Regeneron’s CHORD study evaluating investigational gene therapy DB-OTO for otoferlin-related hearing loss — a rare condition caused by variants in the OTOF gene — has revealed that 10 of 11 children with at least one post-treatment hearing assessment experienced notable improvements, including dramatic gains in speech perception.
The OTOF gene is crucial for the inner ear’s ability to transmit sound signals to the brain, and when it malfunctions, the natural communication pathway is disrupted, leading to congenital deafness.
DB-OTO works by delivering a functional copy of the gene directly into the cochlea — the spiral-shaped organ responsible for hearing — using a dual adeno-associated virus (AAV) vector system. This safe, precise method employs a modified virus to introduce the therapeutic gene, while a proprietary cell-specific Myo15 promoter ensures expression only in the inner hair cells essential for auditory processing.
Dr. Jay Rubinstein, a CHORD clinical trial investigator, noted that a year after DB‑OTO treatment, a profoundly deaf child experienced transformative hearing gains — enabling enjoyment of music and play — even after the removal of a cochlear implant from the untreated ear.
Regeneron added DB-OTO to its gene therapy portfolio — a move that is paying off — during its 2023 acquisition of Decibel Therapeutics, which also brought in preclinical programs targeting GJB2-related and STRC-related hearing loss.
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The CHORD trial, a Phase I/II first-in-human study, involved 12 children aged 10 months to 16 years. Nine participants received an intracochlear injection in one ear, while three received injections in both ears via a procedure similar to cochlear implantation, making it suitable even for young infants.
Detailed clinical observations revealed that the first participant, dosed at 10 months, demonstrated dramatic improvements by 48 weeks — with hearing thresholds nearing normal levels across key speech frequencies (0.25 to 2.0 kilohertz). These were measured via pure tone audiometry (PTA), the gold standard for behavioral assessment, and corroborated by auditory brainstem responses (ABR), which gauge the brain’s electrical response to sound.
Speech perception tests showed the child progressing from recognizing simple sounds to correctly identifying words like “mommy,” “cookies” and “airplane” at conversational levels.
Among participants evaluated at 24 weeks, three of five achieved nearly normal or normal hearing thresholds, while one showed no change.
Safety assessments were reassuring; only transient vestibular effects — mild dizziness and nausea — were observed, resolving within six days.
Each year, more than 6,000 US infants — about 1.7 per 1,000 screened — are identified with permanent hearing loss, with 50% to 60% of cases attributed to genetic factors.
The CHORD study is a key part of Regeneron’s larger Auditory Program, which aims to restore the full spectrum of sound by employing inner ear cell‑specific promoters and AAV vectors.
In related news, Eli‑Lilly last published promising Phase I/II data for its investigational candidate, AK‑OTOF, developed by its subsidiary Akouos, with the first 11‑year‑old participant experiencing restored hearing — improving from 65 to 20 dB HL across tested frequencies — within 30 days of a single intracochlear administration.
More recently, Sensorion’s candidate, SENS‑501’s Audiogene — a gene therapy targeting congenital sensorineural hearing loss — received a positive recommendation from its data monitoring committee during its Phase I/II trial, although it remains in earlier stages of development.
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