Skip to main content
Premium Trial:

Request an Annual Quote

After Promising Early Efficacy, Eli Lilly Eager to Study Hearing Loss Gene Therapy in More Children

Eli Lilly biotechnology center in San Diego

NEW YORK – Eli Lilly is advancing a first-in-human clinical trial of a gene therapy for a rare, genetic form of deafness in AK-OTOF, a product candidate it bought as part of an acquisition just over a year ago.

In December 2022, pharmaceutical giant Lilly acquired Akouos, a Boston-based genetic medicines company that aims to treat hearing loss disorders, as part of an effort to bulk up its gene therapy assets. Lilly acquired the firm for about $487 million upfront, and Akouos is eligible to receive additional payments if it achieves certain clinical trial and regulatory milestones related to its lead candidate AK-OTOF and other gene therapy programs.

Akouos, which is now a wholly owned subsidiary of Lilly, in September launched an open-label, dose-escalation Phase I/II trial of AK-OTOF, an experimental treatment for hearing loss caused by a mutation in the OTOF gene. Investigators in the trial, dubbed the AK-OTOF-101 Study, are evaluating the safety and tolerability of the gene therapy based on its administration in just one ear for each participating patient.

AK-OTOF is an adeno-associated viral vector-based gene therapy designed to deliver a functional copy of the OTOF gene to cells in a patient's inner ear, specifically in the cochlea, through a surgical procedure. The goal is for those cells to be able to produce otoferlin, a protein that is needed to transmit signals to the auditory nerve but is lacking in patients with this specific form of deafness.

Now, study sponsors are starting to see early signs of success.

The Children's Hospital of Philadelphia last week shared results from the first patient in the US treated with the experimental gene therapy, an 11-year-old patient named Aissam, who was born deaf in both ears but experienced marked improvements to his hearing within 30 days of receiving the gene therapy.

A second patient, 8 years old, has been enrolled at the trial's clinical site at the National Taiwan University Hospital, said Jennifer Wellman, chief development officer at Akouos. Preliminary results from both patients will be presented next month at the Association for Research in Otolaryngology's MidWinter Meeting in Anaheim, California.

Currently, patients with hearing loss due to OTOF mutations require cochlear implants — devices placed in the ear to reproduce and deliver sounds by directly stimulating the auditory nerve. This is for patients with severe hearing loss that can't be aided by hearing aids, which only amplify sound.

However, while the signals transmitted through cochlear implants provide wearers with representations of sounds, the devices don't restore hearing. Unlike cochlear implants, which work by bypassing the cells in the cochlea that don't function as intended, AK-OTOF has the potential to be curative by restoring otoferlin expression. "AK-OTOF is designed to treat the underlying cause of otoferlin gene-mediated hearing loss," Wellman said.

However, since the gene therapy restores protein expression, other components of a patient's inner ear must be functional for the treatment to effectively restore hearing. That's why one of the eligibility criteria for the Phase I/II trial is a measure of preserved cochlear function.

Aissam was an ideal candidate for AK-OTOF in many ways, according to John Germiller, an attending surgeon and director of clinical research in the otolaryngology division at CHOP and an associate professor at Perelman School of Medicine at the University of Pennsylvania, who treated Aissam.

While Aissam had profound deafness from birth, which was confirmed to be caused by the OTOF gene, "Aissam's inner ears are also healthy otherwise," said Germiller, who is also a principal investigator on the AK-OTOF-101 Study. For example, other than the lack of otoferlin, Aissam's ears had intact auditory hair cells, which sense sound. That suggested to investigators that Aissam's ears could be able to function properly after therapy.

Germiller said CHOP is scheduled to treat the next patient in this clinical trial in February and a third patient is scheduled for June, both of whom are 3 years old. The US Food and Drug Administration had required that the first two patients treated in the trial be at least 7 years old, but that the study could be expanded to those as young as 2 years of age if there were no severe side effects.

As the trial continues, it will be interesting to see whether hearing improvement from the gene therapy will be better than what's achieved with cochlear implants, Germiller said. Some patients are receiving the gene therapy in one ear, and have a cochlear implant in the opposite ear, so comparing hearing with the two methods may be possible.

Germiller also said he's keeping tabs on details like how long the hearing improvement lasts. So far, hearing improvement after gene therapy administration seems durable for Aissam, who received the gene therapy in October.

As Lilly advances AK-OTOF, the firm will face competition from multiple drugmakers developing gene therapies for OTOF-related hearing loss, including Sensorion, Refreshgene Therapeutics, and Decibel Therapeutics, which was acquired by Regeneron Pharmaceuticals in September.

It makes sense that OTOF-related deafness would be a dominant area of interest as gene therapy developers look to treat hearing loss, Germiller said. "OTOF was a logical choice for all the various developers to start with, since it is well known that OTOF patients have otherwise normal, healthy inner ears," Germiller said. 

"In most other types of genetic hearing loss, inner ear cells or their function have abnormalities other than the single gene that is defective," and in those cases, drugmakers may have to regenerate the cells as well as administer the gene therapy, he noted.

Akouos is continuing to recruit patients into the Phase I/II trial, with a goal of enrolling 14 patients. Alongside CHOP and the National Taiwan University Hospital, the University of Iowa is also an active clinical trial site for the study.

Wellman said that it's too early to discuss a potential regulatory approach for the gene therapy, since those plans will be informed by clinical data and ongoing conversations with regulators. "We can't speculate at this time how long trial completion will take but remain diligent in our quest to bring this potential therapy to patients as soon as possible," she said. "We look forward to our continued discussions with regulatory authorities as we progress in this trial."