RARE Daily

Regeneron’s Experimental Gene Therapy Restores Hearing to Normal Level in Deaf Child

May 8, 2024

Rare Daily Staff

Regeneron Pharmaceuticals said its experimental gene therapy DB-OTO improved hearing to normal levels within 24 weeks in a child dosed at 11 months of age.

A second child dosed at age 4 showed initial hearing improvements six weeks after dosing. 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.

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 annual conference.

Congenital deafness is a significant unmet medical need that affects approximately 1.7 out of every 1,000 children born in the United States. Although approximately half of these cases have genetic causes, otoferlin-related hearing loss is ultra-rare. This specific condition is caused by variants in the otoferlin gene, which impairs the production of the OTOF protein that is critical for the communication between the sensory cells of the inner ear and the auditory nerve. While hearing aids and cochlear implants can amplify sound to improve hearing for individuals with a range of hearing loss, these devices do not currently restore the full spectrum of sound.

DB-OTO is an experimental cell-selective, adeno-associated virus gene therapy designed to provide durable, physiological hearing to individuals with profound, congenital hearing loss caused by variants of the otoferlin gene. The treatment aims to deliver a working copy to replace the faulty otoferlin gene using a modified, non-pathogenic virus that is delivered via an injection into the cochlea under general anesthesia.

In this gene therapy, the newly introduced otoferlin 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.

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 CHORD trial is a phase 1/2 first-in-human, multicenter, open-label trial to evaluate the safety, tolerability, and preliminary efficacy of DB-OTO in infants, children and adolescents with otoferlin variants.

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 behavioral confirmation of sound, such as turning the head towards sound, emitted at different intensity levels. ABR corroborates these behavioral responses, serving as an objective confirmation of hearing function, by measuring electrical brainstem responses to sound emitted at different decibels.

At baseline, both participants had no behavioral or electrophysiological responses at maximum sound levels. Following treatment with DB-OTO, both children showed auditory responses at the first efficacy assessment of four weeks.

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.

“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.”

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