Outlook Therapeutics’ second attempt to market an ophthalmic version of Roche’s tried-and-true Avastin in the U.S. has been knocked back by the FDA.
In a new complete response letter, the FDA has declined to approve Outlook’s bevacizumab product Lytenava (ONS-5010) for the treatment of wet age-related macular degeneration, the company announced Thursday.
Outlook’s stock tanked about 52% as of publication time Aug. 28.
In turning down Outlook’s second request, the FDA flagged one deficiency—a lack of evidence of effectiveness.
The FDA had previously rejected Lytenava in 2023, raising manufacturing issues and the need for additional confirmatory clinical evidence. Following that setback, Outlook agreed with the FDA to conduct a second phase 3 trial, called Norse Eight, to validate the drug in wet AMD.
However, word came out in November that the trial did not meet the prespecified noninferiority endpoint at eight weeks. The drug was compared with Roche and Novartis’ Lucentis, another anti-VEGF agent approved for various eye conditions, including wet AMD.
Nevertheless, Outlook refiled for approval based on a 12-week analysis that showed Lytenava matched up to Lucentis. Lytenava led to a mean improvement of 5.5 letters in best corrected visual acuity (BCVA), compared with 6.5 letters for Lucentis.
The FDA flagged Norse Eight’s failure to meet its primary endpoint in its complete response letter, even though the first trial, Norse Two, was positive, Outlook’s newly minted CEO Bob Jahr told investors on a conference call Thursday.
However, the FDA did not explicitly request another study, Jahr said. The company plans to meet with the FDA to gain clarity on the agency’s expectations and to determine the best path forward.
“I want to emphasize this is not the end of the road for Outlook Therapeutics,” the chief executive said.
The fact that the agency didn’t raise any other issues “means the foundation of our program is solid and that the path forward depends on addressing one defined issue,” he said.
That left analysts on the call wondering what that path could possibly look like. The Outlook management team didn’t have a good answer for that question—at least at the moment.
“We’ll have to wait till we engage with them on what the confirmatory information that they’re looking for and if we possess it,” Jahr said in response to a question on whether the company is considering a new trial.
The FDA already has all the datasets supporting Lytenava, “so it’s a matter of how we’re looking at that data, or what exactly the agency is looking for, and then we’ll be able to evaluate timing and what’s necessary to provide it to them,” Jennifer Kissner, Ph.D., Outlook’s EVP of medical, clinical & regulatory affairs, said on the call.
The anti-VEGF mechanism is well established in certain retinal diseases, with several approved drugs. Bevacizumab has been widely used off-label for the treatment of wet AMD, representing about 55% of the anti-VEGF market in the U.S., according to Jahr.
Outlook’s hope is to introduce the first ophthalmology formulation of bevacizumab for intravitreal injection—rather than its current oncology version for intravenous infusion—that ensures consistent dosing, reliable quality and the oversight of a regulated product.
Even as the FDA balks at Lytenava, the European Commission approved the Outlook drug in May 2024. The company launched Lytenava in Germany and the U.K. in June of this year.
Real-world data could be one of the possible avenues for Lytenava with the FDA, as the U.S. regulator has been accepting such data more and more, Kissner said. However, the R&D exec stressed that the company still needs to understand exactly what the FDA is willing to accept as confirmatory evidence.
In the meantime, Outlook will be “laser-focused on cash conservation” and expanding its commercial footprint in Europe, Jahr said. The company expects to have enough cash till the end of 2025.