According to Outlook, in the FDA’s recently issued CRL it concluded it could not approve the BLA during this review cycle due to several CMC issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence.
Outlook Therapeutics Inc announced that a Type A Meeting request has been submitted to the FDA to discuss the Complete Response Letter (CRL) dated August 29, 2023, regarding the Biologics License Application (BLA) for ONS-5010, an investigational ophthalmic formulation of bevacizumab under development to treat wet AMD.
According to a company news release, in the FDA’s recently issued CRL, although the agency acknowledged the NORSE TWO pivotal trial met its safety and efficacy endpoints, it concluded it could not approve the BLA during this review cycle due to several CMC issues, open observations from pre-approval manufacturing inspections, and a lack of substantial evidence.
The company said in the news release it is committed to working with the FDA to address its concerns.
Russell Trenary, president and CEO of Outlook Therapeutics, said in a statement the company looks forward to clearing up the issues.
“Our belief remains unwavering that the retina community needs an FDA-approved ophthalmic bevacizumab to deliver an alternative on-label bevacizumab option for patients with wet AMD,” he said in the news release. “We look forward to a productive meeting with FDA to discuss the CRL with the goal of obtaining a clear understanding of the items that need to be addressed to resubmit our BLA for ONS-5010 at the earliest opportunity,” said Russell Trenary, President and CEO of Outlook Therapeutics.
According to Outlook Therapeutics, ONS-5010 is an investigational ophthalmic formulation of bevacizumab under development as an intravitreal injection for the treatment of wet AMD and other retinal diseases. No FDA-approved ophthalmic formulations of bevacizumab is currently available, and clinicians wishing to treat retinal patients with bevacizumab have had to use unapproved repackaged IV bevacizumab provided by compounding pharmacies—products that have known risks of contamination and inconsistent potency and availability.
If approved, Outlook Therapeutics noted that ONS-5010 would provide an FDA-approved option for physicians who currently have no choice but to prescribe unapproved repackaged oncologic IV bevacizumab from compounding pharmacies for the treatment of wet AMD.
NORSE ONE was a clinical experience trial involving 61 wet AMD participants at nine trial sites in Australia. NORSE ONE compared bevacizumab-vikg to ranibizumab (LUCENTIS®) as a treatment for wet AMD and showed the first markers of efficacy and safety in humans for ONS-5010 ophthalmic bevacizumab. In the trial, bevacizumab-vikg efficacy and safety data were consistent with historical published studies of bevacizumab in ophthalmology, and NORSE ONE also supported the trial design and inclusion/exclusion criteria for NORSE TWO, the pivotal Phase 3 registration clinical trial.
The NORSE TWO Phase 3 pivotal trial enrolled a total of 228 wet AMD patients at 39 clinical trial sites in the United States. It was designed as a superiority study comparing the safety and efficacy of bevacizumab-vikg ophthalmic bevacizumab dosed monthly against ranibizumab (Lucentis) dosed according to the PIER dosing regimen described in the Lucentis label. The trial data met both the primary and secondary endpoints with high statistical significance and clinical relevance.
For its primary endpoint, 41.7% (p = 0.0052) of patients gained ≥ 15 letters of vision, and for its secondary endpoints, 56.5% (p = 0.0016) of patients gained ≥ 10 letters of vision and 68.5% (p = 0.0116) gained ≥ 5 letters.
The key secondary endpoint, mean change in BCVA from baseline to Month 11, was 11.2 letters gained (p = 0.0043) compared to 5.8 letters gained in the ranibizumab arm. The NORSE TWO data also showed that the drug was well-tolerated, consistent with previously reported data for ONS-5010 and prior research.
NORSE THREE was an open-label safety study of bevacizumab-vikg in 197 patients conducted in the United States to provide the necessary number of retina patients dosed with bevacizumab-vikg 5010 to complete the safety requirements for the BLA submission.
Safety results across the first three NORSE trials demonstrated a strong benefit-to-risk safety profile. Across all three bevacizumab-vikg registration trials, there was only one ocular inflammation adverse event, which was reported in NORSE TWO; the event was treated topically and resolved without sequelae. The most common adverse reaction (≥ 5%) reported in patients receiving bevacizumab-vikg was conjunctival hemorrhage associated with the needle injection procedure (5%).