The impact potential of aflibercept biosimilars

A biologic drug is a medication produced from or containing components of living organisms. Given the rigorous testing that originator biologics undergo to establish Food and Drug Administration (FDA) Biologics License Application (BLA) approval, their subsequent price yields a high burden on healthcare systems (1). Biologics account for 37% of prescription drug spending, despite comprising only 2% of all prescribed medications (2). Biosimilar medicines are designed to have active properties that are “highly similar” to a previously licensed reference product, leading to increased chemistry, manufacturing, and controls (CMC), analytical, immunogenicity, pharmacokinetic (PK) and pharmacodynamic (PD) review, but shorter and much less expensive clinical trials to obtain FDA approval (3). This abbreviated FDA pathway established in the Biologics Price Competition and Innovation Act of 2009 for approval of biosimilars is less expensive and much faster, presenting an opportunity to mitigate treatment costs and increase access for patients.

In ophthalmology, anti-vascular endothelial growth factor (VEGF) medications are an example of biologics that are the cornerstone of treatment of a variety of retinal conditions. In a recent JAMA Ophthalmology publication, Bressler et al. presented the results of the INSIGHT trial, a randomized double-masked multi-center clinical trial, which demonstrated the aflibercept biosimilar, MYL-1701P, to be equivalent to reference aflibercept in treatment outcomes and safety events in patients with diabetic macular edema (DME) (4). Subsequently, MYL-1701P, received FDA approval in May 2024 for the treatment of DME, in addition to neovascular age-related macular degeneration (AMD), diabetic retinopathy (DR), macular edema following retinal vein occlusion (MEfRVO) and retinopathy of pre-maturity (ROP). Though the INSIGHT trial demonstrated the safety and efficacy of an additional biosimilar that ophthalmologists may use to treat retinal diseases, barriers remain preventing increased adoption of biosimilars such as MYL-1701P across the ophthalmology community, which may ultimately limit their desired financial impact. These barriers include lack of trust in biosimilar efficacy and confidence in serious adverse events, lack of education surrounding the availability of biosimilars, lack of financial incentive to switch medications, and administrative burdens associated with obtaining new medications.

In the INSIGHT study, 355 patients with type 1 or 2 diabetes and central visually significant DME were randomized to either reference aflibercept or MYL-1701P. The primary outcome was mean change in best corrected visual acuity (BCVA) from baseline to week 8. This time point was chosen because it is considered a point at which the most rapid clinically significant differences between drugs may be detected, as demonstrated in prior studies comparing intravitreal medications in which treatment-naïve patients demonstrated the most pronounced BCVA gain at week 8 prior to efficacy plateau (5). At week 8, the authors found the mean change in BCVA to be +6.60 letters in the MYL-1701P group and +6.56 letters in the reference group, with an estimated mean treatment difference of 0.04 letters [90% confidence interval (CI): −1.16 to 1.24 letters]. Of note, vision outcomes have previously been shown to differ in DME patients with baseline visual acuity (VA) of 20/50 or worse across various anti-VEGF agents (6). Importantly, in the INSIGHT study, VA subgroup analysis comparing MYL-1701P with reference aflibercept had no difference in outcome, indicating MYL-1701P is clinically comparable to reference aflibercept with sustained effects among DME patients presenting with worse VA.

A secondary outcome of the study was mean change in BCVA from baseline to week 52. At week 52, mean change in BCVA from baseline were +10.76 letters in the MYL-1701P group vs. +10.52 letters in the reference group, indicating sustained benefits from the medication with no significant difference from the reference product. Another key secondary outcome was mean change in central retinal thickness (CRT) from baseline to week 52. At week 52, mean change in CRT was −170.14±7.198 µm in the MYL-1701P group vs. −167.67±7.260 µm in the reference group. Of note, the European Medicines Agency (EMA) prefers evaluating the non-inferiority of the mean change from baseline in central subfield thickness (CST) at 4 weeks for approval, and this outcome was also met in the INSIGHT study.

In summary, the studied primary and secondary outcomes indicated no statistically significant difference between the two drugs, meeting the prespecified equivalence margin per FDA regulatory requirements. Most notably, there was no difference in patients with worse VA at baseline, an effect unique to aflibercept in DME in prior clinical trials when compared to other anti-VEGF agents ranibizumab and bevacizumab (6).

While only 89 of 355 patients were included in PK analysis, the mean plasma concentration of drug was comparable between treatment arms across time points without accumulation of free drug systemically seen with repeat dosing. Most safety events occur at up to 1 year of treatment; therefore, a 52-week follow-up period is deemed sufficient to assess the safety of MYL-1701P (5). The incidence of non-ocular treatment-emergent adverse events (TEAEs) was 65.2% for MYL-1701P and 65.3% for reference aflibercept, with ocular TEAEs of 30.9% for MYL-1701P and 29.5% for reference aflibercept. There were no cases of ocular inflammation nor endophthalmitis in the MYL-1701P arm. Overall, these results indicate no significant difference in the safety profile of these two medications.

