Aflibercept biosimilars – update on the development progress

In the past 2 years, there have been multiple approvals of ranibizumab biosimilars across the globe. There are some that are approved by the local regulatory authority of a country; for example, the Drug Controller General of India has approved two ranibizumab biosimilars (Ranieyes, by Lupin Ltd and Ranizurel by Reliance Life Sciences) in India [1]. The Ministry of Food & Drug Safety of South Korea approved CKD-701 by Chong Kun Dang Pharmaceutical Corp [2]. Furthermore, the Pharmaceuticals and Medical Device Agency of Japan has approved Ranibizumab BS1 by Senju Pharma [1]. Apart from these three ranibizumab biosimilar molecules, other drugs such as Byooviz by Samsung Bioepis South Korea, Cimerli (USA)/Ongavia (UK)/Ranivisio (Europe) from Coherus, USA received approval from both United States Food and Drug Administration (US-FDA) and the European Medical Agency (EMA) [1]. Ximluci by STADA, Germany, has received approval from the EMA and the Biologics License Application (BLA) has been filed for US-FDA [3].

The approval of ranibizumab biosimilars was a welcome change to improve the access of ranibizumab to many patients across the globe by making it cost-effective. However, over time Eylea (Aflibercept, Regeneron, USA) has become the most common anti-vascular endothelial growth factor (anti-VEGF) used across the globe due to its better efficacy [4]. Recently, the first Eylea biosimilar (YESAFILI by Biocon Pharmaceuticals, India/previously known as MYL1701P from Momenta Pharmaceuticals/Viatris) received European Commission approval for market authorization in the European Union [5]. Probably this is the beginning of a larger change that the retina speciality will see in upcoming years in terms of access to the aflibercept at an affordable price. Biocon has not yet revealed the price point but based on the experience from ranibizumab biosimilars, it could be anywhere between 25 and 50% less than the originator aflibercept (Eylea).

There are at least five Eylea biosimilar molecules that are in the final stages of approval. The following is the development update on aflibercept biosimilars.

FYB 203 (Formycon AG/Klinge Biopharma GmBH)

The FDA has accepted the abbreviated Biologics License Application (aBLA) for FYB 203, which was submitted in June 2023. FYB 203 became the second biosimilar developer to announce the submission of aBLA for an Eylea biosimilar after Mylan’s (now Viatris’s) submission in October 2021 (Mylan has since transferred its rights to Biocon Inc.). According to Formycon, the US- FDA assigned a target action date for the aBLA of June 2024 [6].

CT-P42 (Celltrion, USA)

The phase 3 trial has been completed successfully and results are reported. The only difference from the other Eylea biosimilar trials is that CT-P42 had done trials in diabetic macular oedema (DMO) instead of neovascular-age-related macular degeneration (n-AMD). This is the second Eylea biosimilar after YESAFILI that has done trials in DMO not in n-AMD. It submitted an aBLA in June 2023 seeking approval to market for the full range of non-paediatric approved indications of Eylea. Celltrion is the third company to file an aBLA for Eylea biosimilar after YESAFILI from Biocon and FYB 203 from Formycon [7].

SB15 (Samsung Bioepis, South Korea)

Successful phase 3 trial results have been presented and published [8]. However, there is no information about the submission to the regulatory authority.

ABP 938 (Amgen, USA)

The phase 3 trial has been completed successfully in n-AMD. Probably this is the only company other than Sandoz that has completed trials with the use of pre-filled syringes (PFS) [9].

SCD411 (Sam Chun Dang Pharmaceuticals)

Sam Chun Dang Pharmaceutical licensing-out agreement to supply its biosimilar referencing Eylea (aflibercept), SCD411, to Apotex, a Canadian pharmaceutical company. Sam Chun Dang Pharmaceuticals looking forward to becoming the first company in Canada to provide SCD411 available in PFS [10]. SCD411 has been proven equivalent based on the final results of the phase 3 trial [11].

SOK583A1 (HEXAL; Sandoz, USA)

Sandoz completed a phase 3 trial (MYLIGHT Study) in n-AMD (In adults, In the elderly, and Treatment-experienced) in USA. Efficacy data from a phase-III trial in n-AMD were released by Sandoz recently. To the best of our knowledge, this is the only Eylea biosimilar that has been tested with PFS in a phase 3b study, probably due to the proprietary technology of Novartis, which other biosimilar manufacturers couldn’t achieve till now [12].

AVT06

Alvotech has signed an exclusive agreement with Polifarma to commercialise AVT06, a planned biosimilar to Eylea (aflibercept), in Turkey [13].

ALT-L9 (Alteogen, South Korea)

Completed patient enrolment in global Phase 3 clinical trial. Early 2024 is projected for Phase 3 completion and product launch in Europe is expected after obtaining approval in the first half of 2025. An aBLA will be submitted to the relevant health authorities in early 2024. Furthermore, Alteogen recently announced that it has registered a Taiwanese patent for the PFS (pre-filled injection) formulation of ALT-L9 [14].

OT-702 (Ocumension Therapeutics/Shandong Boan Biological Technology, China)

The Phase 3 clinical study (comparative clinical study of efficacy and safety) of BA9101 (Aflibercept Intravitreous Injection) has completed the enrolment. The clinical study is being conducted by Boan Biotech in collaboration with its partner Ocumension Therapeutics (BA9101 is coded-named OT-702 at Ocumension Therapeutics) [15].

According to the life sciences consultancy Spherix Global Insights, Eylea holds a 43.4% market share, with Avastin (bevacizumab, Genentech/Roche) at 34%, Lucentis at 9.4% and Vabysmo at 7.6% filling out the market [4]. These statistics show how Eylea biosimilars might bring a change in reducing the financial burden on the overall health system. The above statistics are from the USA; however, there are many countries, such as India, where Eylea has the least market share due to poor affordability. Eylea biosimilars might improve these statistics in countries such as India and more patients might have access to this molecule. The uptake of Ongavia in the developed world such as the UK is a sign that aflibercept biosimilars might bring change in the practice even in the developed world. It is to be seen how the recent approval of high-dose Eylea (8 mg) will impact the approvals of Eylea 2 mg biosimilars. Furthermore, most of the companies seem to be in a race to bring PFS biosimilar Eylea. Pre-filled syringing technology looks simple to achieve but it has its own challenges due to narrow space and existing technology patents [16]. Retinopathy of prematurity is likely not to be included by biosimilar companies because of the Orphan Drug Designation, which gives 7 years of exclusivity for the indication in the USA. Overall, though the anti-VEGF space looks crowded with recent approvals such as Faricimab and high-dose Eylea, aflibercept biosimilars might prove a financial balancer for patients and health systems.

Author contributions

AS: conception, analysis, drafting, integrity check, final approval. AL, NP, NK, BDK: drafting, revision, analysis, integrity check.

Competing interests

AS—consultant: Novartis, Allergan, Bayer, Lupin and Intas and speaker fee: Biogen. AL—consultant: Allergan, Novartis, Roche, Notal Vision, ForSight Labs, Beyeonics, Bayer Health Care. NP—None. NK—None. FB—consultant: Allergan, Bayer, Boehringer Ingelheim, FidiaSooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics, Zeiss. BDK—clinical research: Alcon, Alimera, Allegro, Allergan, Apellis, Clearside, Genentech, GSK, Ionis, jCyte, Novartis, Regeneron, ThromboGenics and consultant: Alimera, Allegro, Allergan, Cell Care, Dose, Eyedaptic, Galimedix, Genentech, Glaukos, Interface Biologics, jCyte, Novartis, Ophthotech, Regeneron, Revana, Theravance Biopharma.