A Guide to Biosimilars for Retinal Diseases

In a review article discussing the role of biosimilars in neovascular retinal diseases, the authors said biologics have significantly improved outcomes in these conditions, noting that vascular endothelial growth factor (VEGF) inhibitors are now considered first-line treatments.

The authors aimed to provide retinal specialists with an introduction to biosimilars, as the first biosimilar ranibizumab (Byooviz) was recently approved by the European Medicines Agency (EMA) and US FDA, and several candidates for ranibizumab and aflibercept biosimilars are currently in development. After the publication of the review, a second ranibizumab biosimilar (Ranivisio) was approved by the EMA.

While some retinal specialists likely have experience treating noninfectious uveitis with biosimilar adalimumab, the reviewers expected that many are not familiar with biosimilars. Their article outlined how biosimilars are developed, the regulatory approval pathway, and their potential for managing neovascular retinal diseases in clinical practice.

Current Use and Cost of VEGF Inhibitors for Retinal Neovascular Diseases

Anti-VEGF biologics, such as ranibizumab (Lucentis) and aflibercept (Eylea) are used to treat neovascular retinal diseases, but are high in cost. The authors cited an estimate that ranibizumab and aflibercept together comprise about 12% of the Medicare Part B budget every year. They also cited real-world studies suggesting that high costs may cause patients to cut their therapy short, having fewer injections and compromising their potential visual outcomes.

To reduce the cost of anti-VEGF therapy, some retinal specialists have begun prescribing other anti-VEGF biosimilars off-label. The reviewers anticipate that some physicians may ask why they should use biosimilars when these off-label options are available.

Bevacizumab is currently only approved for solid tumors, although studies suggest it is noninferior to ranibizumab and aflibercept in neovascular age-related macular degeneration ( wet AMD) and diabetic macular edema (DME). Biosimilars to bevacizumab are currently available. Another VEGF inhibitor, ziv-aflibercept, which is approved for treating colorectal cancer, has been investigated for treating wet AMD.

The reviewers advise using caution regarding these off-label options instead of biosimilars approved for the indication. In addition to the fact that they are being used off-label, there are concerns regarding inflammation and infection after intravitreal administration of both bevacizumab and ziv-aflibercept. Also, both require additional compounding before use in retinal diseases, and bevacizumab is not available in all countries. Furthermore, there are concerns about potential retinal damage from ziv-aflibercept due to its hyperosmotic properties, and ophthalmic use of ziv-aflibercept is contraindicated in the European Union for this reason.

Immunogenicity, Extrapolation, Interchangeability, and Switching

The authors discussed important issues and concepts surrounding biologics and biosimilars, including immunogenicity, their potential to induce the formation of anti-drug antibodies. Although immunogenicity is a key consideration in biosimilar development, they wrote that for currently authorized biosimilars in Europe and the United States in many therapeutic areas, “the rate of immunogenicity was found to be similar between biosimilars and their reference products.”

They explained the rationale for extrapolation of a biosimilar to indications in which the drug would work by the same mechanism of action, and the differences in the definitions of interchangeability between Europe and the United States. The EMA treats interchangeability as a scientific term and leaves decisions on interchangeability to member states, whereas in the United States, it is a legal designation that requires additional clinical evidence. They added that the first biosimilar product to achieve interchangeable status, insulin glargine-yfgn (Semglee), did so just last year.

The reviewers said that a key question for patients and prescribers on biosimilars is whether switching will lead to loss of disease control, adverse events, or increased immunogenicity. These questions have been addressed by “a large number of studies have provided reassurance that switching from reference biologics to biosimilars is effective and safe,” they wrote.

Comprehensive Knowledge of Biosimilars Is “Critical” to Their Widespread Adoption

The reviewers wrote that evidence from clinical trials and real-world studies “has failed to find clinically relevant differences between biosimilars and their originator products in terms of efficacy, safety, and immunogenicity,” and stressed that conveying this information to patients is crucial.

To incorporate biosimilars into treatment of retinal diseases, physician understanding of biosimilars and physician patient-communication “can have a large impact on the success of a biosimilar switch,” and adequate communication can help to prevent poor treatment outcomes due to the nocebo effect. They recommended physicians build comprehensive knowledge of what biosimilars are and how they are approved and pass their confidence in biosimilars on to their patients.

The authors said that biosimilars could help “optimize clinical outcomes while providing substantial cost savings that can be reinvested into healthcare systems,” and they expect that their review article will act as a guide for retinal specialists and help them to discuss biosimilars with their patients.

Reference

Hariprasad SM, Gale RP, Weng CY, Ebbers HC, Rezk MF, Tadayoni R. An introduction to biosimilars for the treatment of retinal diseases: a narrative review. Ophthalmol Ther. 2022;11(3):959-982. doi:10.1007/s40123-022-00488-w