Gene Therapy for OTOF-Mediated Hearing Loss Gets Green Light to Enter the Clinic


In nonclinical studies, AK-OTOF was well-tolerated in both mice and non-human primates.

The FDA has cleared an investigational new drug (IND) application for Akouos’ AK-OTOF, an investigational dual adeno-associated viral (AAV) vector-based gene therapy intended for the treatment of otoferlin gene (OTOF)-mediated hearing loss, clearing the way for a clinical trial to begin.1

AK-OTOF delivers transgenes encoding OTOF, the disease-targeted gene, to the inner hair cells (IHCs) of the cochlea via a single unilateral intracochlear administration. The IND clearance was supported by data from nonclinical studies, which demonstrated that AK-OTOF led to durable expression of OTOF in OTOF-knockout mice. The data additionally demonstrated that AK-OTOF was well-tolerated in both mice and nonhuman primates, with no adverse events reported in clinical pathology, otic pathology, systemic histopathology, or auditory or cochlear function. AK-OTOF previously received orphan drug designation and rare pediatric disease designation from the FDA in April 2021.

“The AK-OTOF IND clearance from FDA is an important step toward achieving our mission of making healthy hearing available to all,” Manny Simons, PhD, co-founder, president, and chief executive officer, Akouos, said in a statement regarding the news.1 “This first in human clinical trial for AK-OTOF is groundbreaking and highlights Akouos’s leadership in the field -- we expect this to be the first clinical trial for a genetic inner ear condition, the first in which an AAV gene therapy is administered to the inner ear, and the first for any inner ear condition to begin in a pediatric population.”

The nonclinical data, which were presented at the American Society of Gene and Cell Therapy 25th Annual Meeting, May 16-19, 2022, in Washington, DC, additionally showed that intracochlear administration of AK-OTOF in OTOF-/- mice led to expression of full-length human OTOF only in the target IHCs.2 Systemic exposure of AK-OTOF was limited, and while there were detectable levels of vector sequences and OTOF mRNA expression in non-target tissue types, no OTOF protein expression was detected in any of the nontarget tissue types evaluated. Restoration of auditory function was observed as early as 2 weeks after administration and was sustained for at least 6 months. However, unlike in the mice, in nonhuman primates no effect of AK-OTOF on auditory function was observed.3

“The AK-OTOF nonclinical data demonstrate durable restoration of auditory function and show that the product candidate was systemically and locally well tolerated in two translationally relevant animal species,” Simons said in a May 2022 statement regarding the presentation.

A phase 1/2 dose-escalation clinical trial for AK-OTOF is planned.1 The trial will seek to recruit pediatric patients with OTOF-mediated hearing loss, with the first 2 participants potentially being as young as 7 years of age and additional participants potentially being as young as 2 years of age. The study will seek to assess safety and tolerability. It is also planned to examine efficacy, with end points including auditory brainstem response (ABR). The company intends to announce an update on clinical trial initiation activities before the end of 2022.

“We are excited to advance AK-OTOF into clinical development,” Jen Wellman, chief operating officer of Akouos, added to the statement regarding the IND clearance.1 “There is a significant unmet need in OTOF-mediated hearing loss, as individuals typically have Severe to Profound sensorineural hearing loss from birth, and there are currently no approved pharmacologic options. This clinical trial is designed not only to evaluate the safety and potential benefit of AK-OTOF for individuals with OTOF-mediated hearing loss, but also to help us demonstrate the applicability of our novel delivery approach to a broad range of inner ear conditions. We look forward to sharing what we learn from this pioneering work.”

1. 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. 
2. Akouos presents nonclinical data supporting the planned clinical development of AK-OTOF and strategies for regulated gene expression in the inner ear at the american society of gene and cell therapy 25th annual meeting. News release. Akouos, Inc. May 19, 2022. 
3. Hickox AE, Gao Y, Francis SP, et al. Nonclinical in vivo expression, durability of effect, biodistribution/shedding, and safety evaluations support planned clinical development of AK-OTOF (AAVAnc80-hOTOF vector) for OTO-mediated hearing loss. Poster presented at: American Society of Gene and Cell Therapy 25th Annual Meeting; May 19, 2022; Washington, DC.
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