hamper Its, Other Adalimumabs’ Uptake

Less than three months after granting interchangeable status to a biosimilar for the first time, the FDA has approved that status for a second biosimilar, Boehringer Ingelheim Pharmaceuticals, Inc.’s Cyltezo (adalimumab-adbm). It and multiple other biosimilars of AbbVie Inc.’s Humira (adalimumab) are slated to come onto the U.S. market in 2023, but plans should be preparing now for the drugs’ launches, say industry experts. Still, a handful of factors could pose an issue with the agents’ taking market share from the reference product.

On Oct. 15, 2021, the FDA granted interchangeability status to Cyltezo for all of its approved uses. Boehringer Ingelheim’s Phase III VOLTAIRE-X clinical trial found no meaningful clinical differences in pharmacokinetics, efficacy, immunogenicity and safety over multiple switches between Humira and Cyltezo. Per the Biologics Price Competition and Innovation Act (BPCIA) of 2009, the drug will have one year of exclusivity upon launch during which the FDA cannot grant interchangeable status to another Humira biosimilar.

In a statement on the status change for Cyltezo, Janet Woodcock, M.D., the FDA’s acting commissioner, commented that “the biosimilar and interchangeable approval pathway was created to help increase access to treatment options for patients with serious medical conditions. We continue to be steadfast in our commitment to provide patients with alternative high-quality, affordable medications that are proven to be safe and effective.”

“Overall, the granting of interchangeable status for Cyltezo is momentous and groundbreaking,” declares Lynn Nishida, R.Ph., head of clinical operations at Evio, “not to mention that it will allow more flexibility of options to be considered to that of Humira, since pharmacies may be able to substitute Cyltezo for Humira (as a least costly option),” barring state law restrictions.

Physicians must specifically prescribe biosimilars without interchangeable status. But agents with that designation may be dispensed at the pharmacy level without provider intervention. However, as of earlier this year, every state and Puerto Rico had 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.

The FDA initially approved Cyltezo, a subcutaneous injectable, on Aug. 25, 2017, for eight of Humira’s 11 indications:

(1) Adults with moderately to severely active rheumatoid arthritis,

(2) Adults with active psoriatic arthritis,

(3) Adults with active ankylosing spondylitis,

(4) Adults with moderately to severely active Crohn’s disease,

(5) Adults with moderately to severely active ulcerative colitis,

(6) Adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate,

(7) Pediatric patients at least 2 years old with moderately to severely active polyarticular juvenile idiopathic arthritis, and

(8) Pediatric patients at least 6 years old with moderately to severely active Crohn’s disease.

The 351(k) biosimilar pathway was created through the BPCIA, which was included in the Affordable Care Act, which then-President Barack Obama signed into law March 23, 2010. But it took nearly five years for the FDA to approve the first biosimilar — Novartis Pharmaceuticals Corp. division Sandoz Inc.’s Zarxio (filgrastim-sndz), approved March 6, 2015.

As of AIS Health press time, the FDA had approved 31 biosimilars.

AbbVie Has Successfully Delayed U.S. Competition for Humira

AbbVie has created a so-called “patent thicket” around Humira that many suggest is mainly an attempt to stave off competition. A May 2021 report by the U.S. House of Representatives’ Committee on Oversight and Reform examined increases in drug prices for Humira and another AbbVie drug, Imbruvica (ibrutinib). It noted that Humira — the highest grossing drug globally — brought in $16 billion in 2020 U.S. net revenue and that its annual price of around $77,000 is 470% more than what it was in 2003 when the drug launched. As of the report’s release, AbbVie had raised Humira’s price 27 times.

Although it’s unclear at this point what kind of discount to Humira’s price the biosimilars will launch with, “analysts suggest that the discounts (vs. Humira) of up to 50% as seen in Europe may be the upper limit in the U.S.,” writes Bill Sullivan, longtime industry analyst and executive editor of the Anton Rx Report, in an Oct. 21 entry. “Even a 30+% discount would deliver huge $$ savings in the U.S.”

