Outlook Therapeutics announced receipt of the CRL exactly one year after resubmission of their BLA for ONS-5010 as a treatment for wet age-related macular degeneration, which would have been the first indication for a retinal disease given to an ophthalmic version of bevacizumab.
The prospect of an FDA-approved ophthalmic formulation of bevacizumab for the treatment of retinal conditions has hit a significant delay, with Outlook Therapeutics announcing the receipt of a Complete Response Letter (CRL) to for their Biologics License Application (BLA) for ONS-5010, or bevacizumab-vikg (LYTENAVA), in the treatment of wet age-related macular degeneration (AMD).
Announced by Outlook Therapeutics on August 30, 2023, the FDA concluded it could not approve the BLA during this review cycle, despite the pivotal NORSE TWO trial meeting its safety and efficacy endpoints, due to several Chemistry Manufacturing and Controls issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence.1
“We continue to believe in the public health need to provide the retina community with an FDA-approved bevacizumab treatment option for wet AMD. We will request a formal meeting as soon as possible with the FDA to further understand the BLA deficiencies and how best to resolve them. Following this meeting with the FDA, the Company will be able to discuss next steps and the expected timing for resolution,” said Russell Trenary, President and CEO of Outlook Therapeutics.1
The journey towards a regulatory decision for ONS-5010 started in March 2022 with the company’s initial submission of a BLA for the agent. In May 2022, the company announced the FDA had requested additional information in order to complete the filing of the BLA for treatment of wet AMD. As a result of this request, the company withdrew its BLA and announced plans to resubmit a revised BLA by September 2022.2,3
The BLA resubmission was announced in August 2022 and the company announced the FDA acceptance of their resubmission in October 2022. According to the October 2022 release, Outlook Therapeutics estimated ONS-5010 was expected to receive 12 years of regulatory exclusivity in the US if approved.4,5
“The retina community needs an FDA-approved ophthalmic bevacizumab to deliver an alternative targeted on-label treatment for patients with wet AMD,” said Julia A. Haller, MD, ophthalmologist-in-chief at Wills Eye Hospital and an Outlook Therapeutics Board member.1
The BLA submission for ONS-5010 is based on a clinical program consisting of 3 trials: NORSE ONE, NORSE TWO, and NORSE THREE. The NORSE TWO trial was a phase 3 trial aimed at assessing the efficacy and safety of ONS-0510 against ranibizumab, which was dosed as one of the regimens directed in the label.5
The trial’s primary endpoint of interest was the difference in proportion of patients who gained at least 15 letters in best corrected visual acuity (BCVA) at month 11. The key secondary endpoint of interest was mean increase in BCVA from baseline.6
Results of the trial suggested ONS-5010 met both primary and secondary endpoints. In the trial, 41.7%, 56.5%, and 68.5% of patients receiving ONS-5010 gained 15 or more, 10 or more, and 5 or more letters of visual acuity. The mean increase in BCVA among patients receiving ONS-5010 was 11.2 letters (P = .0043).6
According to Outlook Therapeutics, only one subject reported ocular inflammation in across all 3 trials. In NORSE TWO, there was one related ocular serious adverse event reported in the ONS-5010 trial arm, which was an iritis. Outlook Therapeutics noted this was resolved and was not followed by any further unanticipated safety signals. The company went on to note the most common ocular adverse event in the trial was intravitreal injection-related conjunctival hemorrhage and this resolved without any sequela.6