The FDA determined 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 today the FDA has issued a complete response letter (CRL) to Outlook Therapeutic’s biologics license application (BLA) for ONS-5010, an investigational ophthalmic formulation of bevacizumab under development to treat wet age-related macular degeneration (AMD).
While the FDA acknowledged the NORSE TWO pivotal trial met its safety and efficacy endpoints, it determined 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 said in a press release.
Russell Trenary, president and CEO of Outlook Therapeutics, said the company continues to believe in the 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,” he said in the news release. “Following this meeting with the FDA, the Company will be able to discuss next steps and the expected timing for resolution.”
Julia A. Haller, MD, ophthalmologist-in-chief at Wills Eye Hospital and an Outlook Therapeutics Board member, echoed Trenary’s statement in the news release.
“The retina community needs an FDA-approved ophthalmic bevacizumab to deliver an alternative targeted on-label treatment for patients with wet AMD,” she said in a statement.
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, the company noted that ONS-5010 would provide an FDA-approved option for physicians that 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%).