Regeneron Pharmaceuticals announced groundbreaking results for its investigational gene therapy DB-OTO, showing dramatic hearing restoration in children with profound genetic hearing loss. The latest data from the pivotal CHORD trial, published in The New England Journal of Medicine and presented at the American Academy of Otolaryngology-Head and Neck Surgery meeting, demonstrated that 11 out of 12 participants experienced clinically meaningful hearing improvements.
Remarkable Clinical Outcomes
The CHORD trial evaluated pediatric participants aged 10 months to 16 years with profound hearing loss caused by variants of the otoferlin (OTOF) gene. Among the 12 participants, nine received the gene therapy unilaterally and three received bilateral treatment through a single intracochlear infusion procedure similar to cochlear implantation.
Three participants achieved normal hearing levels, while six could hear soft speech without assistive devices. Notably, three participants were able to detect whispers, achieving normal hearing sensitivity. The trial met its primary endpoint with 9 participants experiencing hearing improvements at a threshold of ≤70 decibel hearing level as assessed by behavioral pure tone audiometry at week 24.
"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 Columbia University College of Physicians and Surgeons and a trial investigator. "This registrational data set showcases consistent, rapid and robust responses to DB-OTO."
Sustained and Progressive Benefits
Eight participants with longer follow-up visits of ≥36 weeks (up to 72 weeks) showed stability or continued improvement in their hearing. Among three participants who completed speech assessments after at least 48 weeks of follow-up, all demonstrated significant improvements. One participant showed the ability to identify one- and two-syllable words with no visual cues and could respond to distant sounds and speech in noisy environments.
One participant who did not meet the primary endpoint at week 24 further improved to achieve "nearly normal" hearing sensitivity at week 48, demonstrating the therapy's potential for continued benefit over time.
Safety Profile and Treatment Approach
The surgical procedure and DB-OTO were well tolerated across all 12 participants, with no DB-OTO-related adverse findings reported. Two participants experienced serious adverse events: one attributed to a cochlear implant surgical complication and another to a recent vaccination. Some participants experienced transient post-surgical vestibular adverse events including nystagmus, nausea, dizziness, and vomiting, all of which fully resolved.
DB-OTO is a cell-selective, dual adeno-associated virus vector gene therapy designed to deliver a working copy of the OTOF gene to replace the non-functional otoferlin protein. The treatment uses a modified, non-pathogenic virus delivered via cochlear infusion under general anesthesia, with the OTOF gene under control of a proprietary cell-specific Myo15 promoter to restrict expression to hair cells.
Addressing an Ultra-Rare Condition
Otoferlin-related hearing loss affects approximately 20-50 newborns per year in the U.S., representing a subset of the 1.7 out of every 1,000 children born with permanent congenital hearing loss. The condition results from variants in the OTOF gene that lead to lack of functional otoferlin protein, which is critical for communication between inner ear sensory cells and the auditory nerve.
Regulatory Pathway Forward
Regeneron plans to submit a U.S. regulatory application for DB-OTO later this year, pending discussions with the FDA. The therapy has received multiple FDA designations including Orphan Drug, Rare Pediatric Disease, Fast Track, and Regenerative Medicine Advanced Therapy status. The European Medicines Agency has also granted Orphan Drug Designation.
The CHORD trial continues to enroll children under 18 years of age across sites in the U.S., United Kingdom, Spain, and Germany, with the expansion cohort evaluating bilateral treatment at the selected dose from the initial phase.
