Lunsotogene parvec-cwha (Otarmeni) is a gene therapy found to improve hearing thresholds in most pediatric patients with OTOF-related hearing loss, supporting accelerated approval despite limited sample size and follow-up.
The FDA has granted accelerated approval to lunsotogene parvec-cwha (Otarmeni), an adeno-associated virus (AAV) vector-based gene therapy for patients with severe-to-profound or profound sensorineural hearing loss associated with biallelic OTOF variants, according to Regeneron.1
Clinically, the decision is notable because it marks the first FDA-approved gene therapy for this form of genetic hearing loss and, according to the company, the first approved in vivo gene therapy intended to restore hearing function in this setting.1
“The FDA approval of Otarmeni signals a new era in the treatment of genetic forms of hearing loss, where reinstating 24/7 natural hearing is now possible,” said A. Eliot Shearer, MD, PhD, an investigator in the CHORD trial, in the company’s announcement.1
The approval also introduces a new treatment option for a condition that has largely been managed with hearing devices or cochlear implantation rather than molecularly targeted therapy.2
The indication covers pediatric and adult patients with severe-to-profound and profound sensorineural hearing loss, defined in the release as any frequency greater than 90 dB hearing level, with molecularly confirmed biallelic OTOF variants, preserved outer hair cell function, and no prior cochlear implant in the same ear.
Regeneron said the therapy is not recommended when preoperative imaging shows that access to the inner ear is not feasible because of anatomic factors. The company also said it will provide the drug at no cost in the US to clinically eligible patients, although out-of-pocket expenses may still apply.
The approval was based on the ongoing registrational Phase 1/2 CHORD trial, a multicenter, open-label study enrolling infants, children, and adolescents younger than 18 years with OTOF-related hearing loss.1 In part A, participants received unilateral intracochlear infusion; in part B, bilateral treatment was given at the selected dose. The surgical approach was described as similar to cochlear implantation and performed under general anesthesia.
In the pivotal dataset cited by Regeneron, 20 participants aged 10 months to 16 years received a single dose, with 10 treated unilaterally and 10 bilaterally.1 At 24 weeks, 16 of 20 participants (80%) reached the primary endpoint of hearing improvement on average pure tone audiometry (PTA) to 70 dB hearing level or better.
One additional participant reached that threshold by week 48. Regeneron stated that this level of hearing generally corresponds to a range permitting natural hearing without typically requiring cochlear implantation, although functional outcomes in individual patients may vary.
For the key secondary endpoint, 14 of 20 participants (70%) demonstrated an auditory brainstem response at 90 dB or less by week 24. Among the 12 participants with 48-week follow-up reported in the release, all prior responders maintained response, and 5 of 12 (42%) achieved hearing thresholds in the normal range, including perception of whispers at 25 dB or less.
The accelerated approval was specifically based on improvement in hearing sensitivity by PTA at week 24, with continued approval contingent on verification of clinical benefit in the confirmatory portion of CHORD.
The adverse event profile reported in the company statement was shaped both by the product and the intracochlear delivery procedure. In the CHORD safety population of 24 patients, the most common adverse reactions, occurring in at least 5%, were otitis media, vomiting, nausea, dizziness, procedural pain, gait disturbance, and nystagmus.
The press release also listed potential serious risks associated with the surgery required for administration, including vertigo, tinnitus, cerebrospinal fluid leak, partial facial paralysis or weakness, meningitis, mastoiditis, and inner ear inflammation.
OTOF-related hearing loss is an ultra-rare cause of auditory neuropathy spectrum disorder, arising from loss of functional otoferlin, a protein essential for synaptic vesicle exocytosis at inner hair cell ribbon synapses.2,3 Patients may have intact outer hair cell function despite severe auditory dysfunction, which helps define the biologic rationale for gene replacement.
The treatment landscape has centered on hearing aids in some cases and cochlear implantation in more severe disease, with cochlear implants often providing meaningful benefit but requiring device implantation and lifelong management.2
Lunsotogene parvec is designed to deliver a functional copy of OTOF to cochlear hair cells using an AAV-based vector under a cell-specific promoter, according to the company.1 The FDA action adds to a growing body of early-stage clinical research in genetic hearing loss, but interpretation remains cautious given the small, uncontrolled dataset and relatively short follow-up available to date.
Questions remain about durability beyond 48 weeks, outcomes in adults covered by the label but not represented in the company’s described trial population, comparative effectiveness versus cochlear implantation, and the reproducibility of results across broader surgical settings.
The regulatory pathway is also worth watching. Lunsotogene parvec has received Orphan Drug, Rare Pediatric Disease, Fast Track, and Regenerative Medicine Advanced Therapy Designations from the FDA, and Orphan designation from the European Medicines Agency.
Additional regulatory filings are planned outside the US.1
