Outlook Therapeutics a step closer to FDA approval of bevacizumab-vikg for treatment of wet AMD

Outlook Therapeutics announced positive clinical and highly statistically significant top-line results from its pivotal Phase 3 NORSE TWO safety and efficacy trial evaluating bevacizumab-vikg (ONS-5010, Outlook Therapeutics Inc.) for the treatment of wet age-related macular degeneration (wet AMD).

If approved, bevacizumab-vikg would be the first ophthalmic formulation of bevacizumab approved to treat retinal conditions. It is a full-length, humanized anti-vascular endothelial growth factor (VEGF) recombinant monoclonal antibody (mAb) that inhibits VEGF and associated angiogenic activity. It is an investigational ophthalmic formulation of bevacizumab under development to be administered as an intravitreal injection for the treatment of wet AMD and other retinal diseases.

C. Russell Trenary III, president and CEO of Outlook Therapeutics, said in a statement that the company is pleased with the results observed in the trial.

“We plan on bringing the first ophthalmic formulation of bevacizumab to market, if approved,” he said in the statement. “Currently there are a vast number of off-label injections of bevacizumab to treat retinal disease in the United States, and we want to offer an alternative for patients and retinal surgeons that is approved and formulated and packaged specifically for wet AMD.

Trenary added that the successful completion of the trial is the final step needed in Outlook’s clinical evaluation of bevacizumab-vikg to enable it to submit a Biologics License Application to the FDA in the first calendar quarter of next year.

According to the company, the NORSE TWO pivotal Phase 3 clinical trial enrolled a total of 228 subjects with wet AMD across 39 clinical trial sites in the United States. Participants in the trial were treated for 12 months. The primary endpoint for the study was the proportion of patients who gain at least 15 letters in the best corrected visual acuity (BCVA) at 11 months.

The trial compared bevacizumab-vikg dosed monthly to LUCENTIS, which was dosed as one of the regimens listed in the LUCENTIS label (i.e., patients were treated monthly for the first three months followed by less frequent dosing; the PIER regimen). The key secondary endpoint for NORSE TWO was the mean change in the BCVA through 11 months.

According to Terry Dagnon, chief operating officer of Outlook Therapeutics, the company cleared several hurdles in the trial.

“In meeting both the primary and key secondary endpoints in NORSE TWO with highly significant clinically relevant results, the company has achieved the requirements agreed upon with the FDA, and when combined with our previously reported clinical trials, this completes the clinical package necessary for the submission of our BLA,” he said in a statement. “We look forward to working with the FDA and other global authorities to potentially bring this new option to providers, clinicians, and patients as quickly as possible as an alternative to off-label IV repackaged bevacizumab, that is not approved for ophthalmic use.

The company reported that top-line data from NORSE TWO showed that bevacizumab-vikg met the primary and key secondary endpoint for efficacy with clinically impactful change observed for treated patients.

The NORSE TWO primary endpoint difference in proportion of subjects gaining at least 15 letters BCVA was met and was highly statistically significant and clinically relevant. 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 bevacizumab-vikg was 41% (p = 0.0052).

The primary endpoint was also statistically significant and clinically relevant in the secondary per-protocol (PP) dataset (p = 0.04) where the percentages were almost identical, at 24% with ranibizumab and 41% with bevacizumab-vikg. The key secondary endpoint BCVA score change from baseline to month 11 in the primary ITT dataset was also highly statistically significant and clinically relevant (p = 0.0043). A mean change in BCVA was observed with ranibizumab of 5.8 letters and the mean change with bevacizumab-vikg was 11.2 letters. The results were also statistically significant in the secondary PP dataset (p = 0.05) with a mean change in letters with ranibizumab of 7.0 letters and with bevacizumab-vikg 11.1 letters.

The safety results demonstrated in NORSE TWO are consistent with previously reported safety results from Outlook Therapeutics’ NORSE ONE and NORSE THREE clinical trials. Following exposure to bevacizumab-vikg, there was only one subject who reported an adverse event of ocular inflammation in all three trials. In NORSE TWO, there was only a single related ocular serious adverse event reported in the bevacizumab-vikg trial arm, which resolved and no unanticipated safety signals were detected.

The most common ocular adverse event was intravitreal injection-related hemorrhage in the tissues on the surface of the eye (conjunctival hemorrhage) that resolved without any sequela. The ONS-5010 safety database continues to be consistent with previously published results for bevacizumab, such as in the 2011 CATT clinical trial.

“As an Investigator in the NORSE TWO trial, I find these clinically relevant results, most notably the 41% of bevacizumab-vikg patients who gained three lines of vision, to be very exciting for the retina community and confirm what we all had hoped to see in the investigation of bevacizumab-vikg to treat wet AMD,” Firas Rahhal, MD, senior partner at Retina-Vitreous Associates Medical Group and associate clinical professor of ophthalmology at the UCLA School of Medicine, said in a statement.

Rahhal also noted that in the trial bevacizumab-vikgappears to be a potential option as an ophthalmic bevacizumab.

“As a clinician, I look forward to supporting the submission for FDA approval and including bevacizumab-vikg as an important treatment option for wet AMD patients, if approved,” Rahhal concluded.

With the registration clinical trials now completed, Outlook Therapeutics said it plans to submit a BLA under the Public Health Service Act (PHSA) 351(a) regulatory pathway in the first quarter of calendar 2022. If the BLA is approved, it is expected to result in 12 years of marketing exclusivity for bevacizumab-vikg as the first and only ophthalmic formulation of bevacizumab approved by the FDA to treat wet AMD.

Pre-commercialization planning underway
In anticipation of potential FDA marketing approval in 2022 for bevacizumab-vikg, Outlook Therapeutics said in the statement that it has begun commercial launch planning, including manufacturing with drug substance manufacturer FUJIFILM Diosynth Biotechnologies and drug product manufacturer Aji Biopharma Services, distribution, sales force planning, physician and payor advisory board outreach, key opinion leader support and payor community engagement.