The gene therapy DB-OTO brought hearing to a level that generally avoids cochlear implantation in nine of 12 children with otoferlin-related deafness at 24 weeks, and clinicians rated speech perception as much or very much improved in six of nine children assessed at 48 weeks, according to results from the CHORD trial presented at the AAO-HNSF 2026 Annual Meeting.
John H. Greinwald Jr., MD, FAAP, of Cincinnati Children's Hospital Medical Center, a trial investigator, presented the speech data. The 24-week results were published in the New England Journal of Medicine.
The authors noted that biallelic variants in OTOF, the gene encoding otoferlin, account for 1% to 3% of congenital genetic deafness. Without otoferlin, inner hair cells stay structurally intact but cannot transmit signals to the cochlear nerve. No medicines exist for the condition, and children typically receive cochlear implants. DB-OTO is a dual adeno-associated virus 1 vector that delivers human OTOF complementary DNA under the control of a hair cell-specific promoter.
Study Design
CHORD is an open-label, single-group, phase 1-2 study enrolling up to 30 participants. Eligible children were younger than 18 with biallelic OTOF variants, profound deafness (average threshold above 90 dB HL) and markers of intact outer hair cell function. Participants received an intracochlear infusion of 7.2×1012 vector genomes per ear through the round window. The 12 participants in the NEJM analysis were 10 months to 16 years old; nine were treated in one ear and three in both. The primary endpoint was a behavioral pure-tone average of 70 dB HL or less at Week 24.
DB-OTO Improves Hearing at Week 24
Nine of 12 participants (75%; 95% confidence interval [CI], 43-95) showed a pure-tone average of 70 dB HL or less at Week 24, and the same number had an auditory brainstem response at or below 90 dB normalized hearing level. Six participants reached soft-speech sensitivity (45 dB HL or less) and three reached normal sensitivity (25 dB HL or less). Both participants who were 16 years old at the time of treatment showed improvements in hearing in the treated ear.
Of the three participants who missed the endpoint, one had no improvement and received a cochlear implant in the treated ear at 36 weeks. In an interview, Greinwald said the lack of response remains unexplained, although this participant had a relatively modest neutralizing antibody response to AAV1, which “may have indicated insufficient delivery.”
Speech Outcomes at 48 Weeks
Ten participants completed Global Impression Scales at Week 48. Clinicians rated speech perception as much or very much improved in six of nine participants, and caregivers in six of ten. Most participants with better hearing also had rapid gains on the LittlEARS questionnaire, the Auditory Skills Checklist or both.
Greinwald pointed out that one participant who had not met the response threshold at Week 24 achieved a pure-tone average threshold of 70 dB HL or less by Week 48, bringing the total to ten of 12 participants (83%) who achieved this threshold by Week 48.
Safety
In the NEJM analysis, 67 adverse events began or worsened after treatment. Investigators considered 17 related to the surgical delivery of DB-OTO. None led to study discontinuation. Two adverse events were serious (mastoiditis associated with the cochlear implant in the untreated ear, and walking instability after a varicella vaccination), both grade 3 and resolved without sequelae. No persistent vestibular findings were identified.
No DB-OTO-related adverse reactions were reported in the 48-week analysis. Greinwald said treatment-emergent adverse events occurred in 20 of 24 patients in the latest data, 54.2% mild and 20.8% moderate, all transient. Two patients had severe events unrelated to DB-OTO. There were no deaths.
The study is small, open-label and single-arm. Greinwald said an optimal treatment age has not been established and that hearing gains have been durable through 48 weeks, with follow-up continuing.
The study was funded by Regeneron Pharmaceuticals, Inc. Greinwald reported financial relationships with Regeneron Pharmaceuticals, Inc. (clinical trial investigator).
