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

Official title

A Phase 1/2, Open-Label, Multicenter Trial With a Single Ascending Dose Cohort With Unilateral Intracochlear Injection Followed by a Bilateral Injection Expansion Cohort to Evaluate the Safety, Tolerability, and Efficacy of DB-OTO in Children and Infants With Biallelic hOTOF Mutations

Overview

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 pediatric and adult participants who have severe-to profound and profound 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

Interventions

• Genetic DB-OTO
  Administered per the protocol

Primary outcome measures

• Incidence and severity of Treatment-Emergent Adverse Events (TEAEs) [Time frame: Up to week 104]
• Achievement of a hearing sensitivity threshold of ≤70 dB assessed by average Pure Tone Audiometry (PTA) [Time frame: Up to week 104]

Secondary outcome measures (12)

• Auditory Brainstem Response (ABR) to click stimulus at ≤90 dB normalized Hearing Level (nHL) [Time frame: Up to week 48]
• Achievement of hearing sensitivity threshold of ≤45 dB assessed by average PTA [Time frame: Up to week 104]
• Achievement of hearing sensitivity threshold of ≤25 dB assessed by average PTA [Time frame: Up to week 104]
• Achievement of a score ≥3 on the Early Speech Perception (ESP) test [Time frame: At week 104]
• Achievement of a score of 4 on the ESP test [Time frame: At week 104]
• Speech perception scores by age-appropriate tests [Time frame: Up to week 104]
• Speech Awareness Threshold (SAT): achievement of a threshold of ≤70 dB [Time frame: Up to week 48]
• SAT: achievement of a threshold of ≤45 dB [Time frame: Up to week 48]
• SAT: achievement of threshold of ≤25 dB [Time frame: Up to week 48]
• Severity in speech perception ability assessed by Global Impression scales (clinician and parent/legal guardian) [Time frame: At week 104]
• Change in speech perception ability assessed by Global Impression scales (clinician and parent/legal guardian) [Time frame: At week 104]
• Average PTA threshold in the subset of participants who achieved an average PTA threshold ≤70 dB [Time frame: Up to week 104]

Eligibility criteria

Inclusion criteria

• Willingness to provide written informed consent (by at least one parent/legal guardian for pediatric participants, and with participant to provide assent, when applicable, or by the adult participant) and willingness to comply with trial protocol
• Willingness to consent to genetic testing for the participant (by at least one parent/legal guardian for pediatric participants, and with participant to provide assent, when applicable, or by the adult participant) in order to evaluate a panel of hearing loss-related genes
• Willingness to consent to vaccinations for the participant (by at least one parent/legal guardian for pediatric participants, and with participant to provide assent, when applicable, or by the adult participant) in accordance with the country-specific, age-appropriate immunization schedule, as described in the protocol
• Participant able to perform all necessary assessments to qualify for enrollment and dosing in the corresponding cohort at the time the participant or parent/legal guardian signing the informed consent form (and participant providing assent, when applicable)
• Presence of biallelic, likely pathogenic or pathogenic OTOF variants
• No clinically significant laboratory findings on clinical laboratory tests at time of Screening as described in the protocol
• Audiological Criteria:

• Investigator diagnoses the participant with profound sensorineural hearing loss (SNHL; >90 dB HL) based on behavioral and physiologic measurements (ABR) of inner ear function
• Outer hair cell presence is confirmed via presence of otoacoustic emissions (≥6 dBSNR) at ≥3 frequencies from 1 to 8 kHz in the ear(s) to be infused with DB-OTO. Alternatively, for participants >24 months of age, outer hair cell presence can be confirmed via presence of the cochlear microphonic in the ear(s) to be infused with DB-OTO.
• No evidence from measures of hearing loss that show a dependence on body temperature
• From study start and for the duration of the short-term follow-up period (48 weeks): Female participants of childbearing potential and fertile males, must agree to use highly effective contraception. Female participants must agree not to become pregnant. Fertile male participants must agree not to father a child or donate sperm, for 48 weeks and in cases of early withdrawal, for at least 12 months after DB-OTO administration.

Exclusion criteria

• History of prior treatment with gene therapy
• Surgical anatomy that would preclude or meaningfully impact the planned surgical approach as indicated by medical imaging (eg, Computed Tomography \[CT\] or Magnetic Resonance Imaging \[MRI\]) in the ear(s) to be infused with DB-OTO
• History or presence of other permanent or untreatable hearing loss conditions
• Prior or current history of malignancies
• Prior or current history of meningitis
• History or presence of cochlear implants in the ear(s) to be infused with DB-OTO
• History of risk factor(s) for auditory neuropathy not caused by OTOF pathogenic variants including but not limited to: prematurity, low birth weight, hyperbilirubinemia, Neonatal Intensive Care Unit (NICU) admission, and/or low Apgar scores as described in the protocol

Note: Other protocol-defined inclusion/exclusion criteria apply

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 9 centers

• University of California Los Angeles Medical Center — Los Angeles
• Rady Children's Hospital — San Diego
• Nemours Children s Clinic — Jacksonville
• Nemours Childrens Hospital — Orlando
• Boston Children's Hospital - Main — Boston
• Columbia University Irving Medical Center — New York
• Cincinnati Children's Hospital Medical Center — Cincinnati
• Seattle Children's Hospital — Seattle
• … and 1 more center

Spain · 4 centers

• Clinica Universidad de Navarra- Pamplona — Pamplona
• Hospital Sant Joan de Deu — Barcelona
• Hospital Universitario Materno Infantil en las Palmas de Gran Canaria — Las Palmas de Gran Canaria
• Ramon y Cajal University Hospital — Madrid

United Kingdom · 2 centers

• Addenbrooke's Hospital, Cambridge University Hospitals NHS FT — Cambridge
• Great Ormond Street Hospital For Children NHS Foundation Trust — London

Germany · 1 center

• University Hospital Tubingen — Tübingen

Japan · 1 center

• Shinshu University Hospital — Matsumoto-shi

Publications

• Valayannopoulos V, Bance M, Carvalho DS, Greinwald JH Jr, Harvey SA, Ishiyama A, Landry EC, Lowenheim H, Lustig LR, Manrique M, Nash R, Polo R, Pritchett CV, Rubinstein JT, Shearer AE, Del Castillo I, Anderson JJ, Corrales CE, Quigley TM, Riggs WJ, Weber P, Wilson G, Irvin SC, Hassan HE, Chen Y, Liu R, Drummond MC, Sabin LR, Musser BJ, Yancopoulos GD, Kyratsous CA, Herman GA, Baras A, Whitton JP; PMID 41085057

Identifiers

NCT: NCT05788536 · DB-OTO-001 · 2022-000079-38 · 2024-511342-40-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