Publication
Article
Digital Edition
Biosimilars for retinal diseases: The long and winding road into clinical practice
Author(s):
Aflibercept biosimilars have cleared several hurdles on their way to marketplace
Image by Jennifer Toomey / MJH Life Sciences using AI
Reviewed by Priya Sharma Vakharia, MD
The anti-VEGF biosimilars to treat retinal diseases are slowly being adopted by physicians into clinical practice.
Ranibizumab-nuna (Byooviz, developed by Samsung Bioepis, marketed by Biogen) was approved by the FDA in 2021, and ranibizumab-eqrn (Cimerli, Coherus BioSciences) was approved in 2022. Both are considered interchangeable with the reference drug ranibizumab (Lucentis, Genentech).
Byooviz was approved to treat wet age-related macular degeneration, macular edema associated with retinal vein occlusion, and myopic choroidal neovascularization. Cimerli was approved to treat all ranibizumab indications.
Two aflibercept biosimilars that received FDA approval in May 2024 are Yesafili (Biocon Biologics) and Opuviz (Samsung Bioepis, Biogen) and are interchangeable with the reference product Eylea (Regeneron Pharmaceuticals).
The aflibercept biosimilars, however, may have to navigate a more tortuous path than that traveled by ranibizumab and may enter the marketplace at a later date as the result of ongoing litigation, according to Priya Sharma Vakharia, MD, who is in private practice at Retina Vitreous Associates of Florida, Tampa.
An online report by Pearce IP1 indicated that Regeneron filed a first complaint against Celltrion in November 2023, in which Regeneron alleged infringement of 38 patents, including the 25 patents asserted in the second complaint, which was filed in May 2024. The complaints included the method of treatment, formulation, and manufacturing claims about aflibercept. Regeneron also has filed other complaints that are pending in relation to aflibercept biosimilars, against Amgen, Mylan, Samsung Bioepis (2 actions), and Formycon, according to Pearce IP.
Acceptance into clinical practice
The uptake of the ranibizumab biosimilars into clinical practice has not been as robust as the manufacturers might have envisioned. This lower-than-desired rate of acceptance may be because ranibizumab is not generally as widely used to treat retinal diseases as are aflibercept and faricimab (Vabysmo, Genentech), according to Vakharia.
Moreover, vitreoretinal specialists expressed skepticism when ranibizumab biosimilars were first launched. In contrast, the future may be brighter for the aflibercept biosimilars considering the extensive use of the reference aflibercept product.
The slow adoption of the ranibizumab biosimilars may actually work in favor of the aflibercept biosimilars, that is, as a soft launch for the aflibercept biosimilars, by providing the time for physicians to learn about, accept, and to also become comfortable with using biosimilars.
Top-line consideration: Safety
When the aflibercept biosimilars finally become available, the obvious question is the level of acceptance by retina specialists.
A consideration regarding physician acceptance surrounds the nature of the clinical trials in which the biosimilars are evaluated—that is, they are much smaller and shorter than for the reference products.
“Safety,” Vakharia commented, “is always the top-line concern. The trials of the biosimilar are not the large clinical trials that physicians are accustomed to. These trials often have a primary 8-week visual acuity end point. Thus, it is likely that retina specialists may delay adoption of biosimilars while they wait for real-world experience.”
The drugs’ safety is followed in study patients over the course of a year. However, Vakharia pointed out, postmarketing surveillance is key to the safety profile and will be of greater importance for the biosimilars than for other drugs on the market to establish their real-world safety.
“Aflibercept biosimilars are in the retina space, and they are on the very distant horizon and may become a force when they enter the marketplace,” Vakharia said. “Postmarketing surveillance is key to the use of these drugs to ensure safety.”
The ranibizumab experience
The physician response to the performance of ranibizumab biosimilars in practice may foretell what will happen with the aflibercept biosimilars when they come to market.
“The experience with the ranibizumab biosimilars has been slow but positive. Clinicians are seeing clinical results similar to that of ranibizumab and are not seeing many safety issues,” she and Carl C. Awh, MD, explained.
Awh, who is in private practice at Tennessee Retina in Nashville, reported that the reference ranibizumab with both the 0.5-mg and 0.3-mg doses was approved in 2006 based on a 21.6-letter improvement in vision compared with sham injections with which the vision decreased.
The approval of the ranibizumab biosimilars was based on the results of the clinical trials that included about 700 patients. In these trials, the formulations were considered to be clinically equivalent to the reference product in safety and efficacy.
The biggest question surrounding the ranibizumab biosimilars, then as now, remained the appearance of any unanticipated clinical outcomes associated with the new ranibizumab biosimilars. That concern, Awh pointed out, is answered with clinical experience.
He described the extensive US clinical experience with Byooviz and Cimerli in 5,085 eyes with 13,459 injections, ie, 5,049 injections and 8,410 injections, respectively. All patients had a minimum of 28 days of follow-up after injection.
More than 200 participating retina specialists looked for new findings of anterior chamber or vitreous cells; endophthalmitis, uveitis, or vasculitis; or other adverse events.
The results showed no significant difference in the visual acuity at 1, 2, and
3 months after the injections (P = .12) following 1.65 additional biosimilar injections after the first treatment.
The adverse events were minimal anterior chamber or vitreous cells with no vision loss in 9 cases and 3 cases of presumed endophthalmitis (1 case for both ranibizumab biosimilars). Moreover, no cases of retinal vasculitis or inflammation secondary to a drug reaction developed.
“Our initial experience with ranibizumab biosimilar agents revealed no unexpected adverse outcomes,” Awh noted. “The clinical efficacy of the biosimilar agents seems equivalent to that of Lucentis.”
Awh also noted that surveillance of the biosimilars continues.
Reference:
Awh CC, Donkor R, Miller MC. Efficacy and safety of biosimilar ranibizumab-nuna and ranibizumab-eqrn in clinical use by a consortium of retina specialists. Presented at: 41st American Society of Retina Specialists Annual Meeting; July 28-31, 2023; Seattle, WA.
