FDA Approves Byooviz, First Biosimilar for Ocular Use

The FDA approval of the first biosimilar for ocular use is poised to bring savings to a costly class, particularly in Medicare. However, ophthalmologists’ and retinologists’ lack of experience with biosimilars is a potential roadblock to these drugs’ uptake. Payers should focus on provider education and outreach ahead of these drugs’ launches in order to ease concerns about their use, say industry experts.

On Sept. 20, the FDA approved Samsung Bioepis Co., Ltd. and Biogen Inc.’s Byooviz (ranibizumab-nuna) for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO) and myopic choroidal neovascularization (mCNV). The drug is a biosimilar of Roche Group unit Genentech USA, Inc.’s Lucentis (ranibizumab). Under an agreement with Genentech, Samsung Bioepis and Biogen will be able to market the therapy in the U.S. in June 2022.

According to Magellan Health, Inc. division Magellan Rx Management’s eleventh annual Medical Pharmacy Trend Report, released in May, ophthalmic injections accounted for the second-highest category of spend in Medicare in 2019, behind only oncology. Lucentis ranked No. 5 in the top 10 Medicare medical benefit drugs by spend. Among commercial plans, Lucentis had 20% of the ophthalmic injectable market, behind Genentech’s Avastin (bevacizumab), with 32%, and Regeneron Pharmaceuticals, Inc.’s Eylea (aflibercept), with 37%. In Medicare, Lucentis had a 22% share, compared with 43% for Avastin and 27% for Eylea, and in Medicaid, Lucentis had an 18% share of the market, compared with Avastin’s 55% and Eylea’s 27%.

Those drugs, along with Novartis Pharmaceuticals Corp.’s Beovu (brolucizumab-dbll), are vascular endothelial growth factor (VEGF) inhibitors that are injected directly into a person’s eye.

“Eylea dominates the branded products in market share, and Lucentis is the second most highly utilized FDA-approved ophthalmic VEGF inhibitor,” Dea Belazi, Pharm.D., M.P.H., president and CEO of AscellaHealth, tells AIS Health, a division of MMIT. “Avastin, used off-label for ophthalmic indications, represents the third most highly utilized VEGF inhibitor most likely due to its very low cost (about $200 per year).”

Beovu, notes Winston Wong, Pharm.D., president of the W-Squared Group, has showed “a higher rate of vision loss and blindness due to occlusive retinal vasculitis, retinal artery occlusion and intraocular inflammation” that “has pretty much taken it out of the market. The FDA updated the label to reflect these safety concerns.”

Avastin’s $200 annual price compares with $8,000 per year for Beovu, $12,025 for Eylea and $25,350 for Lucentis, says Rachel K. Anderson, Pharm.D., C.S.P., clinical program manager at AllianceRx Walgreens Prime. If Byooviz is priced at a 20% discount to Lucentis, that would put its price at $20,280.

“The impact and uptake of Byooviz will be directly related to the cost at which this biosimilar enters the market,” maintains Renee Rayburg, R.Ph., vice president of specialty clinical consulting at Pharmaceutical Strategies Group, who adds that biosimilars generally come onto the U.S. market at a discount of 10% to 30% off the reference product’s price.

The anti-VEGF space “is an interesting category where there is no clear superior agent,” says Wong. “I believe what drives the debates of ‘which agent to use’ is cost from the payer perspectives. Retinal specialists, while they do look at cost, are also considering clinical efficacy, familiarity with the anti-VEGF product and manufacturer loyalty.”

According to Anderson, “payers often tend to lean toward the most cost-effective products when making formulary decisions. Prescribers may present patients with a narrative about disease pathology and choose intervention with any of the available anti-VEGF biologics, as product differentiation is absent in terms of efficacy in treating the different ophthalmological conditions, but cost and coverage may dictate product selection for many patients. If a decision is made to convert a patient from one agent to another, the protocols of most published studies cite lack of efficacy of the initial agent as the rationale for converting to an alternate therapy.”

And while management of the anti-VEGFs varies by payer, those with “limited formularies, with tighter benefit structures or more robust utilization management programs may require the use of Avastin across all indications, but more open formularies and benefit structures will most likely align with the FDA-labeled indications,” says Belazi.

“Generally it is not clinically feasible to prefer one anti-VEGF agent across indications,” says Robert Kinyua, Pharm.D., senior director of clinical program development at Prime Therapeutics LLC.

