Regeneron’s Gene Therapy DB-OTO Improves Hearing in Children With Otoferlin-Related Hearing Loss
Out of 11 treated children who had at least 1 posttreatment assessment, 10 showed improved hearing at various decibel hearing levels.
Regeneron’s DB-OTO, an investigational adeno-associated virus (AAV) dual-vector-based gene therapy intended to treat otoferlin (OTOF)-related hearing loss, has improved hearing in pediatric patients treated in the phase 1/2 CHORD clinical trial (NCT05788536).1
The company presented the findings orally at the Association for Research in Otolaryngology’s (ARO) 48th Annual MidWinter Meeting, held February 22 to 26, 2025, in Orlando, Florida. Notably, out of the 11 treated children who had at least 1 posttreatment assessment, 10 showed improved hearing at various decibel hearing levels (dBHL). Furthermore, 1 of the 5 children who had reached their 24-week assessment showed an improvement in average hearing threshold to “nearly normal” hearing levels (≤40 dBHL) and 2 of the 5 children showed an improvement to normal hearing levels (≤25 dBHL). Regeneron noted that 1 of the 11 children who reached the 24-week assessment did not show any change in in hearing from baseline.
Another participant, not included in the aforementioned group of 11 patients, had a 48-weeks posttreatment assessment in which improvement to hearing thresholds within normal limits (0.25-2.0 kHz) in most speech-relevant frequencies were observed. According to Regeneron, positive auditory brainstem responses (ABRs) corroborated the findings. In addition, at 72 weeks posttreatment, this patient showed improvement from 48 weeks posttreatment on formal speech perception tests, with correct identification of words that were presented without visual cues reported.
With regard to safety, Regeneron characterized DB-OTO and the surgical procedure used to provide the gene therapy as “well-tolerated" in the 12 treated patients. There were no adverse events (AEs) or serious AEs deemed related to DB-OTO itself. Transient vestibular adverse events following surgery, such as nystagmus, nausea, dizziness, or vomiting, were seen in 5 of the 12 patients. Although, these AEs resolved within 6 days after receiving the gene therapy.
“Sound is a significant part of the human experience that connects us to each other and our environment,” CHORD investigator Jay T. Rubinstein, MD, PhD, the Virginia Merrill Bloedel Professor of Otolaryngology and Bioengineering and the director of the Bloedel Hearing Research Center at University of Washington School of Medicine, said in a statement.1 “A year after treatment in 1 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. 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.”
DB-OTO is intended to provide a functional copy of OTOF, is delivered with an injection to the cochlea, and includes a cell-selective Myo15 promoter with the intention of limiting expression of otoferlin, the disease-targeted protein, to cochlear inner hair cells.2,3 The first-in-human, open-label CHORD study, which was launched on May 12, 2023, takes the form of a 2-part dose escalation and dose expansion study and will seek to enroll approximately 22 participants in total. CGTLive has previously covered the design of the clinical trial.
Earlier data from CHORD was previously presented by Lawrence R. Lustig, MD, the chair of the Department of Otolaryngology—Head and Neck Surgery at Columbia University College of Physicians, at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD.4 At the conference, CGTLive interviewed Lustig about DB-OTO and the clinical trial.
“This is going to be big for the field,” Lustig told CGTLive. “Now that we have a treatment for genetic deafness, our hope is that this will spur universal genetic testing in all kids with hearing loss, which will give us a much better overview of the genetic landscape of hearing loss in the world. Right now, we know there's a few genes that when they're mutated will lead to deafness, but there's many others for which it's not so clear. So really identifying what genes are exactly involved in hearing loss and in what combinations is really going to help revolutionize our field. We also think that because this is the first successful treatment for genetic deafness, this is going to spark innovation in the field and drive a lot of other groups to develop therapies for other forms of genetic deafness, as well.”
