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Regeneron Pharmaceuticals have announced that the investigational gene therapy DB-OTO improved hearing to normal levels in one child (dosed at 11 months of age) within 24 weeks, and initial hearing improvements were observed in a second child (dosed at 4 years of age) at a 6-week assessment. Both children were born with profound genetic deafness due to variants of the otoferlin gene, and the child dosed at 11 months of age is one of the youngest in the world to receive a gene therapy for genetic deafness. The results are from the ongoing Phase 1/2 CHORD trial, which is currently enrolling infants and children and were detailed during an oral presentation at the American Society of Gene and Cell Therapy (ASGCT) annual conference.
“The opportunity of providing the full complexity and spectrum of sound in children born with profound genetic deafness is a phenomenon I did not expect to see in my lifetime,” said Lawrence R. Lustig, M.D., Chair of Columbia University’s Department of Otolaryngology - Head & Neck Surgery and a clinical trial investigator. “These impressive results showcase the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related deafness, and we are excited to see how this translates into an individual’s development, especially since early intervention is associated with better outcomes for speech development. With the DB-OTO CHORD trial now enrolling participants in sites across the U.S. and Europe, we’re part of the beginning of a new era of gene therapy research that looks to create treatment options that address the root cause of profound genetic deafness.”
In the trial, both children received a single intracochlear injection of DB-OTO in one ear. The surgical procedure leverages the same approach used for cochlear implants, which is amenable for use in young infants. Hearing improvements were assessed by pure tone audiometry (PTA) and auditory brainstem response (ABR). PTA is considered by auditory experts to be the gold standard measurement of hearing and is measured through behavioural confirmation of sound (e.g., turning head towards sound) emitted at different intensity levels (measured in decibels or dB). ABR corroborates these behavioural responses, serving as an objective confirmation of hearing function, by measuring electrical brainstem responses to sound emitted at different dBs.
At baseline, both participants had no behavioural (PTA) or electrophysiological (ABR) responses at maximum sound levels (≥100 dB). Following treatment with DB-OTO, both children showed auditory responses at the first efficacy assessment of 4 weeks.
As presented at ASGCT, the first participant dosed in the trial was 16 months of age at the 24-week assessment and showed:
- Improvement of hearing to normal levels across key speech frequencies, with an average 84 dB improvement from baseline and one frequency measure reaching 10 dB in hearing level per PTA. Across all tested frequencies, an average 80 dB improvement from baseline was observed.
- Positive ABR responses, with best frequency reaching 45 dB.
The second participant dosed in the trial was 4 years of age at the 6-week assessment and experienced consistent results to the first participant at the same timepoint, including:
- Initial improvement of hearing with responses to loud sounds, which was observed across key speech frequencies, with an average 19 dB improvement from baseline and one frequency measure reaching 80 dB in hearing level per PTA. Across all tested frequencies, an average 16 dB improvement from baseline was observed.
- Positive ABR responses, with best frequency reaching 75 dB.
Both the surgical procedure (delivery and post-operation) and DB-OTO were well tolerated, and there were no related adverse events or serious adverse events following treatment.
DB-OTO received Orphan Drug, Rare Pediatric Disease and Fast Track Designations from the U.S. Food and Drug Administration and Orphan Drug Designation was granted by the European Medicines Agency. The potential use of DB-OTO for otoferlin-related hearing loss is currently under clinical investigation, and its safety and efficacy have not been evaluated by any regulatory authority.