FDA turns down Outlook's ophthalmic version of Roche's Avastin over manufacturing, data shortfalls

Even without an FDA approval, Roche’s cancer drug Avastin is widely used by doctors to treat certain eye diseases. Outlook Therapeutics has been trying to get an official approval for a reformulated version, but it instead has received a rejection letter.

The FDA rejected Outlook’s Lytenava, or bevacizumab-vikg, for the treatment of wet age-related macular degeneration (AMD), the New Jersey company said Wednesday.

The drug would have been the first officially labeled, ophthalmic formulation of bevacizumab to enter the market. An approval was largely expected by market watchers given existing knowledge and the long history of off-label use of Avastin in eye diseases.

Instead, the FDA found several problems with Outlook’s application despite the package boasting a positive pivotal trial.

In the complete response letter to Outlook, the FDA flagged several chemistry, manufacturing and controls (CMC) issues, observations from pre-approval manufacturing inspections, and perhaps most damning, the need for further confirmatory clinical evidence, according to the company.

Outlook will request a meeting with the FDA to further understand the deficiencies and try to find a path forward, the company’s CEO Russel Trenary said in a statement.

During a Wednesday call with analysts, Trenary and his team didn’t offer many details about the CRL. The company will have more to share about the agency’s concerns—and a timeline for resolution—after the FDA meeting, the CEO said.

The CMC issues are “addressable” and “manageable,” he added.

Outlook has hired Fujifilm Diosynth Biotechnologies and Ajinomoto Biopharma Services to help make its bevacizumab reformulation. Neither company responded Fierce Pharma’s request for comment by publication time.

Avastin is approved by the FDA to treat various cancers thanks to its ability to prevent the growth of new blood vessels that feed tumors. This anti-VEGF mechanism is also well-accepted in the treatment of diseases featuring abnormal blood vessels in the back of the eye. Regeneron’s Eylea, plus Roche and Novartis’ Lucentis, are blockbuster VEGF inhibitors for the eye.

Even without the FDA’s blessing, doctors have been using unapproved and repackaged bevacizumab provided by compounding pharmacies. These versions “have known risks of contamination and inconsistent potency and availability,” Outlook noted.

Meanwhile, several Avastin biosimilars are available in the U.S. But these copycats can only officially go after the same indications as the originator.

Twelve years ago, a collaboration between the University of Pennsylvania and the National Eye Institute found that Avastin and Lucentis had equivalent effects on improving visual acuity in wet AMD. But those results were never used for an FDA application.

In Outlook’s phase 3 NORSE TWO trial, 42% of wet AMD patients who took Lytenava, also coded as ONS-5010, gained at least 15 letters (three lines) of vision in a common test. The trial met its primary and secondary endpoints with high statistical significance, Trenary stressed.

Outlook has retained several former FDA reviewers and attorneys to help the company understand the FDA’s questions and to vet its answers, Trenary added. Despite the setback, the company is still targeting an FDA approval.