Otoferlin-Related Hearing Loss Gene Therapy Cleared for UK Clinical Trial

Decibel Therapeutics’ DB-OTO, an investigational adeno-associated virus (AAV) dual-vector-based gene therapy intended to treat otoferlin-related hearing loss, has received clearance of its clinical trial application (CTA) from the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).¹

DB-OTO, which is being developed in collaboration with Regeneron Pharmaceuticals, utilizes a cell-selective promoter to enable expression of otoferlin, the disease-targeted protein, in cochlear inner hair cells.² Decibel Therapeutics previously received clearance of an investigational new drug (IND) application for DB-OTO from the FDA in October of last year. The company also submitted a CTA for DB-OTO in Spain in November 2022.³ Earlier, in 2021, the therapy was granted orphan drug designation (ODD) and rare pediatric disease designation by the FDA.¹

“This CTA marks the second regulatory clearance for DB-OTO and what we believe to be the first in Europe for any gene therapy targeting otoferlin,” Laurence Reid, PhD, chief executive officer, Decibel, said in a statement regarding the news.¹ “This is an important milestone as we execute our international clinical development strategy, which addresses pediatric patients of diverse ages, including infants 2 years of age and younger. We believe DB-OTO has transformative potential for individuals with otoferlin-related hearing loss, and we intend to initiate the clinical trial in the first half of 2023. We expect to share initial data from the first cohort of patients in the first quarter of 2024.”

A phase 1/2 dose escalation clinical trial has been planned which will seek to recruit children with congenital hearing loss due to an otoferlin deficiency. The study will assess safety and tolerability, along with auditory brainstem response (ABR), which will serve as a measure of efficacy. ABR was previously used to evaluate responses to DB-OTO in preclinical research with animal models. Decibel Therapeutics noted that more information on the clinical trial’s design is expected to be announced in the middle of 2023.

Several other companies are also developing gene therapies for otoferlin-related hearing loss. Late last year, Sensorion announced that OTOF-GT, which is intended to deliver the otoferlin gene via a dual AAV vector for assembly in place, had been granted ODD by the FDA.⁴ At the time, the company noted that it anticipates submission of a CTA for the therapy in the first half of 2023. OTOF-GT also previously received rare pediatric disease designation from the FDA in November 2022 and ODD from the European Commission in October 2022.⁵ Sensorion announced in January 2023 that it is collaborating with EVEON on an injection system to deliver gene therapies, such as OTOF-GT, into the inner ear.⁶

Meanwhile, Akouos's AK-OTOF, which is also an investigational dual AAV vector-based gene therapy intended for the treatment of OTOF-mediated hearing loss, received clearance of its own IND application from the FDA in September 2022.⁷ The therapy was granted ODD and rare pediatric disease designation by the FDA in 2021. Akuous was acquired by Eli Lilly and Company on December 1, 2022.⁸

REFERENCES

1. Decibel Therapeutics announces approval of clinical trial application by the U.K. Medicines and healthcare products regulatory agency for lead gene therapy candidate DB-OTO. News release. Decibel Therapeutics. January 24, 2023. Accessed January 31, 2023. https://ir.decibeltx.com/news-releases/news-release-details/decibel-therapeutics-announces-approval-clinical-trial 

2. 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 

3. Decibel therapeutics reports third quarter 2022 financial results and corporate update. News release. Decibel Therapeutics. November 9, 2022. https://ir.decibeltx.com/news-releases/news-release-details/decibel-therapeutics-reports-third-quarter-2022-financial 

4. Sensorion announces US FDA grants rare pediatric disease designation to OTOF-GT for the treatment of otoferlin gene-mediated hearing loss. News release. Sensorion. November 30, 2022. https://s27.q4cdn.com/232015521/files/doc_news/2022/11/2022.11.30_-SENS_FDA-ODD-OTOF_ENG.pdf

5. Sensorion announces US FDA grants Rare Pediatric Disease Designation to OTOF-GT for the treatment of otoferlin gene-mediated hearing loss. News release. Sensorion. November 7, 2022. https://s27.q4cdn.com/232015521/files/doc_news/2022/11/2022.11.07_Sensorion_-Rare-Pediatric-Disease-Designation_Eng.pdf 

6. Sensorion and EVEON collaborating to develop an injection system for the delivery of gene therapy treatments into the inner ear. News release. Sensorion. January 31, 2023. Accessed January 31, 2023. https://s27.q4cdn.com/232015521/files/doc_news/2023/01/01.31.2023_SENS_Injection-Device_ENG.pdf 

7. 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 

8. Lilly completes acquisition of Akouos expanding efforts to help people with genetic diseases. News release. Eli Lilly and Company.December 1, 2022. Accessed January 31, 2023.https://lilly.mediaroom.com/2022-12-01-Lilly-Completes-Acquisition-of-Akouos-Expanding-Efforts-to-Help-People-with-Genetic-Diseases