DB-OTO, a dual adeno-associated virus 1 gene therapy delivering human otoferlin complementary DNA, met prespecified hearing endpoints at 24 weeks in 9 of 12 pediatric patients with biallelic OTOF variants and profound congenital deafness in a first-in-human, open-label, single-group registrational study.
The primary behavioral endpoint was a pure-tone audiometry average threshold less than or equal to 70 decibels hearing level, and the key physiologic endpoint was an auditory brain-stem response click threshold less than or equal to 90 dB normalized hearing level; both were achieved by 75 percent of patients. At week 24, 6 patients heard soft speech at 45 dB hearing level or lower, and 3 patients reached average normal hearing sensitivity at 25 dB hearing level or lower.
Among unilateral recipients, 6 of 9 treated ears met the primary endpoint, compared with 0 of 9 untreated contralateral ears. Auditory brain-stem response thresholds less than or equal to 90 decibels normalized hearing level occurred in 7 of 9 treated ears and 0 of 9 untreated ears among unilateral recipients; 2 of 3 bilaterally treated patients had responses detected.
Hearing observed beyond 24 weeks—up to 72 weeks—remained stable or continued to improve. Three of 4 patients assessed at 48 weeks or longer showed improvement on clinician and parent Global Impression Scales and demonstrated gains on Early Speech Perception testing. One patient had no measurable hearing response and underwent cochlear implantation in the ear that received DB-OTO.
“Genetic deficiency of otoferlin, a protein critical to synaptic transmission by the sensory hair cells of the ear, causes congenital deafness,” wrote Vassili Valayannopoulos of Regeneron Pharmaceuticals. This mechanism provides the rationale for restoring otoferlin expression with DB-OTO in pediatric OTOF–related deafness.
Safety findings included 67 adverse events (AEs) that began or worsened after dosing; investigators considered 17 related to the surgical delivery procedure. Two serious AEs occurred—grade 3 mastoiditis in the contralateral implanted ear of one patient and grade 3 walking instability in another patient after a recent varicella vaccination—both of which were resolved without sequelae. Transient or low-titer anti-otoferlin antibodies appeared in about half of patients and were generally negative by week 12. Baseline anti–adeno-associated virus 1 neutralizing antibodies were present in most patients and rose by week 2; a patient with the highest baseline titer still showed hearing improvement. Two patients had focal high-frequency threshold elevations; one coincided with otitis media and stabilized after resolution, and one improved during systemic glucocorticoid treatment.
Patients ranged in age from 10 months to 16 years of age with average audiometric thresholds greater than 90 dB hearing level. Eligibility required biallelic OTOF variants and markers of intact outer hair cell function in the ear or ears designated for treatment. DB-OTO was given as a single intracochlear infusion—7.2 × 10^12 vector genomes per ear—via a round-window approach after mastoidectomy and facial-recess exposure; a lateral semicircular canal fenestration allowed egress of displaced perilymph. Nine patients received unilateral treatment, and three received bilateral treatment.
The study had a small sample and an open-label single-group design without randomization. Conversion to a registrational study meant some endpoints were not originally prespecified. The primary follow-up window was relatively short. A natural-history benchmark indicated negligible spontaneous hearing recovery in OTOF-related deafness.
DB-OTO demonstrated clinically meaningful hearing restoration signals in pediatric OTOF-related deafness with a safety profile consistent with intracochlear surgical delivery. The protocol specified continued follow-up to evaluate durability and longer-term safety.
Full disclosures can be found in the published study.
