Review: Biobetters and Biosimilars Set to Emerge in Ophthalmology

A strong market and development push for “biobetters” is anticipated by authors of a review of biosimilar and new biologic drug development in ophthalmology. Whereas biosimilars have the same amino acid sequence and are highly similar to reference products, biobetters may be modified chemically and have a different amino acid sequence or purification process. This can improve shelf life and pharmacological effects.

Biobetters may require a much larger investment in development than biosimilars, but “the chances of a biobetter reaching the production stage are incredibly high,” the authors write.

Biobetter Examples

An example of a biobetter cited by the authors is Susvimo, an ocular implant that delivers ranibizumab (Lucentis) into the eye, eliminating the need for intravitreal injections. Susvimo, a Genentech product, was approved by the FDA in October 2021. Genetech is also the originator of ranibizumab, which treats neovascular age-related macular degeneration (AMD), macular edema, and diabetic retinopathy.

In the Republic of Korea, Ildong Pharmaceuticals is developing a biobetter for patients receiving ranibizumab that is hoped to improve efficacy and lessen resistance; and Alteogen has patented an aflibercept (Eylea; also for AMD) biosimilar formulation that has an improved shelf life and resistance to heat.

“While the biobetter market is still in the developing phase, it has enormous potential to grow,” the authors wrote. In their review, they stressed a coming wave of biosimilars in ophthalmology and the importance of keeping up for clinicians.

Anti-VEGF Biosimilars

In the United States, the patents for bevacizumab (Avastin), which is used off-label in ophthalmology, and ranibizumab expired in 2019 and 2020, respectively. Aflibercept won’t be off patent in the United States before 2023.

Bevacizumab, ranibizumab, and aflibercept are anti–vascular endothelial growth factor (anti-VEGF) therapies that stop the abnormal growth of blood vessels that lead to subretinal bleeding and harm vision. They also treat diabetic macular edema and retinal vein occlusion.

The authors counted 10 manufacturers currently with ranibizumab biosimilars approved or in development, globally. Byooviz, a Samsung Bioepis biosimilar, was approved in 2021 by the FDA and the European Commission. Other ranibizumab biosimilar candidates are in advanced clinical trials.

Razumab, developed by Intas Pharmaceuticals, is a ranibizumab biosimilar approved in India in 2015. A battery of clinical trials demonstrated high similarity in efficacy and safety to the reference product, but it ran into quality difficulties early, with variations noted between batches. The cause was determined to be higher endotoxin levels in the buffer used during manufacturing, and the problem was resolved, the authors said.

Other ranibizumab biosimilar candidates include:

• FYB201 (Formycon and Bioeq, Germany), for which satisfactory phase 3 clinical results have been reported;
• Xlucane (Xbrane Biopharma, Sweden), which the authors said may be produced with better technology than the reference drug and has reached the phase 3 clinical stage of development;
• R-TPR-024/Ranizurel (Reliance Life Sciences, India), which was approved by Indian regulators in 2020;
• SJP-0133/GBS-007 (Senju Pharmaceutical, Japan), in phase 3 trial development;
• LUBT010 (Lupin, India), under phase 3 development; and,
• CKD-701 (Chong Kun Dang, Republic of Korea), also under phase 3 development.

Bevacizumab Biosimilars

Many bevacizumab biosimilars are already approved and on global markets. In the United States, Avastin, the reference product, is used off label for eye treatment and requires pharmacy compounding for this purpose. So far, bevacizumab has been cheaper to use for eye disease than ranibizumab, but the development of a bevacizumab biosimilar specifically for eye disease could change the pricing dynamics, the authors wrote. In many countries, pharmaceutical compounding services are not readily available, they note.

Outlook Therapeutics is developing ONS-5010, which has been accepted by the FDA for review in the form of an investigational new drug application, not specifically a biosimilar biologics license application. A phase 3 trial in patients with neovascular AMD is underway, and “if the intravitreal formulation is approved, the justification for the use of a compounded version [of bevacizumab] may no longer exist. However, it may lead to a paradoxical rise in the cost of bevacizumab in ophthalmology,” the authors wrote.

Aflibercept Biosimilars

Multiple aflibercept biosimilars are under development. These include:

• MYL-1701P (Momenta Pharmaceuticals and Mylan, United States), and the manufacturers anticipate FDA approval and a launch in 2022 and 2023, respectively;
• ABP 938 (Amgen, United States), in phase 3 development;
• FYB203 (Formycon and Bioeq, Germany), also in phase 3 clinical development, with target US and EU market introduction in 2023 and 2025, respectively.
• SB-15 (Samsung Bioepis, Republic of Korea), which began phase 3 clinical trials in June 2020;
• SOK583A19 (Sandoz, Switzerland), in phase 3 development;
• CT-P42 (Celltrion, Republic of Korea), also in phase 3 clinical development;
• ALT-L9 (Alteogen, Repubic of Korea), which has not yet begun phase 1 trials; and,
• OT-702 (Ocumension Therapeutics and Shandong Boan Biological Technology, China), in phase 3 trials.

With many ophthalmology biosimilars likely to reach market in the next several years, “pharmacovigilance, quality control, and monitoring are extremely important, along with immunogenicity testing before market approval,” the authors concluded.

Reference

Kapur M, Nirula S, Naik MP. Future of anti-VEGF: biosimilars and biobetters. Int J Retin Vitr. 2022;9:2. doi:10.1186/s40942-021-00343-3