FDA Rejects Specific Bevacizumab Formulation for Wet AMD

The FDA has issued a complete response letter (CRL) for Outlook Therapeutics’ biologics license application for Lytenava (bevacizumab-vikg), an ophthalmic formulation of bevacizumab to treat patients with wet age-related macular degeneration (AMD). Regulators indicated that there were issues related to quality, preapproval manufacturing inspections, and a lack of substantial evidence.

Russell Trenary

Russell Trenary, president and CEO of Outlook Therapeutics, said the company will request a formal meeting to resolve these issues and determine next steps. “We are disappointed and were not expecting to receive a CRL back from the FDA,” he said in an investor call. “The type A meeting will reveal exactly what they are looking for to confirm the results of NORSE TWO. We looked through the CMC issues and we don’t see any showstoppers there. We believe there is a pathway moving forward.”

He said that based on the FDA letter, regulators said the pivotal trials met its safety and efficacy endpoints, which were statistically significant.

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.

Bevacizumab is a recombinant humanized monoclonal antibody that is a vascular endothelial growth factor (VEGF) inhibitor, which blocks blood vessel growth. The product is available as Avastin to treat cancers such as colorectal, lung, glioblastoma, kidney, cervical and ovarian cancer. It is used off-label to treat wet AMD. In addition, several Avastin biosimilars are available, including Mvasi, Zirabev, Alymsys, and Vegzelma, but these are only approved for the cancer indications

Lytenava, also known as ONS-5010, is an ophthalmic formulation of bevacizumab for intravitreal injection, which is placed in the space in the back of the eye. If approved, it would be the only bevacizumab product to specifically treat AMD. Currently, because bevacizumab must be obtained from compounding pharmacies to be used in the eye. These pharmacies repackage small quantities of bevacizumab into syringes for intravitreal injection.

Outlook Therapeutics executives have said that a new formulation of bevacizumab is needed because of concerns about the quality of compounded bevacizumab, including too-small doses that would not have therapeutic effect and the use of nonstandard materials used in the compounding process.

Outlook Therapeutics’ BLA was based on the NORSE TWO phase 3 clinical trial, which compared Lytenava (dosed monthly) with Lucentis (ranibizumab), Genentech’s anti-VEGF that is also indicated for wet AMD. In the trial, Lytenava consistently improved best-corrected visual acuity (BCVA) by ≥ 15 letters from baseline to 11 months. Additionally, the majority of Lytenava patients maintained or gained BCVA during the study. Only one serious ocular adverse event occurred in the Lytenava group: iritis (an inflammation of the iris) that was treated and resolved.