It was no surprise to those who follow industry and regulatory developments affecting the retina specialty. On September 17, 2021, the U.S. Food and Drug Administration announced the approval of the first ophthalmology biosimilar to ranibizumab (Lucentis, Genentech/Roche), the anti-vascular endothelial growth factor agent Byooviz. But as more biosimilar approvals seem imminent as patents expire, some wonder how this regulatory approach translates to ophthalmology and what impact it could have on community practices and patients downstream.

South-Korea based Samsung Bioepis and U.S. partner Biogen developed Byooviz, or SB11, which has been approved to treat wet age-related macular degeneration, macular edema and myopic choroidal neovascularization, all indications for Lucentis, first FDA-approved in 2006.

Biosimilars are biological products approved based on data showing that they’re highly similar to the “reference product,” a biological product already approved by the FDA, with no clinically meaningful differences in safety, purity or potency. The concept closely mirrors generic drug approvals following a chemical-based, branded drug patent expiration. The program was implemented to lower costs and increase accessibility to patients. 

Neither of these potential benefits are disputed by Timothy G. Murray, MD, MBA, FACS, founding director/CEO of Murray Ocular Oncology and Retina of Miami, president of The Foundation of the American Society of Retina Specialists and immediate past president of ASRS. “If there wasn’t a cost issue and there wasn’t an access issue, then there really is no benefit to a biosimilar,” he says. With branded anti-VEGFs running between $1,800 and $2,000 an injection, many retina specialists have turned to off-label use of bevacizumab (Avastin, Genentech) at roughly $50 per injection, he noted. Thus, short of drug companies lowering their prices, biosimilars are the only option for FDA-approved, affordable anti-VEGF treatments.

While it’s helpful to understand biosimilars in the context of generics, Dr. Murray makes a distinction. “I hold biologics to a much higher standard than simple generics,” in which “production and manufacturing play only a small role,” he says. In the case of biologics, “we have some very good information that how the drug is manufactured, what the biologic process is, and what the standards are, are really critical. I think many of us are very anxious about the approval of biosimilars because there’s such a potential for a bad outcome. I think that’s the biggest concern.” He adds that even branded biologics manufacturers have faced quality issues with some of their lots.

In addition, it may take a larger treatment population for safety issues to emerge. “The most recent example, where we found that with broader use there was a problem with the drug, was brolucizumab,” Dr. Murray recalls, recounting the efforts of the American Society of Retina Specialists Research and Safety in Therapeutics Committee, which analyzed clinical and imaging characteristics from submitted reports of retinal vasculitis related to brolucizumab (Beovu, Novartis), prompting a relabeling of the drug.¹ In the case of Byooviz, “have enough patients been evaluated with this drug to believe that it’s a very similar drug [to ranibizumab] or not?” Dr. Murray asks. 

Approval of Byooviz was based on a randomized, double-masked, parallel group, multicenter Phase III study in which 705 patients were randomized (1:1) to receive SB11 or reference ranibizumab in monthly injections (0.5 mg); 634 patients continued to receive treatment up to week 48. The least squares mean change in best corrected visual acuity from baseline at week 52 was 9.79 letters for SB11, compared with 10.41 letters for reference ranibizumab (difference: -0.62, [90% CI: -2.092, 0.857]). The LS mean change in central subfield thickness was −139.55 µm for SB11 vs −124.46 µm for reference ranibizumab (difference: -15.09, [95% CI, -25.617, -4.563]). Pharmacokinetics, safety (including incidence of treatment-emergent adverse events), and the immunogenicity profile of SB11 and reference ranibizumab were comparable at all timepoints up to week 52.