Avastin is being used off-label, Wong explains, “which technically goes against most medical policies, especially in the early years, and there have been reports of adverse reactions associated with the compounding of bevacizumab.” Nevertheless, “it is my understanding that approximately 50% of practices administer bevacizumab as a first-line agent; however, it is not known if they are being cost conscious or if this is being mandated by the payer through step therapy.”

Belazi notes that “some payers, such as Medicare, do not reimburse sufficiently for Avastin, which leads certain prescribers to utilize the FDA-approved branded products.”

Wong points out that two biosimilar versions of Avastin have been approved for multiple oncolytic indications: Amgen Inc.’s Mvasi (bevacizumab-awwb) and Pfizer Inc.’s Zirabev (bevacizumab-awwb). However, the American Society of Retina Specialists (ASRS) and the American Academy of Ophthalmology (AAO) are warning that the biosimilars may damage people’s vision, particularly Zirabev, which is prepared with edetate disodium dihydrate (EDTA), an agent that “has demonstrated toxicity to corneal and conjunctival epithelial cells. Potential retinal toxicity of EDTA has not been studied.”

ASRS and AAO have been conducting outreach to multiple payers and CMS about this “inappropriate use” of the biosimilars “without a prior clinical trial in eye disease and testing for retinal toxicity.”

Still, at least one FDA-registered 503B outsourcing facility is advertising Mvasi for ophthalmic use. Edge Pharma, which is licensed to sell to all U.S. states except Alabama and Virginia, offers the ability to order the drug online.

Earlier this summer, an Avastin shortage was triggered by a supply chain issue in which a major supplier of the drug “initiated an indefinite halt on the distribution of all [repackaged] bevacizumab syringes.”

ASRS and AAO initially conducted outreach to payers asking them not to require Avastin as a first step in the treatment of eye diseases and to provide coverage for the other branded non-bevacizumab VEGF inhibitors approved for eye diseases. Then that outreach shifted to focus on requesting that payers not encourage the use of the biosimilar forms of Avastin as alternatives to the innovator product in the treatment of eye diseases.

“All of the major payers have Mvasi and Zirabev listed as ocular alternatives,” the AAO tells AIS Health. At least one, UnitedHealthcare, has responded by removing Mvasi and Zirabev from coverage under its ophthalmologic policy for VEGF inhibitors. As of early October, AAO says that is the only plan that has changed its policy. “The Academy is in the process of scheduling meetings with CVS Health and Aetna on this issue,” it says.

Asked if CMS has taken any action, the AAO says that it and ASRS “met with [CMS acting Deputy Administrator & Director and Deputy Director] Cheri Rice and staff at CMS to discuss the issue. CMS took the meeting seriously and are internally discussing next steps. We hope to have follow-up from CMS soon.”

Charles Wykoff, M.D., Ph.D., chair of the practice management committee at ASRS, tells AIS Health that ASRS’s position is based on a lack of evidence for the biosimilars, as well as “experiences with prior products, including the first version of Lucentis that was lyophilized and caused inflammation in some eyes and more recently Beovu,” which was “found to lead to severe retinal vasculitis in a small proportion of patients.” The cause of this event is under investigation, he adds.

“ASRS does not oppose the use of biosimilars in general, but there should be clinical evidence of their safety and efficacy before ophthalmic use,” he maintains.

Interestingly, Outlook Therapeutics, Inc. has a biosimilar of Avastin specifically for ocular use in clinical trials. On Oct. 12, the company reported that data from its NORSE THREE supplemental safety study evaluating ONS-5010/Lytenava (bevacizumab-vikg) “demonstrated no unexpected safety trends and had a safety profile consistent with those of other trials of ONS-5010 as well as prior published data such as that undertaken by the National Eye Institute (e.g., 2011 CATT trial).” The firm said it plans to file a Biologics License Application (BLA) with the FDA in early 2022 for the product’s use in wet AMD. Outlook says it also will conduct clinical trials exploring the drug’s use in branch RVO and DME.

‘Biosimilar Market Entry Is Welcome’

“Given limited treatment options in this space and lack of competition, biosimilar market entry is welcome and bound to be impactful with regard to options to choose from and cost,” maintains Kinyua.