According to the committee report, “internal company documents show that AbbVie views the U.S. patent system as far more protective of its pricing monopoly than patent systems in the rest of the world. AbbVie has obtained or applied for over 250 patents on Humira to block competition from lower-priced biosimilars. The last of these patents is set to expire in 2037. Approximately 90% of AbbVie’s patent applications were filed after Humira was already approved and brought to market, suggesting that they were intended to block competition and protect revenue rather than necessary to incentivize the company’s development of the drug. AbbVie’s CEO has publicly acknowledged the company’s strategy of overwhelming competitors by filing hundreds of patents on Humira, regardless of whether they are valid under U.S. law.”

Cyltezo is one of six Humira biosimilars that the FDA has approved. Patent litigation has kept the agents off the U.S. market, but under settlement agreements with AbbVie, the drugs are cleared to launch on the following dates:

• Amgen Inc.’s Amjevita (adalimumab-atto) on Jan. 31, 2023;
• Samsung Bioepis Co., Ltd.’s Hadlima (adalimumab-bwwd) on June 30, 2023; Merck & Co., Inc will commercialize the drug;
• Cyltezo on July 1, 2023;
• Mylan N.V. (now part of Viatris Inc.) and Fujifilm Kyowa Kirin Biologics Co., Ltd.’s Hulio (adalimumab-fkjp) on July 31, 2023;
• Novartis Pharmaceuticals Corp. division Sandoz Inc.’s Hyrimoz (adalimumab-adaz) on Sept. 23, 2023; and
• Pfizer Inc.’s Abrilada (adalimumab-afzb) on Nov. 20, 2023.

AbbVie also has negotiated agreements with companies whose proposed biosimilars of Humira have not received FDA approval:

• Coherus BioSciences, Inc.’s CHS-1420 on July 1, 2023 (although the company has said it may not launch until December 2023); the FDA is expected to make a decision on its Biologics License Application (BLA) in December;
• Fresenius Kabi AG’s MSB 11022 on Sept. 30, 2023; and
• Johnson & Johnson company Momenta Pharmaceuticals, Inc.’s M923 on Nov. 20, 2023. (The company stopped work on the agent in 2019.)

Drug Is First Interchangeable Monoclonal Antibody

Although Viatris and Biocon Biologics Ltd.’s Semglee (insulin glargine-yfgn) was the first agent to gain interchangeable status, which the FDA granted on July 28, Cyltezo is the first monoclonal antibody to be deemed interchangeable. AIS Health, a division of MMIT, asked industry experts about that distinction.

“It’s pretty significant,” maintains Renee Rayburg, R.Ph., vice president of specialty clinical consulting at Pharmaceutical Strategies Group, an EPIC company. “In March 2020, the FDA made a provision to the Biologics Price Competition and Innovation Act (BPCIA) to transition insulin and other biologic drugs to a new regulatory pathway, making it easier for the development of biosimilar or interchangeable products. Semglee took advantage of this change to seek approval as an interchangeable biosimilar after it had already been FDA approved and available in the market. This is thought to increase access to a more affordable insulin product and result in cost savings for both plan sponsors and members.”

According to Dea Belazi, Pharm.D., M.P.H., president and CEO of AscellaHealth, “being designated as the first interchangeable monoclonal antibody biosimilar will pave the way for other companies to see the impact of this designation and for substitution to occur at the point of dispensing and to initiate and conduct the clinical studies to gain this designation for their product to gain immediate market impact and provide cost-savings to the health system while enhancing patient access to these new and life-changing therapies.”

The approval of the first interchangeable monoclonal antibody is “very significant and demonstrates another roadmap that can be used by others to successfully demonstrate interchangeability of very high-cost medications,” agrees Nishida. “The aspect of interchangeability is important for one more strategy that health plan payers can apply to guide prescribers and patients to the most cost-effective medication options and increase their access.”

With the first two biosimilars gaining interchangeability status within a few months of each other, this momentum has the potential to be the beginning of a push for interchangeability, some industry experts tell AIS Health. Two companies recently disclosed plans to seek this designation.

When Amgen reported its third-quarter 2021 financial results on Nov. 2, the company noted that it was enrolling patients in Phase III studies “to support an interchangeability designation” for Amjevita and ABP 654, a biosimilar of Stelara (ustekinumab) from Janssen Biotech, Inc., a Johnson & Johnson company.

And in its Nov. 2 third-quarter earnings call, Pfizer’s group president of the biopharmaceuticals group, Angela Hwang, stated that the company would be filing for interchangeability status for Abrilada in December. In its Form 8-K filed with the U.S. Securities and Exchange Commission the same day, the company also said it plans to launch a citrate-free version of the drug as early as July 2023.

