A Study of DB-OTO, an Adeno-associated Virus (AAV) Based Gene Therapy, in Children/Infants With Hearing Loss Due to Otoferlin Mutations

Phase 1

Recruiting

• Conditions: Congenital Hearing Loss Secondary to Biallelic Mutations of the Otoferlin Gene (OTOF)
• Interventions: Genetic: DB-OTO

• Registration Number: NCT05788536
• Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary

Regeneron is conducting a study of an investigational new drug called DB-OTO. DB-OTO is a gene therapy that is being developed to treat children who have hearing loss due to changes in the otoferlin gene.

The purpose of this study is to:

* Learn about the safety of DB-OTO

* Determine how well DB-OTO is tolerated (does not cause ongoing discomfort)

* Evaluate the efficacy of DB-OTO (how well DB-OTO works)

Detailed Description

Former Sponsor Decibel Therapeutics

Study Timeline

• Study First Submitted: 2023-03-15
• Study First Submitted QC: 2023-03-15
• Study First Posted: 2023-03-29
• Study Start: 2023-05-12
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-12
• Last Update Posted: 2025-03-17
• Primary Completion: 2031-04-19
• Study Completion: 2031-04-19

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

1. Presence of pathogenic or likely pathogenic mutations in both alleles of the OTOF gene.

2. Patient is <18 years of age and of the appropriate age to qualify for enrollment in the corresponding age cohort at the time the parent/legal guardian signs the informed consent form. Participant to provide assent, when applicable

3. Audiological Criteria:

   US:

   • Investigator determines that minimal benefit has been provided by amplification of the ear to receive DB-OTO.
   • Investigator determines the patient meets cochlear implantation criteria in both ears according to the recommended cochlear implant label

   Infants ≤24 months of age:

   1. Profound sensorineural hearing loss (SNHL; ≥ 90 dB HL) based on behavioral and physiologic measurements (ABR) of inner ear function.
   2. Outer hair cell function is confirmed by presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO

   Children >24 months to <18 years of age:

   1. Profound SNHL (≥ 90 dB HL) based on physiologic measurements (ABR) of inner ear function AND
   2. Behavioral open-set word recognition scores of < 30% in the ear that would receive DB-OTO
   3. Outer hair cell function is confirmed by presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO OR
   4. Presence of a cochlear microphonic in ears to receive DB-OTO.

   UK & Spain:

   Infants ≤24 months of age:

   1. Absence of an ABR neural signal in response to a click stimulus ≤85 dB nHL in the ear(s) to be injected with DB-OTO.
   2. Presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO.

   Children >24 months to <18 years of age:

   1. Absence of an ABR neural signal in response to a click stimulus ≤85 dB nHL in the ear(s) to be injected with DB-OTO.
   2. Presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO OR
   3. Presence of a cochlear microphonic in ears to receive DB-OTO.

4. Willingness of at least 1 parent/legal guardian to consent to vaccinations for the patient in accordance with the country-specific pediatric immunization schedule

5. No clinically significant laboratory findings on clinical laboratory tests at time of Screening

6. No evidence that hearing loss is dependent on body temperature

7. From study start and for the duration of the short-term follow-up period (18 months): Female patients of childbearing potential and fertile males, must agree to use highly effective contraception. Female patients must agree not to become pregnant. Fertile male patients must agree not to father a child or donate sperm.

Exclusion Criteria

1. History or presence of other permanent or untreatable hearing loss conditions.
2. Prior or current cochlear implants in the ear(s) to be injected with DB-OTO
3. History of risk factor(s) for auditory neuropathy not caused by OTOF mutations including: prematurity, low birth weight, hyperbilirubinemia, neonatal intensive care unit (NICU) admission, and/or low Apgar scores.
4. Prior or current history of malignancies.
5. Prior or current history of meningitis.
6. History of prior treatment with gene therapy.
7. Surgical anatomy that would preclude the planned surgical approach as indicated by medical imaging (eg, computed tomography [CT] or magnetic resonance imaging [MRI]) in the ear(s) to be injected with DB-OTO.

Note: additional inclusion/exclusion criteria apply, per protocol.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
DB-OTO - Dose Escalation	DB-OTO	Unilateral intracochlear dosing
DB-OTO - Dose Expansion	DB-OTO	Bilateral intracochlear dosing using the dose selected based on safety and efficacy data from the Dose Escalation phase (Part A).

Primary Outcome Measures

Name	Time	Method
Incidence and severity of treatment-emergent systemic and local adverse events	5 years

Secondary Outcome Measures

Name	Time	Method
Auditory brainstem response (ABR) - change in intensity threshold (decibels Hearing Level [dB nHL]) across frequency domains	5 years
Behavioral audiometry with pure-tone audiometry - change in intensity thresholds (dB HL) in treated ear across frequency domains, and speech awareness threshold (SAT) and speech reception threshold (SRT)- change in threshold in treated ear	5 years

Trial Locations

Locations (12)

University of California Los Angeles Medical Center; 🇺🇸 Los Angeles, California, United States

Nemours Children s Clinic; 🇺🇸 Jacksonville, Florida, United States

Nemours Childrens Hospital; 🇺🇸 Orlando, Florida, United States

Columbia University Irving Medical Center; 🇺🇸 New York, New York, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Hospital Universitario Materno Infantil en las Palmas de Gran Canaria; 🇪🇸 Las Palmas de Gran Canaria, Spain

Ramon y Cajal University Hospital; 🇪🇸 Madrid, Spain

Addenbrooke's Hospital, Cambridge University Hospitals NHS FT; 🇬🇧 Cambridge, United Kingdom

Great Ormond Street Hospital For Children NHS Foundation Trust; 🇬🇧 London, United Kingdom

Seattle Children's Hospital dba Seattle Children's Research Institute; 🇺🇸 Seattle, Washington, United States

Clinica Universidad de Navarra; 🇪🇸 Pamplona, Spain