Regeneron Presents Latest DB-OTO Data Showing Dramatic and Sustained Hearing and Speech Improvements in Children with Profound Genetic Hearing Loss
Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced updated data for its investigational gene therapy DB-OTO for profound genetic hearing loss caused by variants of the otoferlin (OTOF) gene. The findings were published in The New England Journal of Medicine and highlighted during an oral presentation at the annual American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNSF) meeting.
The latest results from the pivotal CHORD trial demonstrate that 11 of 12 participants experienced clinically meaningful hearing improvements, including three achieving normal hearing levels. Among eight participants with longer-term follow-up, hearing either remained stable or continued to improve. Speech assessments completed in three participants revealed significant gains in speech perception and comprehension.
“Until now, genetic OTOF-related hearing loss was considered permanent, which is why so many of us have devoted our careers to this field,” said Lawrence R. Lustig, M.D., Chair of the Department of Otolaryngology–Head and Neck Surgery at Columbia University and a trial investigator. “This registrational dataset shows consistent, rapid, and robust responses to DB-OTO. For those followed over time, we are seeing not only hearing stability but continued improvement in speech understanding. The impact for families is profound—one parent described their child’s progress as ‘unimaginable’ compared to a year ago. This truly represents a new era in the treatment of hearing loss.”
CHORD Trial Overview
The CHORD trial is a registrational Phase 1/2 multicenter, open-label study evaluating DB-OTO in children with profound hearing loss due to OTOF gene variants. Participants received a single intracochlear infusion of DB-OTO, delivered via a surgical approach similar to cochlear implantation, enabling treatment even in very young infants.
Among the 12 pediatric participants (ages 10 months to 16 years), nine received unilateral treatment (one ear) and three received bilateral treatment. The therapy demonstrated rapid and meaningful hearing improvements in 11 of 12 participants (14 of 15 treated ears) within weeks.
The trial met its primary endpoint, with 9 participants achieving hearing thresholds ≤70 decibel hearing level (dBHL) by week 24, as measured by behavioral pure tone audiometry (PTA). This level typically allows for natural acoustic hearing without cochlear implantation. Six participants could hear soft speech without assistive devices, while three reached normal hearing sensitivity, detecting whispers. One participant who did not meet the primary endpoint at week 24 improved to nearly normal hearing by week 48.
Secondary endpoints were also met: nine participants demonstrated auditory brainstem responses (ABR) ≤90 dB, confirming objective hearing improvements.
Sustained Hearing and Speech Improvements
Hearing gains remained stable or continued to improve in participants followed for 36 to 72 weeks. Speech assessments in three participants after 48 weeks showed significant improvements, including the ability to recognize one- and two-syllable words without visual cues and respond to distant sounds in noisy environments.
Safety Profile
Both DB-OTO and the surgical procedure were well tolerated. No therapy-related adverse events were reported. Two serious adverse events occurred: one due to a cochlear implant complication and another linked to a recent vaccination. Some participants experienced transient vestibular events such as nystagmus, dizziness, or vomiting, all of which resolved fully.
Regulatory Pathway
Regeneron plans to submit U.S. regulatory applications later this year, pending discussions with the FDA. DB-OTO has received Orphan Drug, Rare Pediatric Disease, Fast Track, and Regenerative Medicine Advanced Therapy designations from the FDA, and Orphan Drug Designation from the European Medicines Agency. The therapy is currently investigational, and its safety and efficacy have not been evaluated by any regulatory authority.
About OTOF-Related Hearing Loss
Congenital hearing loss affects approximately 1.7 per 1,000 U.S. children, with about half of cases having a genetic origin. Otoferlin-related hearing loss is ultra-rare, impacting 20–50 newborns per year in the U.S. The condition is caused by OTOF gene variants, resulting in non-functional otoferlin protein, which is critical for transmitting signals from inner ear sensory cells to the auditory nerve.
About the CHORD Trial
CHORD enrolls children under 18 across the U.S., U.K., Spain, and Germany. The trial is conducted in two parts:
- Part A: Dose-escalation, single-ear infusion
- Part B: Expansion cohort, bilateral treatment at the selected dose
Hearing improvements are assessed using PTA (behavioral responses to sound) and ABR (objective measurement of electrical brainstem responses to sound). At baseline, participants had profound hearing loss with no ABR responses.
Additional trial information is available at clinicaltrials@regeneron.com.
About DB-OTO and the Regeneron Auditory Program
DB-OTO is an investigational dual AAV vector gene therapy designed to restore hearing in individuals with profound congenital hearing loss caused by OTOF variants. The therapy delivers a functional copy of the OTOF gene using a modified, non-pathogenic virus, targeting inner ear hair cells via a proprietary Myo15 promoter to restrict gene expression to relevant cells.
Beyond OTOF, Regeneron continues to explore other genetic forms of hearing loss as part of its commitment to advancing auditory gene therapy.
