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Akous’ Phase 1/2 AK-OTOF-101 study showcases the achievement of pharmacologic restoration of hearing using a targeted adeno-associated viral (AAV) vector-based gene therapy for sensorineural hearing loss.
Boston-headquartered Akouos Inc., a subsidiary of Eli Lilly and Company, reports that the first individual enrolled in the company’s Phase 1/2 AK-OTOF-101 study—an 11-year-old with profound hearing loss due to a congenital otoferlin (OTOF) deficiency—experienced restoration of hearing capabilities within 30 days of the company’s AK-OTOF administration.
This initial study showcases the achievement of pharmacologic restoration of hearing within a mere 30 days in the inaugural participant—in a person who had profound hearing loss for over a decade. The restoration reportedly spanned all tested frequencies, with thresholds reaching 65 to 20 dB HL, and even attaining the normal hearing range at select frequencies during the Day 30 evaluation. Notably, both the surgical administration procedure and the experimental therapy exhibited excellent tolerability, with no reports of serious adverse events.
“Gene therapy for hearing loss is something physicians and scientists around the world have been working toward for over 20 years,” says John Germiller, MD, PhD, the attending surgeon and Director of Clinical Research in the Division of Otolaryngology at Children's Hospital of Philadelphia, and a principal investigator of the AK-OTOF-101 Clinical Trial who administered AK-OTOF to this participant. “These initial results show that it may restore hearing better than many thought possible.”
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Millions of individuals worldwide have disabling hearing loss because one of their genes generates an incorrect or incomplete version of a protein the ear requires for hearing. In many of these cases—including for some of the estimated 200,000 individuals worldwide who live with OTOF-mediated hearing loss—delivering a healthy version of the gene to a target cell within the inner ear has the potential to restore auditory function and enable high-acuity physiologic hearing.
It's estimated some 200,000 people worldwide grapple with OTOF-mediated hearing loss. Otoferlin is a protein essential for the normal function of sound transmission within the inner hair cells of the cochlea, the key hearing organ of the inner ear. People missing the otoferlin gene typically have severe-to-profound hearing loss. OTOF-mediated hearing loss is thought to account for 1-8% of congenital, nonsyndromic hearing loss and be the leading cause of auditory neuropathy spectrum disorders.
AK-OTOF has been granted Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA, along with a favorable opinion on orphan drug designation from the EMA Committee for Orphan Medicinal Products. As reported by HearingTracker, the company received clearance from the FDA for its pediatric clinical trial in September 2022.
In the AK-OTOF-101 trial, eligible participants undergo a single, unilateral intracochlear administration of AK-OTOF, with the evaluation of hearing restoration conducted through behavioral audiometry and auditory brainstem response (ABR)—a recognized and objective measure of hearing sensitivity. The initial cohort receives AK-OTOF at a dose of 4.1E11 total vector genomes. The Akouos delivery device, being developed in parallel specifically for intracochlear administration, enables a minimally invasive surgical approach to deliver AK-OTOF throughout the cochlea.
OTOF-mediated hearing loss marks the first monogenic form of hearing loss explored in a gene therapy clinical trial. The delivery of a healthy gene version to inner ear target cells holds the potential to reinstate auditory function, facilitating high-acuity physiological hearing.
“Children with OTOF-mediated hearing loss are often born with profound hearing loss, yet only a small fraction have undergone genetic testing to receive a definitive diagnosis,” says Dr. Oliver Haag, a pediatric otolaryngologist and Head of Otolaryngology at Sant Joan de Deu Hospital in Barcelona, and an investigator in Akouos's AK-OTOF-NHS-002 Natural History Study in which the first individual to receive AK-OTOF was participating. “The AK-OTOF-101 Clinical Trial and AK-OTOF-NHS-002 Natural History Study demonstrate the power of international collaboration in the development of new medicines for rare genetic conditions. It is gratifying to see this collaborative effort provide benefit to the first participant to receive AK-OTOF.”
AK-OTOF employs what is called a dual adeno-associated viral (AAV) vector to restore hearing. It transfers and maintains the normal otoferlin protein in the inner hair cells of the cochlea. By using AAVAnc80, a highly effective protein shell for transferring genetic material into the inner hair cells, AK-OTOF ensures targeted expression of otoferlin. This expression has the potential to bring back high acuity in hearing, says the company.
Results, including initial data from a second participant to receive AK-OTOF, will be presented during the Late Breaking Presidential Symposium at the 2024 Association for Research in Otolaryngology (ARO) MidWinter Meeting on February 3 held in Anaheim, Calif.
Source: Eli Lilly and Company and HearingTracker
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about AK-OTOF as a potential treatment for sensorineural hearing loss due to mutations in the otoferlin gene (OTOF) and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, or that AK-OTOF will receive regulatory approvals, or be commercially successful. For further discussion of risks and uncertainties relevant to Lilly's business that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.
