Regeneron and Bayer’s blockbuster drug, Aflibercept (Eylea®) gained its first approval in the US and the EU for Neovascular (Wet) Age-Related Macular Degeneration (AMD) in 2011 and 2012, respectively. This VEGF (vascular endothelial growth factor) inhibitor was subsequently approved for various other retinal disorders such as Macular Edema Following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), Diabetic Retinopathy (DR), Retinopathy of Prematurity (ROP) and myopic choroidal neovascularisation (myopic CNV).
Most recently, in Q3 2023, a high dose version of Eylea® was approved by the FDA as Eylea® HD which is said to be a game-changer in retinal care. With the approval of Eylea® HD, AMD patients will now require lesser injections after their initial monthly doses and still benefitted from the therapeutic effect of Eylea®. As per Regeneron’s recent financial results, the US net sales in Q3 2023 for Eylea® and Eylea® HD were a total of $1.49 billion, including $43 million from Eylea® HD(1).
But how long does this go on? Aflibercept composition of matter US 7,070,959 patent expired in June 2023 (including a patent term extension of 1119 days) and the reference product exclusivity (followed by pediatric exclusivity) expires in May 2024. This has caught the attention of many biosimilar manufacturers and Biocon Biologics is on the top of the ladder.
Aflibercept biosimilars that are on the way as follows:
| Candidate | Manufacturer | Regulatory status |
| Yesafili | Biocon Biologics/Viatris/Mylan (First-to-file) | aBLA under FDA review; Authorised in EU(2) |
| ABP 938 | Amgen | aBLA accepted- pending approval |
| FYB203 | Formycon/Klinge Biopharma GmbH | aBLA accepted- pending approval |
| CT-P42 | Celltrion | aBLA submitted |
| ALT‑L9 | Alteogen/Kissei | Phase III |
| SB15 | Samsung Bioepis | aBLA submitted |
| SOK583A1 | Sandoz | Phase III |
| OT-702/LY09004 | Ocumension Therapeutics/Boan Biotech | Phase III |
However, Regeneron has responded by filing Biologics Price Competition and Innovation Act (BPCIA) litigation suits against the biosimilar manufacturers for its multiple patents protecting Eylea® as follows(3):
| Case number | Parties | Case status | Filing date | Patents in suit |
| 1:22-cv-00061 | Regeneron vs Biocon Biologics | Open | 02/08/2022 | 24 |
| 1:23-cv-00089 | Regeneron vs Celltrion | Open | 08/11/2023 | 38 |
| 1:23-cv-00094 | Regeneron vs Samsung Bioepis | Open | 21/11/2023 | 37 |
| 1-23-cv-00097 | Regeneron vs Formycon | Open | 29/11/2023 | 39 |
These patents include claims protecting the Eylea® formulation, method of use, method of manufacturing and more.
There are multiple Patent Trial and Appeal Board (PTAB) petitions (Decided and Open) seeking cancellation of the patent claims filed by the biosimilar manufacturers. It would be interesting to see how the BPCIA litigation suit decisions unveil and potentially impact one of the blockbuster biologics of the decade.
The bAflibercept may enter the market as early as H2 2024 but some analysts predict the entry not earlier than 2025. The fate of bAflibercept will mostly be decided by these pre-launch litigation suits.
Eylea® is not only threatened by the looming biosimilars but also by the presence of other competitor products on the market such as, Lucentis, Byooviz, Ximluci, Cimerli, Susvimo, Vabysmo, Avastin, Beovu, Conbercept that are approved for or used off-label for same therapeutic indications(4).
It would be interesting to see how Regeneron prevents or limits Eylea®’s ever-increasing competition and its impact on the ophthalmology therapy area.
References:
- https://investor.regeneron.com/news-releases/news-release-details/regeneron-reports-third-quarter-2023-financial-and-operating
- https://www.ema.europa.eu/en/medicines/human/EPAR/yesafili
- https://biologicshq.com/eylea-aflibercept-and-soliris-eculizumab-ipr-updates/
- https://investor.regeneron.com/pdf/2022Form10K