Jay Rubinstein, MD, PhD, explains DB-OTO gene therapy in children with profound hearing loss

New data from the CHORD trial (NCT05788536) demonstrate the potential of DB-OTO, Regeneron Pharmaceuticals’ investigational gene therapy, as a treatment for otoferlin-related hearing loss. DB-OTO is designed to restore hearing in individuals with OTOF gene mutations by delivering a functional otoferlin protein, essential for communication between sensory cells of the inner ear and the auditory nerve. Unlike cochlear implants, which convert sound into electrical signals, DB-OTO aims to restore natural hearing by addressing the genetic cause of hearing loss.^1,2

Jay T. Rubinstein, MD, PhD, Virginia Merrill Bloedel Professor of Otolaryngology and Bioengineering and Director of the Bloedel Hearing Research Center at the University of Washington School of Medicine, emphasized the significance of these findings. "The first child was what we would call a home run. And if you're running any kind of clinical trial, that's the kind of result you want to see in the first subject."

As of February 24, 2025, 12 participants in the CHORD trial have received DB-OTO, with 9 administered an intracochlear injection in 1 ear and 3 receiving bilateral treatment. Data indicate that 10 of 11 participants with at least 1 post-treatment assessment experienced improved hearing at various decibel hearing levels (dBHL). Of 5 participants with 24-week assessments, 3 showed improvements in hearing thresholds to "nearly normal" (n = 1; ≤40 dBHL) or normal (n = 2; ≤25 dBHL) hearing levels.^1,2

READ MORE: DB-OTO improved hearing to normal in child with profound genetic deafness

"Any restoration of hearing would be extraordinary from something like this," Rubinstein said. "Scientifically, clinically, it has to be more than a little bit of hearing restoration to be useful. By being useful, I mean, it working better than a cochlear implant."

Rubinstein noted that fully characterizing the highest-performing subjects will take time. "Hearing is a lot more complicated than just pure tone hearing," he said. "Two of the subjects in the trial were teenagers with normal speech and language that they acquired with a cochlear implant in one ear that was placed when they were young, and neither of them has a good enough hearing result to assess speech discrimination at this time. That very well may change later."

Observations of the first treated child have been particularly promising.

"It's clear from observing the child that they have developed pretty high-functioning auditory skills," Rubinstein said. "They have had some speech perception testing done… but observing the child without their cochlear implant on, it's very clear that they have a remarkable degree of hearing restoration."

DB-OTO has been well tolerated among all 12 participants, with no serious adverse events related to the therapy. Transient post-surgical vestibular adverse events were observed in 5 participants but resolved within 6 days of dosing.^1,2

"These results continue to underscore the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related hearing loss," Rubinstein concluded. With multiple FDA designations, DB-OTO represents a promising step forward in gene therapy for congenital hearing loss.

References:

1. Latest DB-OTO results demonstrate clinically meaningful hearing improvements in nearly all children with profound genetic hearing loss in CHORD trial. Regeneron. Press release. February 24, 2025. Accessed February 24, 2025. https://investor.regeneron.com/news-releases/news-release-details/latest-db-oto-results-demonstrate-clinically-meaningful-hearing

2. Fitch, J. DB-OTO demonstrates improved hearing in 10 of 11 children with profound genetic hearing loss. Contemporary Pediatrics. February 24, 2025. Accessed March 7, 2025. https://www.contemporarypediatrics.com/view/db-oto-demonstrates-improved-hearing-in-10-of-11-children-with-profound-genetic-hearing-loss