Ten of 12 children with profound genetic hearing loss who received Regeneron Pharmaceutical’s gene therapy showed ‘clinically meaningful, notable improvements in hearing’ the 48th ARO conference has heard.
Latest results of the phase 1/2 CHORD clinical trial were presented at the Association for Research in Otolaryngology’s annual midwinter meeting in Florida, America on 24 February 2025.
The children, ranging from infants to teenagers, were from countries including the US and the UK. All had received at least one post-treatment assessment.
In the first child treated, speech and development progress followed dramatic improvements in hearing.
One of the children, British baby Opal Sandy made global headlines in May 2024 when it was revealed that at 11 months of age, she was among the world’s youngest to receive the Regeneron gene therapy.
Six months after a single intracochlear injection delivered via a one-off infusion into her right ear, her hearing had ‘improved close to normal hearing levels’ in the treated ear, doctors said in 2024.
Regeneron, a biotechnology company founded and led by physician-scientists, announced updated data from 12 children in the trial of the investigational gene therapy DB-OTO. They all had profound genetic hearing loss due to variants of the otoferlin (OTOF) gene.
These included 72-week results showing speech and development progress in the first child dosed at 10 months of age, and initial results in 11 children (aged 10 months to 16 years old) including three who received DB-OTO in both ears.
Life-changing interactions
Trial investigator, Dr Jay Rubinstein, Virginia Merrill Bloedel Professor of Otolaryngology and Bioengineering and Director, Bloedel Hearing Research Center, University of Washington School of Medicine, reported findings in an oral presentation.
“A year after treatment in one ear with DB-OTO, a child born profoundly deaf was able to enjoy music, engage in imaginative play and participate in bedtime reading when the cochlear implant on their other ear was removed,” he said.
“These seemingly small interactions are life-changing for these children as well as their families and these results continue to underscore the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related hearing loss.”
Nine of the 12 participants received the therapy via an intracochlear injection in one ear and three received it bilaterally.
Delivers working copy of gene
Regeneron said DB-OTO was an investigational cell-selective, dual adeno-associated virus (AAV) vector gene therapy which aims to deliver a working copy to replace the faulty OTOF gene using a modified, non-pathogenic virus.
The virus is delivered via an injection into the cochlea under general anaesthesia, similar to the procedure used for cochlear implantation, which enables use in young infants.
“The newly introduced OTOF gene is under the control of a proprietary cell-specific Myo15 promoter, which is intended to restrict expression only to inner hair cells that normally express otoferlin,” Regeneron said.
Improvement of hearing to ‘near-normal levels’
The 48-week results from the first participant dosed in the trial, presented at ARO, showed improvement of hearing to near-normal levels across key speech frequencies.
This included hearing thresholds that were within normal limits (0.25-2.0 kHz) in most speech-relevant frequencies and corroborated with positive auditory brainstem responses (ABRs).
Dr Rubinstein said results were particularly encouraging from formal speech perception tests in which the child demonstrated improvement from week 48 to week 72 and correctly identified words – such as mommy, cookies and airplane – that were presented at a conversational level without any visual cues.
Among the 11 participants with at least one post-treatment assessment, 10 demonstrated a notable response, with improved hearing at various decibel hearing levels (dBHL).
Additionally, among five participants with 24-week assessments, three experienced improvements in average hearing thresholds to “nearly normal” (n=1; ≤40 dBHL) or normal (n=2; ≤25 dBHL) hearing levels.
All ABR responses were corroborated by hearing improvements assessed by pure tone audiometry (PTA).
One participant however has not experienced a change from their baseline hearing at 24 weeks post-dosing.
No adverse events
Both the surgical procedure and DB-OTO therapy were well tolerated in all 12 participants. There were no adverse events or serious adverse events that were considered related to DB-OTO.
Five experienced transient post-surgical vestibular adverse events (e.g., nystagmus, nausea, dizziness, vomiting), which resolved within six days of dosing.
DB-OTO received Orphan Drug, Rare Pediatric Disease, Fast Track and Regenerative Medicine Advanced Therapy designations from the US Food and Drug Administration.
The European Medicines Agency granted Orphan Drug Designation.
Regeneron said the potential use of DB-OTO for otoferlin-related hearing loss was currently under clinical investigation, and its safety and efficacy had not been evaluated by any regulatory authority.
Trial details
About half of congenital deafness cases have genetic causes.
Otoferlin-related hearing loss is caused by variants in the OTOF gene, which leads to a lack of a functional otoferlin protein that is critical for communication between sensory cells of the inner ear and the auditory nerve.
The CHORD trial is an ongoing, first-in-human, multicentre, open-label trial to evaluate the safety, tolerability and preliminary efficacy of DB-OTO in infants, children and adolescents with otoferlin variants.
It is currently enrolling children under 18 across sites in the US, UK and Spain and is being conducted in two parts.
In the initial dose-escalation cohort (part A), participants receive a single intracochlear injection of DB-OTO in one ear.
In the expansion cohort (part B), participants receive simultaneous single intracochlear injections of DB-OTO in both ears at the selected dose from Part A.
Hearing improvements are assessed by the gold standard measurement of hearing, PTA, measured through behavioural responses to sound such as head turning towards sound emitted at different intensity levels and measured in decibels.
ABR corroborates these responses, serving as an objective confirmation of hearing function, and is measured through electrical brainstem responses to sound emitted at different decibels.
At baseline, all participants had no behavioral (PTA) or electrophysiological (ABR) responses at maximum sound levels (≥100 dB).
Regeneron said it was committed to also investigating several other targets for genetic forms of hearing loss, including GJB2.
More reading
Gene therapy restores hearing in baby and children with genetic deafness
Addressing the root cause of genetic deafness
