Outlook Therapeutics Reports Positive Efficacy and Safety Data from Phase 3 NORSE TWO Trial of Lytenava for Wet AMD
Outlook Therapeutics announced positive clinical and highly statistically significant topline results from its pivotal phase 3 NORSE TWO safety and efficacy trial evaluating ONS-5010/Lytenava (bevacizumab) for treatment of neovascular age-related macular degeneration (wet AMD).
“We are delighted with the compelling results observed in NORSE TWO, which represent a significant and potentially transformational milepost for patients suffering from wet AMD. We plan on bringing the first ophthalmic formulation of bevacizumab to market, if approved. 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. The successful completion of this trial is the final step needed in our clinical evaluation of ONS-5010 to enable us to submit a Biologics License Application to the FDA in the first calendar quarter of next year,” C. Russell Trenary III, President and CEO of Outlook Therapeutics, said in a company news release. “I would like to thank the trial participants and investigators, our partners, and our employees for their contributions to NORSE TWO.”
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 ONS-5010 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 3 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.
“In meeting both the primary and key secondary endpoints in NORSE TWO with highly significant clinically relevant results, we have achieved the requirements agreed upon with the FDA, and when combined with our previously reported clinical trial results, this completes the clinical package necessary for the submission of our BLA. 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,” Terry Dagnon, Chief Operating Officer of Outlook Therapeutics, said in the news release.
Topline data from NORSE TWO showed that ONS-5010 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 ONS-5010 patients who gained 3 lines of vision, to be very exciting for the retina community and confirm what we all had hoped to see in the investigation of ONS-5010 to treat wet AMD. Clearly, in this trial ONS-5010 appears to be a potential option as an ophthalmic bevacizumab,” commented Firas Rahhal, MD, Senior Partner at Retina-Vitreous Associates Medical Group and Associate Clinical Professor of Ophthalmology at the UCLA School of Medicine. “As a clinician, I look forward to supporting the submission for FDA approval and including ONS-5010 as an important treatment option for wet AMD patients, if approved.”
ONS-5010 (bevacizumab) registration clinical trial program
Outlook Therapeutics’ wet AMD ONS-5010 clinical program for the planned BLA consists of three clinical trials: NORSE ONE, a proof-of-concept clinical experience trial in wet AMD patients; NORSE TWO, the pivotal phase 3 wet AMD trial; and NORSE THREE, a supplemental safety study in patients with wet AMD and other retina diseases undertaken to ensure that a sufficient number of patients have been dosed with ONS-5010 to support the BLA submission. Results from NORSE ONE and NORSE THREE demonstrated positive proof-of-concept and a safety profile consistent with that of prior published research on bevacizumab for ophthalmic use. NORSE TWO provided pivotal data that demonstrated positive and highly statistically significant and clinically relevant efficacy and safety data for treatment of patients with wet AMD.
With the registration clinical trials now completed, Outlook Therapeutics 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 ONS-5010 as the first and only ophthalmic formulation of bevacizumab approved by the FDA to treat wet AMD.
Full data from NORSE TWO will be presented at an ophthalmology conference in the fall of 2022 and submitted for publication in a peer-reviewed journal.
Pre-commercialization planning underway
Per the National Eye Institute (NEI), use of unapproved repackaged IV bevacizumab from compounding pharmacies is estimated to account for approximately 50% of all wet AMD prescriptions in the United States each year. Globally, the nine major markets account for an estimated $13.1 billion market for anti-VEGF drugs to treat retina diseases.
In anticipation of potential FDA marketing approval in 2022 for ONS-5010, Outlook Therapeutics has begun commercial launch planning, including manufacturing with drug substance manufacturer FUJIFILM Diosynth Biotechnologies and best-in-class drug product manufacturer Aji Biopharma Services, distribution, sales force planning, physician and payor advisory board outreach, key opinion leader support and payor community engagement. To bring ONS-5010 to market in a way that benefits all stakeholders—clinicians, patients and payors—Outlook Therapeutics has already commenced collaborative discussions with payors and the retina community. Outlook Therapeutics expects ONS-5010, if approved, to be a safe and cost-effective choice for patients, payors and clinicians worldwide for retinal indications.
Outlook Therapeutics is also developing registration documents on a parallel path for approvals in Europe and expects to submit them shortly after completing the submission to the FDA. Outlook Therapeutics continues to explore potential strategic commercialization partners, such as Syntone Biopharma JV in China.
In addition to the clinical development program evaluating ONS-5010 for wet AMD, Outlook Therapeutics has received agreements from the FDA on three Special Protocol Assessments (SPAs) for three additional registration clinical trials. These SPAs cover the protocols for a planned registration clinical trial evaluating ONS-5010 to treat branch retinal vein occlusion (BRVO, NORSE FOUR), and two planned registration clinical trials evaluating the drug candidate for the treatment of diabetic macular edema (DME, NORSE FIVE and NORSE SIX). Outlook Therapeutics expects to initiate registration clinical trials for ONS-5010 for DME and BRVO later in 2021 or in early 2022.