FDA issues third rejection of bevacizumab to treat wet AMD

The FDA has issued its third complete response letter (CRL) to Outlook Therapeutics’ ONS-5010/Lytenava to treat patients with wet age-related macular degeneration (wet AMD). Regulatory officials recommended that confirmatory evidence of efficacy be submitted. They noted that the additional mechanistic and natural history data information provided in the resubmitted biological license applications (BLA) does not change the agency's previous review conclusion.

Age-related macular degeneration occurs when the macula, part of the retina at the back of the eye, becomes damaged. About 10% of all cases become wet, which leads to vision loss as a result of excess blood vessel growth between two layers of cells in the retina. It is also called neovascular AMD.

Lytenava (bevacizumab-vikg) is an ophthalmic formulation of bevacizumab, a recombinant humanized monoclonal antibody, and it inhibits vascular endothelial growth factor (VEGF), blocking blood vessel growth. It is administered through an intravitreal injection, which is placed in the space in the back of the eye. If approved, Lytenava would be the only bevacizumab product to specifically treat AMD.

Bevacizumab is available as Avastin — along with six U.S.-approved biosimilars — to treat patients with cancers such as colorectal, lung, glioblastoma, kidney, cervical, and ovarian cancer. It is used off-label to treat wet AMD; when used for the eye, bevacizumab can be obtained from compounding pharmacies, which repackage small quantities into syringes for intravitreal injection.

“We are disappointed and disagree with this decision, but we remain fully committed to taking all necessary steps to receive approval in the United States,” Bob Jahr, CEO of Outlook Therapeutics, said in a news release. “We continue to believe strongly in the clinical need and commercial potential of the first on-label bevacizumab product for patients in the United States that is specifically formulated, manufactured, and packaged for intravitreal use.”

Company officials said they are pursuing available pathways for potential approval in the United States and to expand into additional markets in Europe and other regions. Lytenava (bevacizumab gamma) has been granted approval in Europe, Germany and the United Kingdom for wet AMD.

The U.S. BLA resubmission was based on data from the complete data set from the NORSE clinical trial program, which included the NORSE TWO pivotal clinical trial, as well as safety and efficacy data from all other NORSE trials. The resubmission also included data from NORSE EIGHT, a non-inferiority study evaluating Lytenava compared with Lucentis (ranibizumab) in a 12-week study of treatment naïve patients with a primary efficacy endpoint at 8 weeks.

The FDA had issued the first complete response letter for ONS-5010 in August 2023. Regulators at the time had said there were issues related to quality, preapproval manufacturing inspections, and a lack of substantial evidence. Outlook Therapeutics resubmitted the application in February 2025 with data on the efficacy and safety demonstrated in NORSE EIGHT, as well as additional chemistry, manufacturing, and controls (CMC) information requested by the FDA.

The second complete response letter was issued in August 2025, with FDA officials saying ONS-5010 did not meet the primary efficacy endpoint in NORSE EIGHT and that confirmatory evidence of efficacy was recommended. The 12-week safety and efficacy results from this trial indicated that ONS-5010 demonstrated a mean 4.2-letter improvement in best corrected visual acuity, but it did not meet the pre-specified non-inferiority endpoint at week 8 in the special protocol assessment with the FDA.

Outlook Therapeutics once again resubmitted the application for Lytenava in February 2025 with the complete data set for NORSE EIGHT, additional CMC information, and data from the other NORSE clinical trials. At the time, company officials believed that this met the required evidence to support approval in the United States.