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FDA approved lunsotogene parvec for OTOF-related hearing loss based on phase 1/2 data showing improved hearing in a small cohort.
The United States Food and Drug Administration (US FDA) has granted accelerated approval to lunsotogene parvec-cwha (Otarmeni) for severe-to-profound and profound sensorineural hearing loss associated with biallelic OTOF variants, marking the first FDA-approved gene therapy for a genetic form of hearing loss and, according to the company, the first approved gene therapy intended to restore a neurosensory function to normal levels.1 For clinicians, the decision introduces a new option for a narrowly defined population in whom treatment has largely centered on hearing devices and cochlear implantation rather than molecular correction of the underlying defect.1,2
Approval was based on 24-week findings from the ongoing phase 1/2 CHORD study, an open-label multicenter trial enrolling infants, children, and adolescents with OTOF-related hearing loss. The indication includes pediatric and adult patients with molecularly confirmed biallelic OTOF variants, preserved outer hair cell function, and no prior cochlear implant in the same ear.^11
“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,” investigator A. Eliot Shearer, MD, PhD, otolaryngologist in the department of Otolaryngology and Communication Enhancement at Boston Children’s Hospital, Associate Professor of Otolaryngology-Head and Neck Surgery at Harvard Medical School, said in a statement.1 “In the pivotal trial, the one-time gene therapy demonstrated rapid, meaningful and consistent hearing responses, with most children achieving remarkable hearing improvements. I’ve witnessed firsthand my trial participant responding to their mother’s voice, dancing to music and interacting with the world, and these moments are now possible for more children born with this specific form of hearing loss.”
OTOF encodes otoferlin, a protein required for synaptic transmission between inner hair cells and the auditory nerve. Pathogenic variants typically cause auditory neuropathy spectrum disorder or congenital severe hearing loss despite structurally intact cochlear hair cells, making the disorder an attractive target for gene replacement strategies.2,3 The approved product is an adeno-associated virus vector–based therapy delivered by intracochlear infusion under general anesthesia, using a surgical approach similar to cochlear implantation.1
In CHORD, 20 participants aged 10 months to 16 years received a single dose either unilaterally (n = 10) or bilaterally (n = 10).1 All had profound hearing loss by behavioral pure tone audiometry (PTA) at baseline and lacked auditory brainstem response (ABR) at maximum sound levels, according to the release. The primary end point was improvement in hearing sensitivity by average PTA at week 24.
Among the 20 treated participants, 16 (80%) reached a hearing threshold of 70 dB hearing level or better at 24 weeks, meeting the primary end point; 1 additional participant met that threshold by week 48. On the key secondary end point, 14 participants (70%) demonstrated ABR at 90 dB or less by week 24. In longer-term follow-up, all prior responders reportedly maintained response, and 5 of 12 participants (42%) with 48-week follow-up achieved hearing thresholds of 25 dB or less, which the company described as normal hearing including whispers.1 Because approval is accelerated, continued approval may depend on confirmatory evidence from the ongoing CHORD trial.
Safety findings should be interpreted in the context of both the gene therapy and the required otologic procedure. In the CHORD safety population (n = 24), the most common adverse reactions, each reported in at least 5%, were otitis media, vomiting, nausea, dizziness, procedural pain, gait disturbance, and nystagmus.1 The prescribing information summarized in the release also notes risks associated with inner ear surgery, including vertigo, tinnitus, cerebrospinal fluid leak, facial weakness, meningitis, mastoiditis, wound infection, and labyrinthitis. The therapy is not recommended when preoperative imaging suggests that access to the inner ear is not feasible, including abnormal mastoid pneumatization or clinically significant anatomic variation.
The clinical relevance of the approval lies partly in the limitations of current management. Hearing aids may amplify sound but do not correct synaptic transmission defects, and cochlear implantation—while often beneficial in OTOF-related deafness—requires an implanted device and long-term hardware dependence.2,3 Whether gene replacement will alter long-term language acquisition, developmental outcomes, bilateral hearing function, or the timing and need for cochlear implantation remains to be established in larger cohorts with longer follow-up.
The company said it will provide the therapy at no cost in the US, although administration-related costs may still apply.1 That access model is unusual, but it does not change the narrow regulatory scope of the approval or the practical requirement for specialized surgical centers. Regulatory submissions are planned outside the US; the European Medicines Agency has granted orphan designation, but no approval was reported in Europe.
The main limitations of the current evidence are the small sample size, open-label design, mixed unilateral and bilateral treatment cohorts, and reliance on surrogate and intermediate auditory end points at an early time point. Even so, the approval establishes a regulatory pathway for inner ear gene therapy and will likely intensify interest in genotype-specific treatment strategies for hereditary hearing loss.