The ability of the interchangeables to influence other potential agents “will depend upon FDA requirements and whether or not conducting switch studies will be optional,” states Robert Kinyua, Pharm.D., senior director of clinical program development at Prime Therapeutics LLC. “The market response to existing interchangeable biosimilars may also influence how likely manufacturers are to pursue interchangeability status in the future.”

Rayburg says that “now that there seems to be a pathway to interchangeable products,” she expects to see an uptick in companies seeking that status.

Nishida says it’s “more than likely” that this will occur and agrees that the interchangeables’ approval “allows a road map of the study designs and the bar needed by way of results that would be required to be deemed interchangeable.”

Having interchangeability status “eliminates the need to gain the prescribing physician’s authorization to utilize a biosimilar product and potentially the payer’s authorization for a preferred biosimilar,” notes Belazi. “Companies will want to have the most ability to impact their market share, and this will be a key factor in minimizing any obstacles and enhancing product uptake. Companies will likely be following the success of Semglee and Cyltezo as case studies to quantify their market impact to help drive the economic decisions to conduct the additional interchangeability studies required by the FDA.”

What Could Dampen Uptake?

Still, while many are hopeful about Cyltezo’s potential to bring about savings, some potential roadblocks to its uptake exist.

“The impact of the interchangeability status of Cyltezo remains to be seen,” says Kinyua. “In addition to interchangeability status, factors such as product concentration, needle gauge size, delivery device design, excipients and market launch dates will all determine how impactful these products will be in the marketplace.”

Cyltezo and the other biosimilars are approved in doses administered at a lower concentration that have largely been replaced in Humira prescribing. In November 2015, AbbVie received FDA approval for a higher concentration, citrate-free Humira — which it launched in July 2018 — that has gotten most of the physician prescribing. This formulation has fewer excipients that often cause discomfort when injected.

Rayburg points out that Cyltezo is interchangeable with only the lower concentration Humira formulations. In addition, “AbbVie came out with a citrate-free (CF) formulation (Humira 40mg/0.4ml, Humira 20mg/0.2ml), which also cut the volume injected in half and uses a thinner needle, all three changes intended to offer a more comfortable injection experience for patients. Cyltezo is not interchangeable to the CF formulation of Humira. The majority of [Humira] patients have been switched over to the newer formulation.”

She tells AIS Health that “this means two things: (1) Cyltezo could be used as a biosimilar for these patients on the Humira CF formulation, but it will not be interchangeable, so a doctor would have to authorize that switch, and (2) patients who are used to and stable on the Humira CF formulation, experiencing a more comfortable injection, may not be as inclined to switch back to the previous formulation.”

In an attempt to counter this, on Dec. 2, 2020, Boehringer Ingelheim submitted a Citizen Petition requesting a change in the FDA’s interpretation of “strength” in the BPCIA “for parenteral solutions to mean ‘total drug content,’ without regard to concentration.” An article on law firm Rothwell Figg’s Biosimilars Law Bulletin maintains that this change would mainly impact interchangeable biosimilars. “If the FDA modifies its interpretation of ‘strength’ as Boehringer Ingelheim has requested, Boehringer Ingelheim can seek an interchangeability determination of Cyltezo that would apply to Humira’s higher concentration formulation,” it says.

At least a few companies are developing biosimilar Humiras that are at the higher concentration.

In November 2020, Alvotech said the FDA had accepted its BLA for AVT02. The agency initially was expected to make a decision on the application in September 2021, but on Sept. 20, the company said that the FDA was deferring action on the BLA until it could conduct facility assessments, which were being hampered by travel restrictions. The Reykjavik, Iceland-based biopharmaceutical company is partnering with Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical Industries Ltd., on the commercialization of AVT02 in the U.S.

Alvotech also said that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) had given the agent’s application a positive opinion on Sept. 16, recommending its approval in the European Union. The European Commission (EC) is set to make a decision on granting marketing authorization for the drug.

On Sept. 10, the company unveiled positive top-line results for a switching study between AVT02 and Humira that it said support the biosimilar’s approval as an interchangeable product.

