First AAV Gene Therapy for OTOF Hearing Loss Clears FDA

Regeneron's accelerated approval of Otarmeni (lunsotogene parvec-cwha) for OTOF-related hearing loss sets a precedent that CGT manufacturers and regulatory affairs teams cannot ignore: the FDA has now accepted hearing sensitivity via pure-tone audiometry as a surrogate endpoint sufficient for accelerated approval of an AAV-based in vivo gene therapy, opening a defined pathway for similar programs in rare auditory disorders.

Otarmeni is an AAV vector-based gene therapy that delivers a functional copy of the OTOF gene via intracochlear infusion under general anesthesia. A proprietary Myo15 cell-specific promoter restricts transgene expression to inner hair cells, the site of otoferlin-dependent synaptic vesicle fusion. The condition affects approximately 50 newborns annually in the United States. Eligible patients must have preserved outer hair cell function and no prior cochlear implant in the treated ear -- criteria that will directly shape patient identification protocols at treating centers.

The pivotal CHORD trial (NCT05788536), an open-label, multicenter phase 1/2 study, enrolled 20 participants aged 10 months to 16 years. Eighty percent (16 of 20) achieved the primary endpoint of average pure-tone audiometry at or below 70 dB HL at week 24. A key secondary endpoint, auditory brainstem response at or below 90 dB HL, was met by 70% of participants, providing electrophysiological corroboration of behavioral assessments. Among 12 participants with at least 48 weeks of follow-up, all prior responders maintained response, and 42% reached hearing levels in the normal range at or below 25 dB HL. Continued approval remains contingent on confirmatory clinical benefit data from the ongoing CHORD trial.

For QA and manufacturing leads, the intracochlear delivery route introduces device-drug combination considerations under 21 CFR Part 211 and ICH Q10 quality system frameworks. AAV vector production scalability, lot-to-lot consistency, and sterility assurance for a surgically administered product will be central process validation challenges as Regeneron moves toward broader commercial supply. The most common adverse reactions in the safety population (n=24) included otitis media, vomiting, nausea, dizziness, procedural pain, and gait disturbance. Regeneron has stated the therapy will be provided at no cost to clinically eligible patients in the United States, though out-of-pocket costs for the administration procedure may vary.