Nearly all children participating in a clinical trial for Regeneron Pharmaceuticals’ investigational gene therapy DB-OTO experienced significant improvements in hearing, according to new data published in The New England Journal of Medicine and presented at the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNSF) meeting. Of the 12 pediatric participants with profound genetic hearing loss due to variants in the otoferlin (OTOF) gene, 11 showed clinically meaningful hearing improvements, with three achieving normal hearing levels. Eight participants with longer follow-up demonstrated stable or continued improvement.
Among three children who completed speech assessments, all showed significant improvement, including one who was able to identify one- and two-syllable words without visual cues and respond to distant sounds and speech in noisy environments.
“Until now, genetic OTOF-related hearing loss was considered permanent, which is why many of us have dedicated our careers to this field,” said Lawrence R. Lustig, M.D., Chair of the Department of Otolaryngology-Head and Neck Surgery at the Columbia University College of Physicians and Surgeons and a trial investigator. “This registrational data set showcases consistent, rapid and robust responses to DB-OTO, and for those followed to later timepoints, we’ve seen hearing stability as well as continued improvement in understanding of speech. These results are even more poignant when viewed by the families – as one of the parents said, their situation is now ‘unimaginable’ from one year ago. This truly represents a new era in the treatment of hearing loss.”
The CHORD trial enrolled children aged 10 months to 16 years with OTOF-related hearing loss who received a single administration of DB-OTO via intracochlear infusion. Nine participants were treated unilaterally (one ear), while three received bilateral treatment (both ears). The surgical procedure used is similar to cochlear implantation.
Within weeks after treatment, 11 out of 12 participants (14 out of 15 treated ears) showed improved hearing. The primary endpoint was met with nine participants experiencing improvements at a threshold that typically does not require cochlear implantation and enables natural acoustic hearing. Six could hear soft speech unaided; three achieved normal hearing sensitivity by detecting whispers. One participant reached “nearly normal” sensitivity by week 48 after initially missing the primary endpoint at week 24.
For those followed for at least 36 weeks (up to 72 weeks), improvements remained stable or continued to progress. All three participants assessed for speech development after at least 48 weeks showed significant gains.
Both the surgical procedure and DB-OTO were generally well tolerated among all participants, with no adverse findings attributed directly to DB-OTO reported during the study period. Two serious adverse events occurred: one related to a cochlear implant complication, another following vaccination; all post-surgical vestibular issues resolved fully.
A U.S regulatory submission for DB-OTO is planned later this year pending discussions with the Food and Drug Administration (FDA). The therapy has received Orphan Drug, Rare Pediatric Disease, Fast Track, and Regenerative Medicine Advanced Therapy designations from the FDA; it also holds Orphan Drug Designation from the European Medicines Agency.
Permanent congenital hearing loss affects about 1.7 per thousand newborns in the United States; roughly half these cases have genetic causes such as OTOF variants—an ultra-rare condition impacting about 20–50 newborns annually nationwide.
DB-OTO uses dual adeno-associated virus vectors designed to deliver a working copy of the OTOF gene directly into hair cells within the cochlea under general anesthesia—a process similar to cochlear implantation—to restore physiological hearing function in affected individuals.
Regeneron continues clinical investigation into DB-OTO’s safety and efficacy across multiple sites internationally through its ongoing CHORD trial involving infants, children, and adolescents under age eighteen.
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