Approximately one to three of every 1,000 newborns in the U.S. is born with significant hearing loss, and genetic causes account for about half the cases (Hum Genet. doi:10.1007/s00439-023-02595-5). Of these, otoferlin-mediated auditory neuropathy occurs in 1 to 8% of the patients. For decades, management for children with auditory neuropathy has focused on hearing devices, including the cochlear implant, which can restore auditory input but fails to restore “natural” hearing. That changed on April 23, 2026, when the U.S. Food and Drug Administration (FDA) granted accelerated approval to Otarmeni (lunsotogene parvec-cwha), a one-time gene therapy developed by Regeneron Pharmaceuticals (FDA. https://tinyurl.com/s8wmvk4a). Otarmeni is the first-ever drug approved to specifically treat a genetic form of hearing loss. For otolaryngologists managing patients with congenital hearing loss, the approval marks a pivotal moment, but this new treatment also introduces new clinical responsibilities.
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September 2026Understanding OTOF-Related Hearing Loss
Children with hearing loss due to OTOF are affected by auditory neuropathy spectrum disorder (ANSD) due to abnormal transmission of sound from the functional cochlea to the auditory nerve. Affected children will characteristically have normal otoacoustic emissions (OAEs), indicating a functional cochlea, and absent or abnormal auditory brainstem response (ABR) (Gene Reviews. https://tinyurl.com/5y28t5d2). The OTOF gene encodes otoferlin, a calcium-sensing protein essential for synaptic vesicle fusion at the inner hair cell ribbon synapse. Without functional otoferlin, the neurotransmitter glutamate is not released from inner hair cells, and auditory signals are not transmitted from the cochlea to the auditory nerve. OTOF was selected as the first target for gene therapy of the inner ear because the inner hair cells and auditory neurons remain intact for years, providing a lengthy time window for restoration of the critical otoferlin protein.
How Otarmeni Works
Otarmeni (rhymes with ‘harmony’) treats a specific, rare form of congenital hearing loss caused by genetic variants in the OTOF gene. Otarmeni is a gene replacement therapy in which a functional copy of the OTOF gene is delivered using a viral vector into the inner hair cells, allowing safe, specific targeting. Because the OTOF coding sequence is too large for a single adeno-associated virus (AAV) capsid, two complementary viral vectors carry split portions of the gene. When the AAVs are both present inside the correct cells, the two halves of OTOF reconstitute the full-length transcript. Expression of OTOF is controlled by a proprietary myosin 15 promoter designed to restrict otoferlin production to hair cells. The therapy is delivered via a transmastoid surgical approach to intracochlear infusion via the round window membrane. To prevent damage to the inner ear, a fenestration is made in the lateral semicircular canal to allow egress of cochlear fluid, then patched after the procedure (Regeneron. https://tinyurl.com/3b9h7hfy).
Otarmeni is FDA approved for pediatric and adult patients who meet three criteria: (1) genetic testing confirmation of two pathogenic variants in the OTOF gene, (2) severe-to-profound or profound sensorineural hearing loss (any frequency greater than 90 dB), and (3) preserved outer hair cell function and no prior cochlear implant in the treated ear (Regeneron. https://tinyurl.com/3b9h7hfy). Otarmeni is contraindicated in patients with anatomic variations that preclude safe surgical access to the cochlea. The presence of a cochlear implant is a contraindication to gene therapy for that ear, but the contralateral ear could receive gene therapy.
Clinical Trial Outcomes
Accelerated approval of Otarmeni was based on data from the Phase 1/2 CHORD trial, an ongoing multicenter, open-label study (Regeneron. https://tinyurl.com/bdya7mhd). Of the 20 evaluable participants who received Otarmeni, 80% (16/20) met the primary endpoint: a hearing threshold at or below 70 dB HL by 24 weeks, a level at which cochlear implantation is typically not required. Among the 12 participants with 48-week follow-up, 42% achieved normal hearing thresholds, including the ability to detect sounds as soft as a whisper. Results for 12 patients published in the New England Journal of Medicine confirmed hearing improvement and restoration of natural acoustic hearing in a subset of patients (N Engl J Med. doi:10.1056/NEJMoa2400521). Otarmeni’s accelerated approval status requires ongoing confirmatory data on speech development and quality of life outcomes for continued approval.
Otarmeni gene therapy was found to be generally safe and well tolerated. In data reported from the CHORD trial, there were no serious adverse events related to the gene therapy itself. The most common adverse reactions reported in the CHORD safety population (n=24) included otitis media, nausea, vomiting, dizziness, procedural pain, gait disturbance, and nystagmus.
Ongoing Clinical Trials and Anticipated Future Targets
Although Otarmeni is the first to get FDA approval, other companies have ongoing trials using gene replacement therapy for hearing loss. In the U.S., Eli Lilly has an active clinical trial, also focused on patients with OTOF hearing loss, but using a less invasive transcanal surgical approach. OTOF clinical trials are also underway in France (Sensorion) and China (Otovia Therapeutics). Early trial data from these programs also show promising results in children. Skylark Bio recently started a gene replacement clinical trial for the most common form of pediatric hearing loss, GJB2 (Connexin 26). Clearly, gene therapy will become another tool in our toolbox to treat the many different causes of pediatric hearing loss.
Genetic Evaluation Is Critical to Identify Gene Therapy Candidates
The rapid advancements in gene therapy and anticipated future therapeutic options show that genetic evaluation is an essential and critical component of the evaluation of hearing loss in children. Specifically, with OTOF-related hearing loss, an integrated diagnostic pathway for children with hearing loss is critical to allow for prompt diagnosis. ABR and OAE (OAE) should be used to document the degree of loss and confirm outer hair cell function. An ANSD pattern (absent ABR with present OAEs) should immediately raise suspicion for possible OTOF hearing loss.
It is important to note that not all ANSD is due to OTOF. A comprehensive hearing loss gene panel should be ordered as soon as permanent hearing loss is confirmed, ideally within the first months of life. Identification of biallelic OTOF variants before cochlear implantation preserves the option for Otarmeni, given that prior cochlear implant in the same ear is a contraindication to gene therapy. Delaying genetic testing risks closing the treatment window. Imaging with high-resolution CT and MRI of the temporal bones (based on institutional practice) to assess cochlear and mastoid anatomy and confirm feasibility of intracochlear surgery is also important.
What This Means for Your Practice
The immediate clinical action is straightforward: Otolaryngologists should offer genetic testing in all children with permanent sensorineural hearing loss. If pathogenic OTOF variants are confirmed, the family should be counseled regarding Otarmeni before cochlear implantation is pursued. Identification of other genetic causes is equally important for potential future therapeutic options and also for concurrent management of comorbidities.
Beyond its immediate impact, Otarmeni establishes proof of concept that gene replacement therapy can restore hearing. This new treatment opens the door to dozens of other genes implicated in hereditary hearing loss, including common genetic forms of hearing loss like GJB2 (Connexin 26). The field of surgical gene therapy for hearing loss has arrived, and the best preparation is to be at the forefront of diagnosis.
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