And on Feb. 15, 2021, Celltrion Healthcare reported that the EC granted Yuflyma (CT-P17) marketing authorization across 13 chronic inflammatory diseases.

In an interview posted Feb. 3, 2021, when asked about whether the company had applied for FDA approval, HoUng Kim, Ph.D., head of the medical and marketing division at Celltrion, replied, “we submitted the dossier to the US FDA last November and we are aiming to have full indications approved. We hope this will improve access to high-concentration, low-volume, and less-painful adalimumab.”

In addition to Amgen’s application for an interchangeable version of Amjevita, a ClinicalTrials.gov entry notes that this version is a “new high concentration formulation.” The trial has a completion date in 2023.

What Should Payers Do Now?

Although the Humira biosimilars are not launching in the U.S. until 2023, payers should start talking to manufacturers about their products “as soon as they are able to,” asserts Rayburg. “January 2023 is when the first Humira biosimilar is expected to enter the market, so it is never too early to start having those conversations to be prepared. Plan sponsors may want to start with their PBMs, as many are probably already having these conversations.”

Payers need to understand how the biosimilars are different from each other, “what factors are most likely to influence prescribers and patients, and what support services manufacturers will offer with their product,” recommends Kinyua. Those support services should cover both financial assistance programs, as well as clinical programs, adds Nishida.

In addition, says Rayburg, they’ll want to know the products’ formulations, launch dates, prices and any additional rebates or contracting. “For the PBMs specifically, how will the products be covered, brand vs. biosimilar?” will be important to ask.

“Payers do need to start looking at their current formularies and preferred products and perform predictive modeling and trend forecasting that includes the introduction of the mix of new biosimilars, accounting for changes in price and timing this appropriately,” Nishida tells AIS Health. “A lot of this can be done by following patterns of previous biosimilars that were introduced to the market in other categories, as insights to forecast trends and impact on biosimilar adoption, utilization and cost.”

They also should ask manufacturers about their products’ clinical studies “to gain insight into the efficacy, safety and comparisons of the products to Humira,” says Belazi. “In addition to requesting information on the submitted clinical trial information, approved indications and biosimilar studies, payers will be engaging in contract discussions for pricing concessions and agreed-upon product positioning. Discussions will also engage the support tools available from the manufacturer to assist with the physician education on the biosimilar product(s) as compared to Humira and the potential dosing strength and product formulation differences.”

In a Nov. 9 post on his Drug Channels blog, Adam Fein, Ph.D., CEO of Drug Channels Institute, a subsidiary of Pembroke Consulting, Inc., discusses a potential monkey wrench based on Semglee’s launch. Viatris launched two versions of the interchangeable drug on Nov. 15: branded Semglee and insulin glargine, an authorized interchangeable biosimilar. The company gave the drugs different wholesale acquisition costs: Semglee’s is 5% below the WAC of its reference product, Sanofi’s Lantus (insulin glargine), and the unbranded insulin glargine’s WAC is 65% lower than that of Lantus. PBMs may choose to put Semglee on formulary to get rebates offered by Viatris while excluding the unbranded less expensive product.

In 2023, “will these [Humira] biosimilars launch with list prices that are comparable to or slightly lower than Humira’s list price?” he asks. “Or should they launch with deep list price discounts — or even with higher list prices (so as to maximize rebate dollars)? How will the sequence of launches — and the pricing of the early entrants — determine pricing strategies for subsequent entrants? Will early launches have higher or lower list prices than the later entrants?”

“Competition will surely drive down the net pricing for Humira and [its] biosimilars,” writes Fein. “But the Semglee story shows just how weird 2023 might become.”

According to Belazi, “the Humira biosimilar market will be very competitive given the large number of products that are already approved and have agreements in place with AbbVie for their established product launch. Knowing that there will be a significant number of biosimilar options available, key factors for biosimilar product access will be focused on approved indications, product formulations, product supply and net pricing. It is anticipated that the approved indications and product formulations will closely resemble Humira, so there will be a large emphasis on the net price that will be available, and payers will move towards the product(s) that will drive cost savings for the patient and plan sponsors.”

“With all six slated to enter the market around the same time, as well as experience with other medication biosimilars (infliximab, pegfilgrastim and several cancer drugs), we should anticipate faster adoption and competition than the sluggish uptake that we saw when the first biosimilars became available years ago,” says Nishida. “Prescribers are becoming more receptive to biosimilars when transition is done in a reasonable manner that ensures patients are not impacted by the switch.”

