OTOF-Mediated Hearing Loss Gene Therapy Gets FDA Rare Pediatric Disease Designation


Preclinical research in an OTOF-knockout mouse model demonstrated reversal of deafness.

Sensorion’s OTOF-GT, an investigational gene therapy product intended to treat otoferlin (OTOF) gene-mediated hearing loss, has received rare pediatric disease designation from the FDA.1

OTOF-GT delivers a functional copy of the OTOF gene. Due to the large length of the gene, it is delivered in 2 parts by 2 separate adeno-associated virus (AAV) vectors for assembly in place. Preclinical research in an OTOF-knockout mouse model demonstrated this method to be capable of restoring expression of otoferlin, the disease-targeted protein, in transduced cells and reversing deafness.2 

“We are really pleased that the FDA has acknowledged the urgent need to develop solutions for this condition, for which there are currently no approved therapies,” Géraldine Honnet, chief medical officer, Sensorion, said in a statement.1 “This important regulatory designation will support us in advancing this potentially transformative therapy to patients. This is a key milestone for our important gene therapy franchise, which offers the potential for permanent solutions for these debilitating conditions and is increasingly central to Sensorion’s strategic roadmap.”

OTOF-GT is not the only gene therapy currently in development for OTOF-mediated hearing loss. Decibel Therapeutics’ DB-OTO, an investigational AAV dual-vector-based gene therapy intended to treat otoferlin-related hearing loss being developed in collaboration with Regeneron Pharmaceuticals, received clearance from the FDA for its investigational new drug (IND) application in October of this year.3,4 The therapy utilizes a cell-selective promoter to enable expression of otoferlin in cochlear inner hair cells. It demonstrated the ability to induce expression of otoferlin in preclinical research with both non-human primates and a congenitally deaf, rodent disease model. In the rodent model, durable auditory brainstem responses to sound were observed after DB-OTO administration.

Meanwhile, 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 OTOF-mediated hearing loss. 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.5

Both DB-OTO and AK-OTOF received both ODD and rare pediatric disease designations from the FDA in 2021.3,4,5 In addition to its FDA rare pediatric disease designation, OTOF-GT previously received ODD from the European Commission in October of this year.1

“This important regulatory feedback is great news as the ODD will support us in advancing our OTOF-GT development program to bring this innovative therapy to the patients who need it most,” Valérie Salentey, regulatory affairs and quality assurance director, Sensorion, said in a statement at the time the European Medicines Agency issued a positive opinion regarding OTOF-GT's ODD.6 “We have continued to progress with preclinical and clinical development plans for OTOF-GT and are on track to file a Clinical Trial Application for the program in H1 2023. This is a key part of our growing gene therapy franchise for the restoration of auditory function in a number of indications through our collaboration with Institut Pasteur.”

1. 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 
2. Akil O, Dyka F, Calvet C, et al. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc Natl Acad Sci USA. 2019;116(10):4496-4501. Doi: doi.org/10.1073/pnas.1817537116
3. 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 
4. 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 
5. 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 
6. Sensorion receives positive opinion for Orphan Drug Designation for OTOF-GT for the treatment of otoferlin genemediated hearing loss from the European Medicine Agency. News release. Sensorion. September 12, 2022. https://s27.q4cdn.com/232015521/files/doc_news/2022/09/09.12.22-_-SENS_-EU-ODD-OTOF-Positive-Opinion-_V9.pdf 

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