Could New Therapies for Macular Degeneration Leave Anti-VEGF Biosimilars Behind?

The currently available anti—vascular endothelial growth factor (anti-VEGF) therapies for wet age-related macular degeneration (AMD) are effective but problematic due to the cost, frequency of injections, and expertise required. Biosimilars in clinical development to compete on cost with these drugs will be arriving on the market, according to a review article in The American Journal of Managed Care^®, the sister site of The Center for Biosimilars^®.

Existing anti-VEGF agents

In neovascular AMD, overexpression of VEGF-A drives the formation of abnormal, highly permeable blood vessels, leading to retinal edema and deterioration of retinal function. The introduction of anti-VEGF biologics, starting in 2004 with the approval of pegaptanib, improved treatment for neovascular AMD; rates of blindness due to the disease have fallen by 50% to 70%.

However, the treatment is costly, time consuming, and difficult to administer, plus it blocks neovascularization only temporarily. These drugs must be administered by retinal specialists via intravitreal injection every 4 to 12 weeks. In addition to the cost, the frequency of the injection regime makes adherence difficult. Many patients have difficulty arranging transportation or have comorbidities that take priority, which often result in missed appointments that reduce the effectiveness of treatment. The author noted that “In large-scale clinical trials, anti-VEGF utilization maintained visual acuity in more than 90% of patients,” but vision preservation results from real-world studies fall short compared with those from clinical trials because many patients are not getting the number of injections specified in their regimen.

Pegaptanib is no longer used because other anti-VEGF agents have demonstrated greater efficacy in clinical trials. Three anti-VEGF biologics are currently available: the VEGF-decoy aflibercept (Eylea), antibody fragments ranibizumab (Lucentis), and brolucizumab (Beovu). Plus, bevacizumab has been prescribed off label since 2005, “because of its low cost and comparable efficacy.” Although clinical trials have, overall, shown these anti-VEGF agents are similarly effective, there may be individual differences between patients.

Emerging therapies aim to reduce the injection burden in neovascular AMD

To reduce the burden of regular injections, monitoring regimens to assess the individual patient’s disease activity and extend the dosing interval when appropriate are in use by many retinal specialists. There are several anti-VEGF agents in the pipeline designed to extend the interval between injections or change the delivery of the drug entirely. There is also promising data from a phase 1 clinical trial on gene therapy, in which the DNA sequence for an anti-VEGF agent was introduced via a viral vector into retinal cells “that then act like anti-VEGF factories.”

Abicipar pegol and faricimab are anti-VEGF agents in development, and clinical trial data suggest the dosing interval could be extended compared with existing agents. The FDA is expected to act on the application for abicipar pegol later this year, and an FDA filing for faricimab for use in neovascular AMD is expected as early as 2022. Conbercept, a new VEGF decoy, was approved for use in neovascular AMD in China in 2013 and is in phase 3 development in the United States with results expected in 2022. An FDA filing is expected in 2021 for the ranibizumab port delivery system (PDS), a device implanted into the eye supplying continuous release of the existing anti-VEGF biologic ranibizumab, as an alternative to injections.

ONS-5010, an intravitreal bevacizumab formulation is in phase 3 clinical trials with results expected later this year, and FDA approval is anticipated in 2021 or 2022.

The potential role of biosimilars

The first biosimilar for bevacizumab, Mvasi, entered the US market in July 2019. However, bevacizumab is not approved for neovascular AMD, and it is unclear whether antineoplastic bevacizumab biosimilars will be repackaged for intravitreal administration.

The potential approval and introduction of intravitreal bevacizumab ONS-5010 to the market would prevent bevacizumab biosimilars from use in neovascular AMD for the duration of ONS-5010 market exclusivity. In this case, “compounding facilities would be prohibited from repackaging antineoplastic bevacizumab into syringes.”

The patent for ranibizumab is set to expire in June 2020 and aflibercept in November 2023, and biosimilars are expected to enter the market as these patents expire. Multiple ranibizumab biosimilars are in late-stage clinical development, including FYB201 (Formycon and Bioeq), SB11 (Samsung Bioepis), and Xlucane (Xbrane Biopharma). There are also aflibercept biosimilars in phase 3 clinical development.

The author noted we can “anticipate that the therapeutic landscape in neovascular AMD will become much more crowded and complex over the next few years.”

Reference

Baumal CR. Wet age-related macular degeneration: treatment advances to reduce the injection burden. Am J Manag Care. 2020;26(5 Suppl):S103-S111. doi:10.37765/ajmc.2020.43435