Gene therapy cures profound genetic deafness within 24 weeks

Child having a hearing test

The investigational gene therapy DB-OTO improved hearing to normal levels in a child (dosed at 11 months of age) within 24 weeks, according to trial data presented at the American Society of Gene and Cell Therapy (ASGCT) annual conference.

Initial hearing improvements have also been observed in a second child (dosed at four years of age) at a six-week assessment.

Both children were born with profound genetic deafness due to variants of the otoferlin gene. The results are from the ongoing Phase I/II CHORD trial, which is currently enrolling infants and children in the US and Europe.

“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 Lustig, 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 US 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 January 2024, hearing restoration was observed within 30 days of a single administration of another gene therapy AK-OTOF in a Phase I/II study in sensorineural hearing loss due to mutations in the otoferlin gene (OTOF). Read more.

A new era of gene therapy research

In the trial, both children received a single intracochlear injection of DB-OTO in one ear. Hearing improvements were assessed by pure tone audiometry (PTA) and auditory brainstem response (ABR). PTA is measured through behavioural confirmation of sound (e.g., turning head towards sound) emitted at different intensity levels (measured in decibels or dB). ABR measures 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 four weeks.

As presented at ASGCT, at the 24-weeek assessment, the first participant showed improvement of hearing to normal levels across key speech frequencies, with an average 80dB improvement from baseline.

The second participant experienced consistent results to the first participant at the same timepoint.

The CHORD trial is a Phase I/II first-in-human, multicentre, open-label trial to evaluate DB-OTO in infants, children and adolescents with otoferlin variants.

Currently enrolling children across sites in the US, United Kingdom and Spain, CHORD is being conducted in two parts. In the initial dose-escalation cohort (Part A), participants will receive a single intracochlear injection of DB-OTO in one ear, while in expansion cohort (Part B), participants will receive simultaneous single intracochlear injections of DB-OTO in both ears at the selected dose from Part A.

CHORD is Regeneron’s first clinical-stage auditory program. In addition to DB-OTO, AAV.103 is also being investigated for people with GJB2-related hearing loss.

Diana Spencer, Senior Digital Content Editor, DDW

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