Otoferlin-Related Hearing Loss Gene Therapy Gets IND Clearance

Decibel Therapeutics’ DB-OTO, an investigational adeno-associated virus (AAV) dual-vector-based gene therapy intended to treat otoferlin-related hearing loss being developed in collaboration with Regeneron Pharmaceuticals, has received clearance from the FDA for its investigational new drug (IND) application, which was submitted last month.^1,2

DB-OTO utilizes a cell-selective promoter to enable expression of otoferlin, the disease-targeted protein, in cochlear inner hair cells. It previously demonstrated the ability to induce expression of otoferlin in preclinical research with both non-human primates and a congenitally deaf, rodent otoferlin disease model. In the rodent model, durable auditory brainstem responses to sound were observed after DB-OTO administration. In 2021, DB-OTO was granted both orphan drug designation and rare pediatric disease designation by the FDA.

“We are thrilled to work with families, advocacy groups and clinicians in the deaf and hard of hearing community to advance DB-OTO into the clinic,” Laurence Reid, PhD, chief executive officer, Decibel Therapeutics, said in a statement regarding the news.¹ “Decibel has assembled a compelling preclinical data package showing that DB-OTO demonstrated a favorable tolerability profile and an ability to stably generate full-length otoferlin transcript, express otoferlin protein and provide hearing in animal models. We are at an exciting time in the development of a new wave of precision gene therapies for children who are deaf and hard of hearing.”

A phase 1/2 dose-escalation clinical trial for patients with congenital hearing loss caused by otoferlin deficiency has been planned, and Decibel Therapeutics expects that in the United States portion of the study the first 2 participants could be as young as 7 years old. Additional participants could be as young as 2 years old and younger than 2 years old. The trial will assess the safety and tolerability of DB-OTO and will also utilize auditory brainstem response (ABR) and behavioral measurements of hearing to evaluate efficacy. An update on the design of the trial is expected to be announced at a later date, and the company also intends to submit 1 or multiple clinical trial applications in Europe.

“Otolaryngologists, audiologists, and auditory scientists have long awaited the clinical realization of the promise of biological therapies for hearing loss,” Jay Rubinstein, MD, PhD, professor and Virginia Merrill Bloedel Chair in Otolaryngology, Head and Neck Surgery, University of Washington School of Medicine, added to the statement.¹ “Gene therapy for congenital deafness represents 1 such intervention and it would be an understatement to say that clinicians in the field of hearing loss are quite excited to see its advancement into clinical trials.”

DB-OTO is not the only gene therapy currently in development for otoferlin-related hearing loss. In September of this year, Akouos received clearance from the FDA for an IND application for AK-OTOF, which is also an investigational dual AAV vector-based gene therapy intended for the treatment of otoferlin gene-mediated hearing loss.³ AK-OTOF showed durable expression of otoferlin in otoferlin-knockout mice in preclinical studies. It was well-tolerated in both the mice and in non-human primates. A phase 1/2 dose-escalation clinical trial is planned which will also begin by recruiting participants potentially as young as 7-years-old. The trial will similarly assess safety and tolerability, as well as ABR. The company expects to announce updates regarding the clinical trial’s activation before the end of the year. Akous is also recruiting approximately 150 participants aged up to 44 years old for a natural history study (NCT05572073) for patients with otoferlin gene-mediated hearing loss.

REFERENCES

1. Decibel therapeutics receives FDA clearance of IND application for DB-OTO, a gene therapy product candidate designed to provide hearing to individuals with otoferlin-related hearing loss. News release. Decibel Therapeutics. October 17, 2022. https://ir.decibeltx.com/news-releases/news-release-details/decibel-therapeutics-receives-fda-clearance-ind-application-db 

2. Decibel Therapeutics announces submission of investigational new drug (IND) application for lead gene therapy candidate DB-OTO. News release. Decibel Therapeutics. September 20, 2022. https://www.globenewswire.com/news-release/2022/09/20/2519051/0/en/Decibel-Therapeutics-Announces-Submission-of-Investigational-New-Drug-IND-Application-for-Lead-Gene-Therapy-Candidate-DB-OTO.html 

3. Akouos receives FDA clearance of its IND application for AK-OTOF, a gene therapy intended for the treatment of otof-mediated hearing loss. News release. Akouos, Inc. September 13, 2022. https://investors.akouos.com/news-releases/news-release-details/akouos-receives-fda-clearance-its-ind-application-ak-otof-gene