MYL-1701P is not the first aflibercept biosimilar to be approved by the FDA. SB15 was studied in patients with treatment-naïve neovascular AMD and received FDA approval in May of 2024. The principle of extrapolation is one way the approval pathway for biologic products may be abbreviated, allowing that once a biosimilar is demonstrated to be similar to an FDA-approved biological product, it will be FDA approved for all clinical indications the reference product was approved for without separate clinical studies in each disease. Therefore, through extrapolation, SB15 may be used for all clinical indications reference aflibercept was FDA approved for, including DME. As a result, there are now two aflibercept biosimilars for these indications. With MYL-1701P having been studied in DME patients as opposed to SB15 in AMD patients, the INSIGHT study evaluated a biosimilar in a novel context, promoting further confidence in equivalent safety and efficacy.

The importance of original anti-VEGF drugs upon which biosimilar development is made possible, cannot be overstated given the transformative impact they have had on the management of retinal disease. Biosimilars however, may have the potential to reduce financial burden on healthcare systems and patients with the goal of increasing cost effectiveness. Biosimilars to date have been released at lower prices than their reference products, thereby causing a decrease in reference product pricing due to increased competition (1,7). According to the US Generic and Biosimilar Medicines Savings Report, biosimilar use is estimated to have generated $13 billion USD in savings for healthcare payers between 2015 and 2021 (8). Byooviz^TM (ranibizumab-nuna) was launched in the US with a 40% price discount compared to its reference product. If a patient is to receive an average of 6 injections in the first year of treatment, and the average number of patients receiving injections in the US in 2016 was estimated to be 7 million, the potential healthcare cost savings is huge (9).

Scientifically rigorous comparative equivalence trials like INSIGHT help establish biosimilar safety and efficacy. However, the next step involves increased acceptance to facilitate biosimilar adoption into clinical practice. Though various anti-VEGF agents have been used in retina clinics for almost 20 years, the recent influx of newer medications and biosimilars obtaining FDA approval will complicate clinician choice of therapeutics. In order to facilitate adoption of biosimilars that have potential to drive healthcare cost savings, critical steps need to be undertaken. First, retina providers must be kept up to date regarding availability of biosimilars and associated indications. Second, hospital systems and practice supply chains must determine how to most cost-effectively stock the growing options of available injectable medications. Third, clinic discussions with patients must include education on the safety and efficacy of biosimilars and the various options available (10). Fourth, insurance companies and other payers must accept and reimburse biosimilars when clinically appropriate (11). A recent cost analysis conservatively estimated a paltry 5.9% savings on biologics from 2021 to 2025 due to limited adoption, suggesting larger savings may be achieved if payers instituted polices that increased biosimilar usage and promoted competition (2). Some insurance companies have started to enact step-therapy where using a biosimilar before a reference product has been required. Lastly, post-marketing clinical data with increased provider biosimilar usage will drive further confidence in these medications. In other fields, the use of biosimilar products is second nature. It has not been this way in ophthalmology with very little biosimilar ranibizumab utilization, but this may change with aflibercept biosimilars if the prices of these products are in line with expectations.

In conclusion, the INSIGHT study demonstrated clinical equivalence of biosimilar MLY-1701P to reference aflibercept with regard to efficacy, safety and pharmacokinetics, supporting the use of MLY-1701P as an alternative to reference aflibercept. With subsequent FDA approvals, the utilization of this and other biosimilars in clinical practice may increase cost-effectiveness for a host of retinal conditions including neovascular AMD, DME, DR, MEfRVO, and ROP. While challenges to clinical adoption exist, the retina community should embrace them and approach them head on.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article has undergone external peer review.

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-24-33/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-24-33/coif). P.K.K. reports that he is a consultant for Abbvie, Alcon, Alexion, Alkeus, Allgenesis, Alzheon, Amaros, Annexon Biosciences, AsclepiX, Astellas, Augen Therapeutics, Aviceda, Bayer, Bausch and Lomb, Beacon Therapeutics (AGTC), Biogen Idec, Bionic Vision Technologies, Complement Therapeutics, Endogena Therapeutics, Frontera Therapeutics, Galimedix, Innovent, Invirsa, iRenix, Isarna, Janssen, jCyte, Kanaph Therapeutics, Kanghong, Kera Therapeutics, Kriya Therapeutics, Nanoscope Therapeutics, Ocugenix, Oculis, Omeros, Osanni Bio, Panther Pharmaceuticals, Ray Therapeutics, RegenxBio, Resonance Medicine Inc., RetinaAI Medical AG, Retinal Sciences, ReVana, Revopsis, Roivant, Samsung Bioepis, Sandoz, SGN Nanopharma Inc., SmileBiotek Zhuhai Ltd., Stealth Biotherapeutics, Stuart, Sustained Nano Systems, Takeda, Théa, Tilak, Unity Biotechnology, Vanotech, and VisgenX. P.K.K. is an employee and receives stock from Ocular Therapeutix. P.K.K. is on the Board of Directors and receives stock from AAVAntgarde Bio. He also receives services from Carl Zeiss Meditec. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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