Regeneron's $200M+ Acquired Dual-AAV Gene Therapy DB-OTO Meets Primary Endpoint in Pivotal CHORD Trial

Oct 13, 2025 14:10 CST Updated 14:10

Regeneron

Biopharmaceutical Manufacturer

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On October 12, 2025, Regeneron announced that the latest data on its investigational gene therapy DB-OTO had been published in the journal *The New England Journal of Medicine (NEJM)* and presented at the American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF) Annual Meeting.Latest results from the pivotal CHORD trial show: 11 out of 12 participants experienced clinically meaningful hearing improvement., three of whom reached normal hearing levels. Additionally, among the eight participants who underwent long-term follow-up, their hearing performance remained stable or continued to improve, and all three participants who completed speech assessments showed significant improvement.

Regeneron stated that it plans to submit the U.S. regulatory application for DB-OTO later this year, pending discussions with the U.S. FDA. The therapy has received multiple designations from the FDA, including Orphan Drug, Rare Pediatric Disease, Fast Track, and Regenerative Medicine Advanced Therapy designations. The European Medicines Agency has also granted DB-OTO Orphan Drug designation.

DB-OTO was acquired by Regeneron in 2023 for an upfront payment of $109 million and milestone payments of $104 million through the acquisition of Decibel Therapeutics, a Nasdaq-listed company.DB-OTO is an investigational cell-selective, dual adeno-associated virus (AAV) vector gene therapy designed to provide lasting and physiologically functional hearing for individuals with severe congenital hearing loss caused by OTOF gene mutations. The therapy involves infusing a modified, non-pathogenic virus into the cochlea under general anesthesia (similar to the procedure used in cochlear implant surgery) to deliver a functional OTOF gene, replacing the non-functional otoferlin protein.

The CHORD trial is a registrational Phase 1/2 multicenter open-label trial designed to evaluate the safety, tolerability, and efficacy of DB-OTO in infants, children, and adolescents with OTOF-related hearing loss.The CHORD study was conducted in two parts:In the initial dose-escalation cohort (Part A), participants received a single intracochlear infusion of DB-OTO in one ear. In the expansion cohort (Part B), participants received the selected dose of DB-OTO from Part A in both ears.

The primary endpoint of the study was the pure-tone average (PTA) threshold ≤70 dB HL (achieving natural acoustic hearing) at 24 weeks. The key secondary endpoint was the click-evoked auditory brainstem response (ABR) threshold ≤90 dB nHL at 24 weeks.

The CHORD trial enrolled pediatric subjects with profound hearing loss caused by OTOF gene variants, administering the DB-OTO gene therapy via a single intracochlear infusion. A total of 12 subjects (aged 10 months to 16 years) were included, with 9 treated unilaterally and 3 treated bilaterally. The administration procedure utilized a pathway similar to cochlear implant surgery, applicable for infants and young children.

Almost all subjects (11 of 12 individuals; 14 of 15 treated ears) experienced hearing improvement within weeks after treatment.The published and announced results show that the trial met the primary endpoint:In the 24-week pure-tone audiometry (PTA) assessment, the hearing of 9 subjects improved to ≤70 dB HL, a threshold corresponding to the clinical standard that typically does not require cochlear implantation, allowing for the preservation of natural acoustic hearing. Notably, 6 of them could hear soft speech without hearing aids, and 3 were even able to detect whispers (reaching normal hearing sensitivity). One subject who did not meet the primary PTA endpoint at 24 weeks further improved to "near-normal" hearing sensitivity at 48 weeks. Additionally,Achieve Key Secondary Endpoints of the Trial:Nine subjects had auditory brainstem response (ABR) thresholds ≤90 dB nHL.

Among eight subjects with a follow-up period of ≥36 weeks (up to 72 weeks), hearing improvement remained stable or continued to improve. Speech development assessments were conducted on three subjects who completed 48 weeks of follow-up, all showing significant progress: one subject could distinguish monosyllabic and disyllabic words without visual cues and respond to distant sounds and speech in noisy environments.

In terms of safety: All 12 subjects tolerated both the surgery and DB-OTO well.No adverse event reports related to DB-OTO have been reported. Two serious adverse events occurred: one was due to complications from cochlear implant surgery, and the other was related to recent vaccination. Some participants experienced transient postoperative vestibular adverse events (e.g., nystagmus, nausea, dizziness, vomiting), all of which have fully resolved.

Lawrence R. Lustig, MD, Chair of the Department of Otolaryngology–Head and Neck Surgery at Columbia University Vagelos College of Physicians and Surgeons, and investigator for the CHORD trial, stated："To date, hearing loss caused by OTOF gene mutations has been considered permanent, which is precisely why many of us have dedicated our careers to this field. This registrational dataset consistently shows that DB-OTO takes effect rapidly and demonstrates significant efficacy; in subjects followed up at later time points, we not only see stable hearing preservation but also continued improvement in speech perception. Families of the patients find these results particularly moving – as one parent put it, their situation now compared to a year ago is 'unimaginable.' This truly marks the beginning of a new era in the treatment of hearing loss."

Reference: Company Announcement

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