Steven Baak, M.D., a rheumatologist and medical director of the Arthritis Center in Bridgeton, Mo., tells AIS Health that “we routinely use biosims when it is reasonable, especially when starting a new drug. If there are equivalent drugs that are less expensive, they will be our first try.” Asked about his potential prescribing of Humira biosimilars, he replies, “I absolutely will use biosims rather than Humira in new start patients. Humira has made their money, and cheaper sources are reasonable.” That said, “I also see no need to immediately change from Humira to a biosim in stable cases.” Looking to 2023 and the biosimilar launches, he maintains that “it’s hard to judge” the impact that competition will have. “It is definitely a case that ‘Humira equivalents’ cannot be tried when Humira was a type I or type II failure.”

How Can Cyltezo Capture Market Share? How Can Humira Retain It?

To capture Humira market share, Boehringer Ingelheim will need to “understand the best way to market their product, given the difference in formulation from the Humira CF versions,” declares Rayburg. In addition, an understanding of concerns from all stakeholders will be important, including “physicians who will be prescribing the drug, patients who will be taking the drug and the specialty pharmacies who will be dispensing their product.”

The company “will need to [have] discussions with payers and prescribers to secure positioning, as it will be a couple of months late following [launches of] other adalimumab biosimilars (that are not interchangeable),” Nishida says.

“Boehringer Ingelheim took significant steps in the ability to capture Humira market share by initiating and completing their interchangeability studies and gaining the FDA approval as a biosimilar and interchangeable to Humira for a large number of Humira’s approved indications,” states Belazi. “This will allow the dispensing pharmacist the ability to convert at the point of prescription dispensing. In addition, Boehringer Ingelheim will need to support Cyltezo with a competitive price as compared [not only] to the reference product Humira but also to the other approved adalimumab biosimilars expected to launch in 2023. It is anticipated that at least two other biosimilars to Humira will launch prior to Cyltezo,…with three additional biosimilars due to launch prior to the end of 2023. This will provide a very cost-competitive market, and pricing will be a key factor in the product positioning by payers.”

For AbbVie to retain Humira market share, Rayburg says she expects that the company “will market the difference in the formulations [and] offer deep rebates and contracting opportunities so Humira remains the lowest net cost product. Any market share they retain is a bonus for them.” She points out that the company also is “bringing newer drugs to the market such as Skyrizi and Rinvoq, which treat some of the same conditions for which Humira is indicated. They are actively marketing these newer drugs to move market share away from Humira so they can retain market share on their other brand products which have no biosimilars available.”

The company can leverage their other anti-inflammatory agents “and position their products to address a significant number of disease states as a portfolio offering,” says Belazi. “This would not only include their newer branded products but also continue to offer pricing discounts that are low enough on Humira to make it difficult for payers to not maintain the product availability and continuity of care and avoid the disruption of conversion to the biosimilar products to physicians and patients.”

According to Belazi, “AbbVie has already taken significant steps to retain Humira share through their introduction of the higher strength, citrate-free product formulation and conversion of existing patients and new patient starts. They have moved the majority of current Humira patients to this newer product and will cause additional hurdles for payers to convert physicians and patients back to the older formulation due to dosing and injection site reactions.” In addition, the company’s settlement agreements with biosimilar competitors’ firms will allow AbbVie “to accurately plan for new products entering the market.”

“The expectation of savings from biosimilars is long awaited,” points out Rayburg. “It is encouraging to see changes in the market such as the FDA improving pathways to biosimilars and designating products as interchangeable. Interchangeability is expected to increase access and choice, leading to increases in utilization of lower cost products. Those elements are expected to increase the potential for savings from these products.

“However, more biosimilars entering the market increases competition, which ultimately leads to lower costs of all drugs and savings,” she continues. “So the question still remains: Is it the presence of biosimilars in the market and the competition they create or the use of biosimilars that leads to the most savings?”

Contact Belazi through Caroline Chambers at cchambers@cpronline.com, Kinyua via Jenine Anderson at jenine.anderson@primetherapeutics.com, Nishida at lynn@evio.com and Rayburg through Samantha Rideout at SRideout@psgconsults.com.