Positive, phase 1/2 preliminary data for Regeneron Pharmaceuticals' DB-OTO, an investigational gene therapy for profound genetic deafness, was presented at the 2024 American Society of Gene and Cell Therapy (ASGCT) annual conference.

The gene therapy improved hearing to normal levels in a child born with profound genetic deafness, who was dosed at 11 months of age, within 24 weeks. Additionally, initial hearing improvements were observed in another child, who was dosed at 4 years of age, at a 6-week assessment.

"Both [of the children] received their treatment in the United Kingdom," Lawrence R. Lustig, MD, chair, Department of Otolaryngology-Head & Neck Surgery, Columbia University, and clinical trial investigator, told Contemporary Pediatrics in the video interview above.

"What we saw early on [in the child dosed at 11 months], was a gradual improvement of their hearing thresholds, their auditory thresholds. The most recent data that we captured at about 24 weeks shows that the hearing in the ear that was dosed with the gene therapy, particularly in the speech frequencies, is at a normal to mild hearing loss range, which honestly is jaw-dropping," added Lustig. "I think these results surpassed even our wildest imaginations in this 1 particular child."

Watch the video at the top of this article for Lustig's full interview with Contemporary Pediatrics.

Data stems from the ongoing phase 1/2 CHORD trial, a 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.

Each child received a single intracochlear injection of DB-OTO in 1 ear, with a surgical procedure that leverages the same approach used for cochlear implants. Pure tone audiometry (PTA) and auditory brainstem response (ABR) assessed the hearing improvements. According to Regeneron, PTA is considered to be the "gold standard" measurement of hearing, measured through behavioral confirmation of sound, such as turning the head toward a sound. ABR, as an objective confirmation of hearing function, corroborates behavioral responses by measuring electrical brainstem responses to sound emitted at different decibels.

Both participants had behavioral (PTA) or electrophysiological (ABR) responses at maximum sound levels of 100 decibels or greater at baseline. After treatment with DB-OTO, both children showed auditory responses at the first efficacy assessment of 4 weeks.

The first participant was 16 months of age at the 24-week assessment. Data presented at ASGCT showed the child had improvement of hearing to normal levels among key speech frequencies. The child had an average of 84 dB improvement from baseline, and 1 frequency measure reaching 10 dB in hearing level per PTA. Among all tested frequencies, an average 80 dB improvement from baseline was observed.

The second trial participant was 4 years of age at the 6-week assessment and experienced consistent results to the first participant at the same timepoint, stated Regeneron in a press release.

The second participant demonstrated initial improvement of hearing with responses to loud sounds observed across key speech frequencies, with an average of 19 dB improvement from baseline. One frequency measure reached 80 dB in hearing level per PTA. In this child, an average 16 dB improvement from baseline was observed.

"What we have right now, is the ability to measure hearing on a hearing test to determine what level they can detect sounds," said Lustig. "We don't really know what they're hearing. It's not going to be until the children are older that we see how their speech and language and speech comprehension come along and to listen to how they hear sounds. That's when we are really going to know, but that's not going to be for several years down the road."

Congenital deafness impacts approximately 1.7 out of every 1000 children born in the United States according to Regeneron, and approximately half of these cases have genetic causes. Otoferlin-related hearing loss is "ultra-rare," as the 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," stated Regeneron in the press release.

"I think this has profound impact on the treatment of children in general with hearing loss and how we approach them," said Lustig. "All children born with hearing loss really need to be genetically tested, because this particular form of deafness is relatively rare. Understanding which gene is involved in the deafness in children, if it can be identified, is going to be important."

Watch the video at the top of this article for Lustig's full interview with Contemporary Pediatrics.

Reference:

Latest DB-OTO results show dramatically improved hearing to normal levels in a child with profound genetic deafness within 24 weeks and initial hearing improvements in a second child at 6 weeks. Regeneron Pharmaceuticals. Press release. May 8, 2024. Accessed May 8, 2024. https://investor.regeneron.com/news-releases/news-release-details/latest-db-oto-results-show-dramatically-improved-hearing-normal

Link:

DB-OTO improved hearing to normal in child with profound genetic deafness - Contemporary Pediatrics