“Many of the ophthalmic conditions, if left untreated, can lead to vision impairment or blindness,” says Samsung Bioepis spokesperson Anna Nayun Kim. “It is important that patients receive treatment at the right time, but many patients are still undertreated, often due to financial reasons. The introduction of a safe and effective biosimilar for Lucentis may play a role in reducing the economic burden placed on patients and health care systems by current neovascular age-related macular degeneration (nAMD) therapies and expand patients’ access to this treatment option and support the implementation of an effective treatment regimen.”

According to Anderson, Byooviz’s approval “marked a monumental milestone in the biosimilar landscape.…This is significant because it opens the door for competition in the market as well as expands patient access to critical medication. With an aging population and growing need to treat chronic, complex conditions, specialty biologics are on the rise. In an environment where health decisions are increasingly made on cost, biosimilars like Byooviz will play an important role in improving access to these types of medicines. The launch of biosimilars over the next decade could save consumers a significant amount of money; further, increased affordability may boost access to treatments for millions of patients who may otherwise have forgone treatment or compromised for less effective treatment.”

Byooviz is Samsung Bioepis’ fifth FDA-approved biosimilar:

• Renflexis (infliximab-abda) was approved on April 24, 2017.
• Ontruzant (trastuzumab-dttb) was approved on Jan. 21, 2019.
• Eticovo (etanercept-ykro) was approved on April 27, 2019.
• Hadlima (adalimumab-bwwd) was approved on July 23, 2019.

For the Managed Care Biologics and Injectables Index: Q4 2020, between Dec. 2, 2020, and Jan. 7, 2021, Zitter Insights polled 40 commercial payers with 130.8 million covered lives about Lucentis and Eylea biosimilars. Respondents with more than three-quarters of lives said they were likely to prefer biosimilars over their reference product (see chart). Payers covering 57% of lives said they would cover ocular biosimilars separately from the brand drugs once two biosimilars were available.

Zitter Insights also is an MMIT company.

During the same time period, Zitter Insights polled 52 retinologists on their expected prescribing once biosimilars were available. Sixty-two percent of respondents said they were likely to prescribe a biosimilar Eylea over the reference drug, and 58% said they likely would prescribe a biosimilar Lucentis over the brand drug.

Some Factors Could Slow Uptake

Still, a few factors could impact Byooviz’s uptake in the U.S. One is that “the dosing interval for Byooviz is more frequent at four to six weeks, compared to Eylea at eight to 12 weeks and potential candidates in the pipeline,” says Anderson. A higher dose of Eylea is in Phase III clinical trials, notes Belazi, and it could extend the dosing intervals to every 16 weeks.

On Oct. 22, the FDA approved Genentech’s Susvimo (ranibizumab) for the treatment of people with wet AMD who have responded to at least two anti-VEGF injections. The product, previously called Port Delivery System with ranibizumab, is for intravitreal use via ocular implant that is surgically inserted into the eye during a one-time, outpatient procedure and is refilled every six months. The product will be available in the coming months.

On July 29, Roche said that the FDA had accepted its application for faricimab for the treatment of wet AMD and diabetic macular edema (DME). Dosing for that treatment is every four months. The application has priority review, and a decision is due by January 2022, says Anderson. The FDA also has accepted the application for faricimab in diabetic retinopathy (DR), she notes.

Another potential factor in Byooviz uptake is that it has approval for only three of Lucentis’ five FDA-approved indications. It was not approved for DR and DME. Asked if Samsung Bioepis applied for those two indications, Kim responds that Byooviz is approved for its three indications as a single-use 0.5 mg (0.0 5mL of 10 mg/mL solution) vial, the same as Lucentis. For DME and DR, Lucentis is approved for a different dose: 0.3 mg (0.05 mL of 6 mg/mL solution).

The lack of approval for those two indications could slow uptake of the drug, says Lynn Nishida, R.Ph., head of clinical operations at Evio. However, Mesfin Tegenu, R.Ph., CEO of RxParadigm, points out that Byooviz has approval to treat wet AMD, which is “one of the most frequent retinal degenerative diseases.” According to ResearchAndMarkets.com, between 11 million and 15 million people in the U.S. have AMD, and about 1.7 million of those have wet AMD, which is the No. 1 cause of blindness in people more than 50 years old.

Belazi says estimates show that DME and DR make up only about 25% of Lucentis use.