Earlier this year, Cardinal Health, on behalf of The Center for Biosimilars, conducted research via a series of survey questions with U.S.-based community retina specialists (n=37) suggesting a lack of awareness of biosimilars. When asked about their familiarity with biosimilars, 31 percent of physician respondents (out of 29 total responses) said they aren’t very familiar with biosimilars, and more than half (55 percent) said they have read research about them but are not familiar with issues such as manufacturing, approval processes, and clinical trial design. Nonetheless, 83 percent of respondents said they could envision biosimilars fitting into their treatment plan, and more than half of respondents said they would consider using a ranibizumab biosimilar or aflibercept biosimilar once they become available.²

They’re on the way. At least two more companies are developing biosimilars for Lucentis. Samsung Bioepis and Biogen are also working to steer SB15 toward approval as a biosimilar to Eylea (aflibercept, Regeneron), and at least three more companies are following suit with aflibercept biosimilars in clinical trials. Biogen will take the lead to commercialize Byooviz in the United States as of June 2022, based on a licensing agreement with Genentech, Samsung Bioepis and Biogen. 

To date, the FDA has approved 31 biosimilars, including one interchangeable biosimilar, meaning that it can be substituted without involvement of the prescriber.

^{1. Witkin AJ, Hahn P, Murray TG, et al. Occlusive retinal vasculitis following intravitreal brolucizumab. J Vitreoretin Dis. 2020;4:4:269-279.} 

^{2. Oskouei ST. Opinion: Is the ophthalmology market ready to embrace biosimilars? Center for Biosimilars website. Posted January 16, 2021. Available at: https://www.centerforbiosimilars.com/view/is-the-ophthalmology-market-ready-to-embrace-biosimilars- Accessed September 27, 2021.}

Study Supports Individualized Anti-VEGF Protocols

Developing new injection schedules for patients receiving anti-VEGF agents is always on physicians’ minds, due to the high costs of injections; the intense follow-up schedules; the psychological and physical impacts of these schedules; and the threat of geographic atrophy. Studies suggest that individualized treatment is best for wet AMD patients when taking into account treatment costs and scheduling. A new analysis published in Retina examined treatment-naïve wet AMD patients who received a single injection of ranibizumab/aflibercept; it reported that a subset of these patients demonstrated resolution of choroidal neovascular membrane-associated exudation that lasted more than two years with a single injection.¹

The retrospective, observational study included 63 patients with wet AMD who achieved complete resolution of retinal exudation with a single injection. The researchers defined complete resolution as the total disappearance of intraretinal fluid, cysts and subretinal fluid, as well as a return to a retinal thickness <250 µm on SD-OCT. Follow-up visits occurred on days one, seven and 30 postoperatively, and then monthly. Patients had nine mandatory visits per year if the macula remained fluid-free.

The patients’ mean baseline and final-corrected distance VA were 20/160 and 20/45, respectively. They completed an average of 10.9 follow-up visits per year. The authors also noted that smaller choroidal neovascular membranes (<200 µm), early presentation, better presenting corrected distance VA, subfoveal choroidal neovascular membranes, absence of blood/fibrosis and use of aflibercept (2 mg) were factors associated with resolution after one injection.

Overall, the researchers said that a defined subset of patients receiving just one injection had “very good” visual and anatomical outcomes. These patients showed complete resolution of the neovascular membrane, and only seven required multiple injections after a treatment-free interval of at least 24 months. They noted no adverse events during follow-up.

Of these patients, 63 percent demonstrated a 15-letter gain and 47 percent were able to maintain a 10-letter gain at the end of follow-up (at least three years). A lack of continued therapy didn’t adversely affect the final visual outcome, the researchers noted. The study indicates that, “The three patients who lost vision showed macular atrophy on SD-OCT—probably a consequence of the natural progression of the disease. Overall, the gains noted in the first months after the injection were reduced by the end of the follow-up period; this reflects a continuing degenerative process in all probability, even if there’s no recurrence of the neovascular membrane.”

The researchers say that the purpose of the study wasn’t to challenge established protocols but to call for more flexibility in their execution and provide thought for future studies that look at larger numbers (modified PRN from baseline).

^{1. Bilgic A, Kodjikian L, Mathis T, et al. Single injection response to antivascular endothelial growth factor agents in patients with wet age-related macular degeneration: Incidence and characteristics. Retina. 2021;41:1901-10.}