Investigational Gene Therapy for Genetic Hearing Loss Shows Positive Early Trial Results

In January 2024, Akouos, Inc., a subsidiary of Eli Lilly and Company, announced promising preliminary results from the Phase 1/2 clinical trial of AK-OTOF, a gene therapy designed to restore hearing in individuals with genetic sensorineural hearing loss due to mutations in the otoferlin gene (OTOF). The trial, referred to as AK-OTOF-101, demonstrated that hearing restoration was achieved within 30 days following a single administration of AK-OTOF in the first participant. This individual, who had experienced profound hearing loss since birth, showed significant hearing improvement across all tested frequencies, achieving thresholds between 65 to 20 dB HL, with normal hearing ranges at certain frequencies.

The results of this groundbreaking trial will be highlighted during the Late Breaking Presidential Symposium at the 2024 Association for Research in Otolaryngology (ARO) MidWinter Meeting. The presentation is scheduled for February 3 at the Anaheim Marriott in California.

The AK-OTOF-101 study involves a single, unilateral intracochlear administration of AK-OTOF, with hearing restoration assessed through behavioral audiometry and auditory brainstem response (ABR). Participants in the first cohort received AK-OTOF at a dose of 4.1E11 total vector genomes. The initial findings revealed that both the surgical procedure and the investigational therapy were well tolerated, with no serious adverse events reported.

Dr. John Germiller, an attending surgeon at the Children's Hospital of Philadelphia and a principal investigator of the trial, expressed optimism regarding the potential of this gene therapy to exceed expectations in restoring hearing. Dr. Oliver Haag, a pediatric otolaryngologist and investigator in the AK-OTOF-NHS-002 Natural History Study, also emphasized the importance of international collaboration in the development of treatments for rare genetic conditions and noted the positive impact on the first participant of the study.

Hearing loss is the most common sensory condition worldwide, affecting millions of people, with no approved pharmacological treatments currently available. Mutations in the otoferlin gene, leading to OTOF-mediated hearing loss, hinder the production of a crucial protein necessary for hearing. In these cases, delivering a healthy version of the gene to the inner ear cells can potentially restore auditory function and enable high-acuity hearing. AK-OTOF represents the first attempt to address monogenic hearing loss through gene therapy in a clinical trial.

The trial's promising results underscore the potential impact of genetic medicines in treating OTOF-mediated hearing loss, which affects an estimated 200,000 individuals globally. Emmanuel Simons, CEO of Akouos and SVP of Gene Therapy at Lilly, expressed gratitude to participants, families, and collaborators for their contributions to this pioneering trial, affirming the mission to make healthy hearing accessible to all.

AK-OTOF has received Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA and has been positively reviewed by the EMA Committee for Orphan Medicinal Products.

AK-OTOF utilizes a dual adeno-associated viral (AAV) vector system to deliver the otoferlin gene to the inner hair cells of the cochlea. The gene therapy employs AAVAnc80, known for its high transduction efficiency, combined with a powerful promoter to ensure the expression of otoferlin exclusively in the target cells at levels sufficient to restore hearing.

The AK-OTOF-101 trial is a Phase 1/2 clinical trial assessing the safety, tolerability, and bioactivity of escalating doses of AK-OTOF delivered through a specialized delivery device. The AK-OTOF-NHS-002 Natural History Study aims to characterize the progression and clinical outcomes of OTOF-mediated hearing loss over time.

Lilly, with a long-standing commitment to innovative medical solutions, continues to advance its research and development efforts in genetic medicine, striving to address significant health challenges worldwide.