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B6 - Ophthalmic and Auditory Diseases

10: Intracochlear Administration of DB-OTO Gene Therapy in Pediatric Patients with Profound Hearing Loss Due to Otoferlin Mutations: The CHORD Phase 1/2 Open-Label Trial

Type: Oral Abstract Session

Presentation Details
Session Title: Clinical Trials Spotlight Symposium

Introduction: Biallelic otoferlin gene (OTOF) mutations commonly result in auditory neuropathy characterized by severe-to-profound sensorineural hearing loss. In these patients, the auditory brainstem response (ABR) is absent or severely reduced contrasting with normal outer hair cell function. OTOF gene replacement may provide instatement of high-quality, physiological hearing and be a more effective and durable treatment than cochlear implants. DB-OTO is a dual adeno-associated virus (AAV1) vector designed for intracochlear delivery of a full-length copy of the human OTOF gene under the control of the Myo15 hair-cell specific promoter. In this first-in-human clinical trial with DB-OTO (CHORD, NCT05788536), the safety, tolerability and preliminary efficacy of DB-OTO is being evaluated in pediatric patients with profound hearing loss caused by OTOF mutations. Methods: CHORD is a global, phase 1/2 trial of DB-OTO enrolling pediatric patients with biallelic pathogenic OTOF variants, profound hearing loss, presence of otoacoustic emissions or cochlear microphonic if >2 years. In Part A, the initial unilateral dose escalation phase of the study, DB-OTO is being administered by intracochlear injection using a typical facial recess approach through the round window. A 10-month-old female received a single intracochlear injection of 7.2 x 1012 vector genomes of DB-OTO unilaterally with a cochlear implant placed in the contralateral ear. At baseline the patient had no detectable hearing by behavioral pure tone audiogram (PTA) nor ABR. Results: Through week 12 after treatment, no dose-limiting toxicities and no DB-OTO related adverse events (AEs) were reported, including absence of vestibular manifestations. Hearing recovery was detected at 4 weeks post-treatment, with average behavioral PTA thresholds improving to 55 dB in the best frequencies (2, 4 and 8 kHz) at 12 weeks post‑treatment. Hearing recovery measured by ABR showed a positive wave V amplitude through week 12 (thresholds of 40-80 dB, no response at 100 dB at baseline) in the DB-OTO treated ear, while no improvement was observed in the untreated ear. According to parental reports, as indicated by the LittlEARS auditory questionnaire, an improvement in the patient’s global auditory skill development was also observed at week 12. Parents reported also more natural vocalizations when the patient was not wearing the cochlear implant on the other ear, indicating improved hearing acuity on the DB‑OTO-treated ear. Additional data from this and other enrolled patients will be presented. Conclusions: In this first-in-human gene therapy trial of DB-OTO, an overall positive tolerability profile was reported, with no AEs related to DB-OTO treatment reported. Audiometric data showed improvement in hearing from baseline corroborated by early auditory skills testing and parental reporting. These encouraging results prompt further investigation in other patients with profound hearing loss due to OTOF mutations.

Plain Language Summary
Mutations in a gene called otoferlin often lead to severe-to-profound hearing loss. Although hearing aids and cochlear implants can help people with otoferlin-related hearing loss, they cannot replicate normal hearing. DB-OTO is a type of treatment called gene therapy, which is designed to improve hearing for people with otoferlin-related hearing loss. The CHORD study, currently recruiting from Spain, the UK, and the USA, is the first trial in humans exploring the use of DB-OTO in infants and children with hearing loss caused by this mutation. An 8-month-old female with profound hearing loss joined this trial and was treated with an injection of DB-OTO into her right ear when she was 10 months old. Twelve weeks after treatment the patient did not have any side effects related to the treatment, and improvements in hearing were reported in the treated ear. The patient continues to be evaluated and the study is ongoing.

Lawrence Lustig1, Manohar Bance2, Akira Ishiyama3, Robert Nash4, Ruben Polo5, Angel Ramos6, Manuel Jesus Manrique Rodriguez7, Jay T Rubinstein8, Tera Quigley9, Jason Riggs9, Eduardo Corrales9, Jeffery Anderson9, Vassili Valayannopoulos9

1Department of Otolaryngology - Head & Neck Surgery, Columbia University Medical Center, New York, NY,2Cambridge University, Cambridge, United Kingdom,3UCLA, Los Angeles, CA,4Great Ormond Street Hospital, London, United Kingdom,5Hospital Universitario Ramon y Cajal, Madrid, Spain,6Las Palmas University, Las Palmas Gran Canaria, Spain,7Clinica Universidad de Navarra, Pamplona, Spain,8University of Washington, Seattle, WA,9Regeneron Pharmaceuticals, New York, NY"

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