Retina as a subspecialty has been transformed since the introduction of anti-vascular endothelium derived growth factors (Anti-VEGF) in 2005, thanks to Dr Phil Rosenfeld et al., who discovered the use of bevacizumab (Avastin) for the management of retinal diseases as an off label therapy [1]. Since then multiple anti-VEGF molecules such as ranibizumab (2006), aflibercept (2011), brolucizumab (2019) have been approved by various authorities including the United States Food and Drug Administration (US-FDA) and European Medical Agency (EMA) [2,3,4]. From surveys related to anti-VEGF usage for retinal diseases in various regions, the use of off label bevacizumab (Avastin) has been found to be the most popular anti-VEGF agent primarily due to its comparable efficacy to the other anti-VEGF agents coupled with a significantly lower cost. This demonstrates the need and interest in a cost-effective therapy to provide healthcare access to the greatest population while minimising the financial burden on the world wide health care systems [5]. Off label bevacizumab (Avastin) costs approximately $50-$150 for one dose compared to approved biologics such as ranibizumab and aflibercept costing around $2000 per injection [5]. There was an effort to introduce bevacizumab biosimilars in the US for ophthalmic indications during supply chain issue of bevacizumab (Avastin) but it was not successful [6]. With bevacizumab (Avastin) being the highest used biologic despite it not being approved for ophthalmic use, this manuscript will discuss the challenges and opportunities for on label bevacizumab in the crowded space of anti-VEGFs in retina.

Knowing the great success of off-label bevacizumab (Avastin) since the beginning of the anti-VEGF era in retina, it is understandable that some companies would want to bring on label bevacizumab for ophthalmic use, particularly since the patent for bevacizumab (Avastin) has expired. At present bevacizumab (Avastin) comes in a large 4 ml vial which has to be sent to compounding pharmacies for fractionation, which has created concerns among retinal physicians regarding impurities that could potentially be introduced during the process, sterility, and dosage consistency. There have been outbreaks of endophthalmitis which have been traced back to impurities introduced during preparation of the fractionated doses at compounding pharmacies. The ophthalmic version of bevacizumab, if approved, is anticipated to be in a single use vial to address the primary concerns about fractionation. At present, at least one pharmaceutical team, Outlook Therapeutics is trying to bring bevacizumab (ONS-5010/Lytenava) for ophthalmology [7]. ONS-5010/Lytenava has completed the NORSE ONE, NORSE TWO and NORSE THREE studies. NORSE ONE (proof of concept) and NORSE THREE (open label) studies were primarily to assess safety. Recently results of phase 3 NORSE TWO trials were presented at AAO [8]. This was a superiority trial design, (N = 228, 39 clinical trial sites) for safety and efficacy in patients with neovascular age-related macular degeneration (nAMD) to compare ONS-5010/Lytenava ophthalmic bevacizumab dosed monthly against ranibizumab’s 3 monthly loading doses followed by a q12w dosing based on the PIER study [9]. Participants in the trial were treated for 12 months, with the primary endpoint at month 11 being the difference in proportion of patients who gained at least 15 letters (3 lines) in best corrected visual acuity (BCVA). The key secondary endpoint was the mean change in BCVA from baseline to month 11. The NORSE TWO pivotal data met both primary and secondary endpoints with statistically significant and clinically relevant results: In the trial, ONS-5010/Lytenava achieved highly statistically significant and clinically relevant primary data (p = 0.0052) and key secondary efficacy endpoints (p = 0.0043). In the intent-to-treat (ITT) primary dataset, the percentage of patients who gained at least 15 letters who were treated with ranibizumab was 23%, and the percentage of patients who gained at least 15 letters who were treated with ONS-5010/Lytenava was 41% (p = 0.0052). A mean change in BCVA was observed with ranibizumab of 5.8 letters and the mean change with ONS-5010 was 11.2 letters (p = 0.0043) [7].

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