Outlook blindsided as FDA blocks wet AMD drug once again

Shares in Outlook Therapeutics lost more than half their value after the FDA turned down the company's marketing application for its new formulation of bevacizumab gamma as a treatment for wet age-related macular degeneration (AMD).

The US regulator sent the New Jersey company a complete response letter (CRL) for the VEGF inhibitor, which has the trade name Lytenava and is already approved and on sale in other markets, including Germany and the UK.

The reason for the CRL was "a lack of substantial evidence of effectiveness," according to Outlook, which said it would work with the agency to try to address the issues raised. It is the second FDA rejection for the drug, which was also turned down in 2023, while Outlook also withdrew an earlier filing in 2022.

The decision stems from the failure of one of Outlook's phase 3 clinical trials, NORSE EIGHT, to meet its primary efficacy endpoint, namely non-inferiority with another ranibizumab formulation on best corrected visual acuity (BCVA) at eight weeks, although it did match the comparator on that outcome at the 12-week timepoint.

While another study called NORSE TWO did show efficacy, the FDA typically requires two positive pivotal trials to support approval. Despite that, Outlook opted to press on with a regulatory filing, hoping that the totality of data across the two studies would be enough to support approval.

Compounded bevacizumab formulations are sometimes used to treat wet AMD, but because the reference product (Roche's Avastin/MabThera) is only indicated for cancer conditions, they can only be used off-label for ophthalmic conditions like wet AMD.

Lytenava is being held up by Outlook as a standardised formulation of bevacizumab that can sidestep some of the issues with compounded or repackaged bevacizumab products, which – according to some studies – have variations in drug concentration that could affect their efficacy.

Despite that, off-label repackaged bevacizumab is one of the most frequently used first-line anti-VEGF treatments in Europe, with approximately 2.8 million injections for retinal diseases annually, with another 2.7 million injections a year in the US.

"While we are very disappointed with this outcome, we intend to meet with the FDA to receive additional clarity on their requirements to potentially approve the first on-label bevacizumab product specifically formulated, manufactured, and packaged for intravitreal use in the US," said Bob Jahr, Outlook's chief executive.

"We remain committed to providing patients with a safe and effective alternative to compounded Avastin manufactured in the US," he added.

Outlook has a strategic collaboration with Cencora to support the commercial launch of Lytenava, but has not yet reported any sales figures for the product.

Shares in Outlook on the Nasdaq were trading down 54% at the time of writing today.

Image by Peggy und Marco Lachmann-Anke from Pixabay