The U.S. Food and Drug Administration has been quite active in the retina-verse lately.
First the successes. 2023 has yielded a record number of new approvals. The complement inhibitors pegcetacoplan (Syfovre, Apellis Pharmaceuticals) and avacincaptad (Izervay, Iveric Bio/Astellas Pharma), were approved for treatment of geographic atrophy, while an 8-mg dose of aflibercept (Eylea HD, Regeneron Pharmaceuticals) was approved for neovascular age-related macular degeneration, diabetic macular edema and diabetic retinopathy.
Other recent successes hold promise for future approvals. NT-501 (Neurotech Pharmaceuticals), a surgical implant containing genetically modified retinal pigment epithelium cells that produce ciliary neurotrophic factor, significantly slowed the progression of photoreceptor loss in patients with macular telangiectasia type 2. Emily Chew, MD, presented results from two pivotal trials at the American Society of Retina Specialists meeting.1
I consider retinal imaging another recent success, based on both an explosion of artificial intelligence-based image quantification tools and cumulative FDA feedback that photoreceptor loss can be an approvable endpoint for multiple diseases.
But not all is rosy. The FDA issued two prominent Complete Response Letters (CRL), citing problems in new drug applications. In June, a CRL for aflibercept 8 mg cited inspection findings at an outsourced filler—issues that were efficiently addressed. In August, the FDA sent a CRL for ONS-5010 (Outlook Therapeutics), ophthalmic formulation of bevacizumab, citing chemistry, manufacturing and controls, as well as a lack of substantial evidence.
Other pipeline candidates have encountered unforeseen hurdles. KSI-301, or tarcocimab (Kodiak Sciences), an anti-VEGF biopolymer conjugate,didn’t meet noninferiority compared to aflibercept in pivotal DME trials, and there was also an unexpected increase in cataracts. The future of this molecule is unclear.
FDA guidance on trial design in retina appears to be shifting. First, the practice of using sham injections, historically used in most pivotal trials in retina, may no longer be considered adequate masking, particularly for an endpoint with any possibility of subjectivity.
Second, despite multiple agents approved based on noninferiority, the agency is strongly recommending superiority trial designs; this could lead to less than optimal designs from a patient-outcomes perspective.
While the retina landscape has evolved tremendously since the FDA approved pegaptanib in 2004, our goals remain the same: preserve and restore as much vision as possible, as safely as possible, for each patient. The FDA has proven to be a critical partner in this journey, and it’s playing a more important role than ever in shaping the future of retina. RS
1. Chew E. Phase 3 randomized studies of efficacy and safety of revakinagene taroretcel producing ciliary neurotrophic factor (CNTF) in macular telangiectasia type 2. Paper presented at the American Society of Retina Specialists 41st annual scientific meeting; Seattle, WA; July 30, 2023.