Intravitreal vascular endothelial growth factor (VEGF) inhibitors have revolutionized the practice of retina, but they remain associated with significant costs, both for patients and the health care system.¹ In 2020, the 3 most commonly used anti-VEGF agents — bevacizumab (Avastin; Roche/Genentech), ranibizumab (Lucentis; Roche/Genentech), and aflibercept (Eylea; Regeneron) were each in the top 10 of Medicare Part B spending across all medications, with more than $3.5 billion of annual spending.^1,2 These high costs — combined with recent US patent expirations for Avastin in 2019, Lucentis in 2020, and Eylea in 2023 — have led to the rapid development of anti-VEGF biosimilars.

A biosimilar is defined as a “biologic that is highly similar to and has no clinically meaningful differences from an FDA-approved biologic.”³ The product must demonstrate similar pharmacokinetics, pharmacodynamics, safety profile, immunogenicity, and clinical efficacy compared to the reference product.⁴ In noninferiority clinical trials designed to assess efficacy, results are usually measured at 8 to 12 weeks, during the steepest part of the dose response curve.⁵ Primary endpoints remain similar to those of traditional anti-VEGF clinical trials, and adverse events are usually monitored throughout the entire study period, often 12 months. Immunogenicity is measured by evaluating the proportion of patients with positive serum antidrug antibodies.⁶

Unlike generic drugs, biosimilars are manufactured in living cells rather than chemically synthesized. Their structure is reverse engineered and does not need to be identical to the original biologic, as long as other criteria are met.⁷ Their development process is longer than that of generic drugs but still faster (8 to 10 years compared to 10 to 15 years) and more cost effective (approximately 10% of the cost) compared to developing new biologics.^4,8 Overall, biosimilars are estimated to cost patients around 30% to 40% less than the original biologic.^9,10 Biosimilars are commonly used in rheumatology, oncology, and other fields of medicine.⁹

APPROVED RANIBIZUMAB BIOSIMILARS

The first ophthalmic biosimilar version of ranibizumab, Razumab (Intas Pharmceuticals), was approved in India in 2015 for the treatment of wet age-related macular degeneration (AMD), diabetic macular edema (DME), macular edema from retinal vein occlusion (RVO), and myopic choroidal neovascularization (CNV).⁶ The noninferiority clinical trial included 104 patients with wet AMD.⁷ Two subsequent retrospective real-world studies showed significant improvement in functional and anatomical outcomes in patients receiving Razumab for all listed indications.^11,12 Notably, Razumab was initially recalled due to reports of sterile endophthalmitis, attributed to higher endotoxin levels in the buffer used during manufacturing.¹³ The manufacturing and formulation process was changed, and subsequent studies have demonstrated a safety profile comparable to ranibizumab.^7,14

Since then, multiple ranibizumab and aflibercept biosimilars have been in development. In the United States, there are currently 2 FDA-approved ranibizumab biosimilars (Table 1). The first, ranibizumab-nuna (Byooviz; Biogen/Samsung Bioepis), was approved in September 2021 for wet AMD, RVO, and myopic CNV. The clinical trial leading to its FDA approval consisted of 705 wet AMD patients who received monthly injections of either ranibizumab-nuna or the reference product ranibizumab for 48 weeks. Ranibizumab-nuna was equally effective based on primary endpoints of mean change in best corrected visual acuity (BCVA) at 8 weeks and change in central subfield thickness (CST) at 4 weeks. Equivalence was determined based on prespecified margins of -3 to 3 letters for change in BCVA and -36 to 36 µm for change in CST.¹⁵ The equivalence in efficacy, safety, immunogenicity, and pharmacokinetics was upheld during a 12-month follow-up period.¹⁶ A post hoc analysis showed that immunogenicity was overall low and not associated with efficacy and safety of ranibizumab-nuna and ranibizumab.¹⁷

A second biosimilar, ranizumab-eqrn (Cimerli; Coherus Biosciences), was FDA approved in both 0.3 mg and 0.5 mg doses in October 2022 for DME, diabetic retinopathy (DR), wet AMD, RVO, and myopic CNV.¹⁸ The pivotal clinical trial involved 477 patients with treatment-naïve wet AMD who received monthly intravitreal injections of either the biosimilar or reference product ranibizumab. At 8 weeks, there was no difference in mean change in BCVA between the 2 arms. The equivalence in BCVA also held for secondary endpoints of BCVA change at 24 and 48 weeks. Both groups had similar reductions in CST at 8 weeks and 48 weeks, and the safety and immunogenicity profiles were similar.¹⁹

BIOSIMILARS IN THE PIPELINE

Many other ranibizumab biosimilars are in development (Table 1). Examples include RanizuRel (Reliance Life Sciences), for which a clinical trial of 159 patients with wet AMD showed noninferiority using the primary endpoint of change in BCVA at 16 weeks and 24 weeks.²⁰ Early real-world data have also corroborated its safety.²¹ A clinical trial of Xlucane (Xbrane Biopharma) reached its primary endpoint of noninferior change in BCVA at 8 weeks, and the company plans to file for FDA approval in 2024.^7,22-23 Two other ranibizumab biosimilars, LUBT010 (Lupin Pharmaceuticals) and CKD-701 (Chong Kun Dang Pharmaceuticals), also met their primary endpoints in phase 3 noninferiority clinical trials, with CKD-701 using a pro re nata (PRN) dosing schedule after 3 loading doses.^24,25 Another biosimilar, SJP-0133 (Senju Pharmaceuticals), has pending phase 3 clinical trial results from 338 patients with wet AMD.²⁶