Kinyua also notes that Byooviz has been studied in DR and DME and that the European Medicines Agency approved Byooviz for those indications “based on the totality of clinical evidence,” which may influence how the agent is used in the U.S.

Rayburg points out that all of Byooviz’s indications are for the treatment of eye disorders, and since it “was proven to be both safe and effective for three of the indications, I really am not sure if this [i.e., not having the DME and DR indications] will make a big difference. It will, however, make a big difference to the brand competitor products, and I expect it will be an important part of the marketing message to support the use of those brand products over the use of this biosimilar.” Providers also may choose to prescribe it off-label as they do for cancer drug Avastin, which has undergone clinical trials in eye disorders, but Genentech has never sought FDA approval for them.

Another differentiation between Byooviz and Lucentis (as well as Eylea) is that the biosimilar is available as a single-use vial, while the innovator product is available both in that format and in a prefilled syringe. Asked if there is a prefilled syringe in development for Byooviz, Kim says that Samsung Bioepis is “unable to comment on the PFS at this moment.”

Industry sources are divided on how much of a difference this makes. “Since this is a physician-administered drug, and physicians and their staff are very experienced and used to using a vial and syringe to administer medications, I am not sure if this will have a significant impact,” says Rayburg.

According to Belazi, “studies comparing the administration of Lucentis vials and prefilled syringes have demonstrated that the PFS does reduce preparation times and simplify the preparation procedures. In one study arm, the mean total duration of all syringe preparation steps was 46 seconds with the PFS vs. 75 seconds with the vial. In another, [it was] 46 seconds vs. 63 seconds.

“This equates to a 27%-39% time reduction when using the PFS rather than the vial,” he continues. “The PFS does reduce injection time by a few seconds. However, there are additional advantages, including possible reduced risk of contamination, reduction in intraocular air bubbles and silicone oil droplets, and improved precision in the volume and the dose of intravitreal medication being administered. While all of these factors make the Byooviz vial less attractive for ophthalmologists to administer, it is unlikely to impact the uptake of Byooviz.”

“It comes down to a matter of convenience,” as well as sterility, says Wong. “Although the incidence of eye infections is less than 5% (as quoted to me by a retinal specialist), it still remains a concern. In short, in the face of similar pricing, I believe being only in a vial will impact uptake.”

“While dosage form differences are unlikely to impact the market landscape from a payer perspective, prescribers may be somewhat reluctant to use a less convenient product, and, drawing up the precise dose may be time consuming for retinal specialists to perform,” states Anderson. “Most Lucentis patients appear to be treated with injections administered from prefilled syringes.”

Ultimately, says Tegenu, uptake of the biosimilar “would probably be more dependent on whether the products are covered by the payer or if there is a preferred or nonpreferred status.”

Ophthalmologists’ Lack of Biosimilar Experience Could Pose Issue

Perhaps most importantly, ophthalmologists have not had experience with biosimilars, which also could hamper the drugs’ use. Payers have time, though, ahead of Byooviz’s potential June 2022 launch, to address this issue.

“Unlike other specialists who have had the advantage of using biosimilars more regularly (e.g., rheumatologists, gastroenterologists, oncologists), ophthalmologists have very little experience with biosimilars, and it will take some time for them to become familiar with treating patients with a biosimilar,” states Nishida. Payers’ “key areas of focus should be on prescriber education and outreach to glean their insights as well as discuss/gauge their acceptance or willingness to prescribe biosimilars, if not for Lucentis, but also for other biosimilars that are anticipated to become available soon.”

“As familiarity and confidence in biosimilars increase, so will utilization,” asserts Belazi. He says that “to drive biosimilar adoption, they [i.e., payers] should proactively educate providers and patients on biosimilars. Ophthalmologists need to be educated on the regulatory approval pathway, clinical trial foundations and the interchangeability nuances of biosimilars.”

The first move payers need to make is to “talk to their retina specialists to first determine if they are educated on the biosimilar evaluation process, as well as their comfort level with using a biosimilar,” Wong says, pointing out that it took “several years” for oncologists to become comfortable with using biosimilars.

In addition, before Byooviz comes to market, “payers would generally want to consider their current medical policy for the therapeutic class, total utilization and conduct formulary management strategies to control costs and ensure access to patients,” says Tegenu.

Step therapy, prior authorization, site-of-care optimization and quantity limits are crucial in keeping costs down, says Anderson. “Payers and specialty pharmacies should also strategize innovative programs focused on opportunities to further prevent waste, improve adherence and reduce overall spending.”

