Akouos Seeks to Tackle Otoferlin Gene-Mediated Hearing Loss With Phase 1/2 Clinical Trial and Associated Natural History Study


AK-OTOF delivers transgenes encoding OTOF, the disease-targeted gene, to the inner hair cells of the cochlea via a single unilateral intracochlear administration.

Eli Lilly and Company subsidiary Akouos’ AK-OTOF (AAVAnc80-hOTOF), an investigational dual adeno-associated viral (AAV) vector-based gene therapy intended for the treatment of otoferlin gene (OTOF)-mediated hearing loss, is currently being evaluated in the phase 1/2 AK-OTOF-101 clinical trial (NCT05821959).1 AK-OTOF delivers transgenes encoding functional OTOF to the inner hair cells of the cochlea via a single unilateral intracochlear administration.2

The AK-OTOF-101 study, which was initiated on September 15, 2023, is led by study director Kathy Reape, MD, the chief medical officer of Akouos. The trial has a dose escalation design, and seeks to enroll an estimated 14 participants in total. The participants will receive AK-OTOF at either a low dose level (4.1x1011 total vg/cochlea; DL1) or a high dose level (8.1x1011 total vg/cochlea; DL2). Furthermore, participants will be assigned to 1 of several cohorts. Cohort 1a will include patients aged 7 to 17 years and will treat them at DL1. Cohort 1b will include patients aged 2 to 17 years and will treat them at DL1. Cohort 2 will include patients aged 2 to 17 years and will treat them at DL2.

According to the clinicaltrials.gov page for AK-OTOF-101, which was most recently updated on October 12, 2023, the study is currently recruiting at University of Iowa in Iowa City, Iowa; Children's Hospital of Philadelphia, in Philadelphia, Pennsylvania; and National Taiwan University Hospital in Taipei City, Taiwan. The trial has an estimated completion date of October 2028. Notably, AK-OTOF will be administered to patients in the trial via an investigational one-time use, sterile medical device, referred to as the Akouos Delivery Device.

The primary end point for AK-OTOF-101 is safety measured via the frequency of adverse events that are related to AK-OTOF or to the administration procedure and Akouos Delivery Device. Secondary outcome measures for the study include the efficacy of AK-OTOF as measured by changes from baseline in auditory brainstem response (ABR) intensity threshold and performance of the Akouos Delivery Device as measured by the frequency of device deficiencies during the administration of the gene therapy to the intracochlear space. All end points will be evaluated from treatment through trial completion.

AK-OTOF-101 is open to patients aged 2 to 17 years old with biallelic mutations in OTOF who have profound bilateral sensorineural hearing loss as assessed by ABR. Patients must additionally have preserved distortion product otoacoustic emissions and must be willing to participate in a separate long term follow-up study after AK-OTOF-101 is finished. Patients with bilateral cochlear implants, persistent ear infections, abnormalities of the ear, or contraindications to the surgical administration procedure for AK-OTOF will be excluded from participation in the study. Patients who have participated in any investigational drug’s clinical trial within the past 6 months, and those who have ever previously participated in a gene therapy clinical trial, will also be excluded from AK-OTOF-101.

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In addition to AK-OTOF-101, Akouos is also conducting a natural history study (AK-OTOF-NHS-002; NCT05572073) for patients with OTOF-mediated hearing loss. The natural history study, which was initiated on July 14, 2022, is also currently recruiting according to the clinicaltrials.gov page, which was last updated on October 24, 2023. The study seeks to enroll approximately 150 patients aged up to 44 years. The primary end point is ABR and the secondary end point is otoacuostic emissions. Both end points will be measured from the first data in the participants’ medical records through 5 years of prospective follow up. The study has an estimated completion date of February 2029. The first participant to have received AK-OTOF in AK-OTOF-101 had previously participated in the natural history study.1

"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," Oliver Haag, Dr Med, a pediatric otolaryngologist and head of otolaryngology at Sant Joan de Deu Hospital in Barcelona, and an investigator in AK-OTOF-NHS-002, said in a Janaury 2024 statement.1 "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."

The investigational new drug (IND) application for AK-OTOF-101 was originally cleared by the FDA in September 2022.2 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.

“We are excited to advance AK-OTOF into clinical development,” Jen Wellman, MS, the chief operating officer of Akouos, said in a September 2022 statement.2 “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.”

Initial clinical results from AK-OTOF-101 are being presented by Akouos at the currently ongoing 2024 Association for Research in Otolaryngology (ARO) MidWinter Meeting, held February 3 to 7, in Anaheim, California.1 Although the details of the data from the February 3 presentation have not yet been announced by the company outside of the conference, Eli Lilly noted in a January 23, 2024, press release that the first participant in the clinical trial, who had a greater than 10 year history of profound hearing loss, showed pharmacologic hearing restoration within 30 days of the one-time administration of the gene therapy. It was noted that the patient, who was 11 years old at the time of treatment, showed restored hearing across all tested frequencies and was within normal hearing range at some frequencies.

"We are grateful to the participants, their families, the investigators and other collaborators who are working together with us on this pioneering trial," Emmanuel Simons, PhD, MBA, the CEO of Akouos and senior vice president of gene therapy at Lilly, said in the press release.1 "These initial results highlight the potential impact genetic medicines could have on individuals with OTOF-mediated hearing loss and reinforce our mission to make healthy hearing available to all."

1. Positive phase 1/2 clinical trial data for an investigational gene therapy for genetic hearing loss to be presented at the association for research in otolaryngology 2024 midwinter meeting. News release. January 23, 2024. Accessed February 5, 2024. https://investor.lilly.com/news-releases/news-release-details/positive-phase-12-clinical-trial-data-investigational-gene
2. 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. Accessed February 5, 2024. https://investors.akouos.com/news-releases/news-release-details/akouos-receives-fda-clearance-its-ind-application-ak-otof-gene
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