There are currently no FDA-approved aflibercept biosimilars, but many are in the development process (Table 2). A phase 3 clinical trial of biosimilar SB15 (Samsung Bioepis) in 449 patients with treatment-naïve wet AMD showed equivalent change in BCVA at 8 weeks (primary endpoint) and comparable safety and efficacy up to 32 weeks. Participants were randomized to receive 2 mg of SB15 or reference product aflibercept every 4 weeks for 12 weeks, then every 8 weeks until 48 weeks. There were no significant differences in the incidence of adverse events or immunogenicity.²⁷ Another proposed aflibercept biosimilar, MYL-1701P (Momenta Pharmaceuticals and Viatris), was recently studied in patients with DME. The clinical trial involved 355 patients with center-involving DME who received either MYL-1701P or aflibercept. The primary endpoint, mean change in BCVA at 8 weeks, was equivalent between the 2 drugs, and the proportion of patients with BCVA improvement greater than 5, 10, or 15 letters was also similar at 8 weeks. There were no differences in adverse events and immunogenicity through 52 weeks.²⁸

Several other aflibercept biosimilars are in development (Table 2). Two drugs, FBYB203 (Formycon AG/Bioeq) and CT-P42 (Celltrion), have met the primary endpoint of mean change in BCVA at 8 weeks in phase 3 noninferiority clinical trials in patients with wet AMD.^29,30 Four other proposed aflibercept biosimilars have phase 3 clinical trials that are currently under way. These include ABP-938 (Amgen), SOK583A1 (Sandoz), ALT-L9 (Alteogen), and OT-702/LY09004 (Ocumension Therapeutics and Boan Biotech).^31-34

CONCERNS OVER BIOSIMILARS

Over the last few years, anti-VEGF biosimilars have begun to enter the US and global markets, with many more expected in the coming years. Biosimilars can be developed faster and are more cost effective than original biologics. They have the potential to reduce the large financial burden of existing anti-VEGF treatments, improve patient access, and increase treatment compliance. However, in a recent survey of 112 retina specialists in the United States and Europe, 56.3% felt that they needed more information and real-world data before incorporating biosimilars into their practice. Half of respondents reported concerns about biosimilar safety, efficacy, and immunogenicity.³⁵ These concerns are understandable, especially given Razumab’s initial recall due to sterile endophthalmitis. That adverse event was attributed to bacterial endotoxins acquired during manufacturing or improper sterilization, but systemic inflammation mediated by development of antidrug antibodies was also considered.³⁶ All phase 3 clinical trials of biosimilars now compare the proportion of patients who develop antidrug antibodies for the biosimilar and reference biologic, and no differences have been reported thus far. In addition, the FDA currently recommends <0.2 EU/mL of endotoxin for any intraocular pharmaceutical, although strict limits are not enforced.^36,37

Only 1 phase 3 trial is required for biosimilar approval, compared to at least 2 phase 3 trials for the original reference drug. Because the biosimilar is not tested on as many patients, the trial may not be able to detect adverse events that occur with more limited frequency. Some retina specialists may opt to wait until further safety data from retrospective real-world studies become available, citing examples of medications like brolucizumab, where occlusive vasculitis became evident in real-world studies after the pivotal clinical trials that led to FDA approval were completed.¹⁰ In addition, if a biosimilar is approved, the approval may apply to all indications of the original biologic, even if the pivotal clinical trial only enrolled patients with 1 type of retinal condition.⁴ For instance, the pivotal trial for ranibizumab-eqrn (Cimerli) was conducted in patients with wet AMD but it can be used in all ranibizumab indications, including DME, DR, RVO, and myopic CNV. In fact, Cimerli was the first FDA-designated interchangeable biosimilar, meaning it can be substituted for reference ranibizumab at the pharmacy level even without the intervention of an ophthalmologist.¹⁸

Ultimately, how anti-VEGF biosimilars will shape retina practice will be determined in part by what insurers choose to cover and which agents are selected for hospital or clinic formularies. Given the differences in cost, insurers will likely strongly encourage or even mandate the use of biosimilars as first-line therapy despite these concerns. Many retina specialists may still try compounded, off-label bevacizumab first when there are cost concerns, although the possible FDA approval of the ophthalmic preparation of bevacizumab (Lytenava; Outlook Therapeutics) may lead to removal of the more cost-effective, off-label bevacizumab option.³⁸ Retina specialists who do adopt the usage of biosimilars will still carefully monitor their patients for adverse events. Continued education of retina specialists on the definition of biosimilars and the current landscape of anti-VEGF biosimilars is crucial to ensuring that these new agents can be used in the most safe and effective manner. RP

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