Early clinical data from the CHORD trial supported accelerated approval of the first gene therapy targeting OTOF-related hearing loss under the FDA Commissioner’s National Priority Voucher program.
The FDA has granted accelerated approval to Otarmeni (lunsotogene parvec-cwha), an adeno-associated virus (AAV) vector–based gene therapy for pediatric and adult patients with severe-to-profound or profound sensorineural hearing loss associated with biallelic OTOF variants, according to Regeneron.1
The decision, granted under the
Clinically, the approval matters because OTOF-related hearing loss has historically been managed with hearing devices or cochlear implantation rather than disease-targeted treatment.
“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, a CHORD trial investigator at Boston Children’s Hospital and Harvard Medical School, in the company’s announcement.1
The indication is limited. Per the press release, Otarmeni is approved for patients with molecularly confirmed biallelic OTOF variants, preserved outer hair cell function, and no prior cochlear implant in the same ear.1
The therapy is delivered through intracochlear infusion under general anesthesia and is not recommended when preoperative imaging suggests inner-ear access is not feasible because of anatomic constraints.
The approval was based on the ongoing Phase 1/2 CHORD trial, a multicenter, open-label registrational study enrolling infants, children, and adolescents with OTOF-related hearing loss.
In the pivotal dataset cited by the company, 20 participants aged 10 months to 16 years received a single dose either unilaterally (n = 10) or bilaterally (n = 10). All participants reportedly had profound hearing loss by behavioral pure tone audiometry (PTA) at baseline and no auditory brainstem response (ABR) at maximal sound levels.
At 24 weeks, 16 of 20 participants (80%) reached the primary endpoint of hearing improvement to a PTA threshold of 70 dB hearing level or less; 1 additional participant reached that threshold by week 48. A key secondary endpoint was met by 14 of 20 participants (70%), who demonstrated an ABR response at 90 dB or less by week 24.
Among 12 participants followed through 48 weeks, all prior responders reportedly maintained response, and 5 patients (42% of those followed) achieved hearing thresholds of 25 dB or less, which the company described as normal hearing including whispers.
The FDA granted accelerated approval on the basis of week-24 PTA improvement, with continued approval contingent on verification of clinical benefit in the confirmatory portion of CHORD. In terms of safety, caution is suggested as the dataset is small and treatment requires surgery.
In the CHORD safety population (n = 24), the most common adverse reactions, each occurring in at least 5%, were otitis media, vomiting, nausea, dizziness, procedural pain, gait disturbance, and nystagmus. The prescribing information summarized in the release also notes procedure-related risks associated with inner-ear surgery, including vertigo, tinnitus, cerebrospinal fluid leak, partial facial weakness, meningitis, mastoiditis, wound infection, and inner-ear inflammation.
The disease target is biologically distinct. OTOF encodes otoferlin, a protein needed for synaptic transmission between inner hair cells and the auditory nerve; pathogenic biallelic variants are a known cause of autosomal recessive nonsyndromic deafness, often classified as DFNB9.2,3
Because cochlear hair cell structures may remain anatomically present, OTOF-related hearing loss has been considered a plausible candidate for gene replacement strategies.2 Preclinical work has supported AAV-mediated otoferlin delivery, although clinical evidence remains early.3
For patients with confirmed OTOF-related disease, a gene therapy could alter the timing and sequencing of these interventions, unresolved questions include durability beyond the first year, outcomes in adults, comparative effectiveness vs cochlear implantation, and reproducibility across broader surgical settings.
Regeneron said it will provide the product free of charge in the US to clinically eligible patients, while noting that out-of-pocket costs may still fall outside the company’s control.1
