Preliminary Efficacy and Safety of AK-OTOF Gene Therapy for Otof-mediated Hearing Loss

Introduction: The otoferlin gene (OTOF) encodes otoferlin, a protein critical for signaling at the inner hair cell synapse; individuals with mutations in OTOF typically present with congenital, severe to profound sensorineural hearing loss, with preserved otoacoustic emissions early in life. Advances in gene therapy and intracochlear delivery support the potential to restore hearing in individuals with OTOF-mediated hearing loss using a local administration of AK-OTOF (AAVAnc80-hOTOF). A multicenter clinical trial (NCT05821959) has been evaluating AK-OTOF gene therapy and the Akouos Delivery Device (ADD) used to administer AK-OTOF to the intracochlear space.

Methods: Participants in Part A of the AK-OTOF-101 Clinical Trial have profound hearing loss at baseline, as assessed by auditory brainstem response (ABR). Using a minimally invasive transcanal approach, a one-time intracochlear administration of AK-OTOF is given either unilaterally or bilaterally. Safety assessments and hearing restoration, including by ABR, behavioral audiometry, and functional hearing outcomes using developmentally appropriate metrics, are assessed over the one-year trial and an additional four-year long term follow-up period.

Results: As of December 2025, 18 participants received administration of AK-OTOF (n = 8 receiving up to 4.1E11 total vg/cochlea and n = 10 receiving up to 8.1E11 total vg/cochlea), including four participants who received bilateral administration. The safety profile has been favorable, with no related serious adverse events and no adverse events related to AK-OTOF or the ADD. Updated trial data will be presented, including long-term assessments from Cohort 1, available results from Cohort 2, and initial data from the Bilateral Expansion Cohort.

Conclusions: Data suggest AK-OTOF may be safely administered and demonstrate significant and clinically meaningful improvement in auditory function, including to levels that do not require cochlear implantation or, in some cases, to normal hearing.