Payers also should conduct “forecast modeling of when it makes the most sense to embrace biosimilars like Byooviz that will drive price competition,” Nishida maintains.

“It is important for payers to have insight into their data, specifically the utilization and cost of all of these products, including the new biosimilar,” recommends Rayburg. “They will also need to factor in any contracting and/or rebate options available per product and position them to prefer the lowest net cost product(s).”

“It will be necessary to have early payer engagement and education to facilitate sound clinical and financial formulary decisions,” says Belazi. “Also, access to ophthalmic biosimilars like Byooviz via preferred formulary placement and step therapy strategies can promote biosimilar utilization.”

“Payers need to start playing the chess game early,” maintains Wong. “They need to start talking to the innovators to determine what their strategy will be, or not be, to maintain market share. They need start talking to Biogen to try to get a feel with what the list price will be and if there will be any discounting to try to make a dent upon the market.…They need to look at the nAMD and DME pipeline to determine if the need for current anti-VEGF therapy will remain.”

More Biosimilars Are in Pipeline

Multiple biosimilars for both Lucentis and Eylea are in the late-stage pipeline.

On Oct. 1, Coherus BioSciences, Inc. said that the FDA had accepted its BLA for CHS-201 (also known as FYB201), a Lucentis biosimilar candidate, from its partner, Bioeq AG. Coherus acquired U.S. commercial rights to the drug — which has an FDA action date of Aug. 2, 2022 — from Bioeq AG in 2019.

According to the most recent U.S. Biosimilar Report from AmerisourceBergen, updated Sept. 23, there are two Lucentis biosimilars in Phase III trials, one of which is Xlucane. On July 27, 2021, Xbrane Biopharma AB said that Xlucane had met its primary endpoint demonstrating equivalent efficacy in its Phase III trial and that it plans to submit a BLA to the FDA in fourth-quarter 2021. Lupin Ltd.’s LUBT010 also is in Phase III trials.

The report also shows that seven Eylea biosimilars are in Stage III trials. One of those is SB15, which Biogen and Samsung Bioepis are developing. On June 30, 2020, Samsung Bioepis said it had started a Phase III clinical trial; company spokesperson Kim confirms that trial is ongoing. “While we are unable to make predictions on the next clinical or regulatory milestones, we will endeavor to bring this important medicine to the market soon,” she says.

Belazi says that Eylea biosimilars could come onto the U.S. market as soon as 2024. Those products “are expected to be more impactful than Lucentis biosimilars. Eylea currently has over $5 billion in annual sales, and Lucentis has just over $2 billion in annual sales.…A rise in competition due to multiple Eylea biosimilars will likely erode utilization of the Eylea brand. This, in turn, will provide cost-saving opportunities for payers. Since Eylea is a market leader, having multiple biosimilar options will provide options for payers and providers to select highly effective, lower cost options.”

“The availability of additional biosimilars in treating ophthalmological conditions may have a major impact in the space.,” asserts Anderson. “As more biosimilars launch, more cost-effective treatment options may mean more competitive pricing and steeper discounts for a payer’s bottom line and patients’ pockets alike.”

“In general, biosimilar uptake in the U.S. has steadily picked up steam over the past several years for many reasons, including increased prescriber confidence and familiarity with biosimilars, practical administrative/billing with separate codes and payment rates to differentiate products and payment schedules that encourage their use” and their lower costs, which help drive down their reference drugs’ prices, says Nishida.

“In our experience, we have seen the entrance of additional biosimilars drive costs down for all products, including the brand innovator products,” Rayburg tells AIS Health. “The presence of additional biosimilars creates additional competition and should continue to drive a decrease in costs for all products.”

For more information on the Zitter data, contact Jill Brown Kettler at jbrown@aishealth.com.

Contact Anderson via Adrienne Foley at Adrienne.foley1@alliancerxwp.com, Belazi through Caroline Chambers at cchambers@cpronline.com, Kim at nayun86.kim@samsung.com, Kinyua through Karen Lyons at KLyons@primetherapeutics.com, Nishida at lynn@evio.com, Rayburg through Samantha Rideout at SRideout@psgconsults.com, Tegenu at Mesfin.Tegenu@rxparadigm.com and Wong at w2sqgroup@gmail.com.