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Regeneron Gene Therapy Restores Hearing in Infant With Genetic Form of Deafness, Data at ASGCT Show

A close-up of a woman with her hand by her ear, listening

BALTIMORE – An infant with profound hearing loss caused by a rare genetic condition is now able to hear at near-normal levels after receiving Decibel Therapeutics' experimental gene therapy, and another patient has shown early signs of restored hearing after the treatment, researchers reported at the American Society of Gene & Cell Therapy's annual meeting last week.

Before receiving DB-OTO within a Phase I/II trial, researchers said that these patients did not have any detectable signs of hearing. However, after receiving a single dose of the treatment, the first patient showed signs of early hearing recovery four weeks post-treatment, and hearing reached normal levels 24 weeks after, according to a preliminary data readout from the trial.

DB-OTO is an investigational gene therapy that's designed to treat patients suffering from hearing loss caused by certain mutations in the OTOF gene, which typically produces otoferlin, a protein that supports transmission of signals to the auditory nerve.

"We feel that this is going to be a viable treatment for genetic deafness for otoferlin-related hearing loss," said Lawrence Lustig, chair of the department of otolaryngology-head and neck surgery at Columbia University in New York and first author on the abstract. In presenting the early data on Wednesday at the meeting, he said he hopes the availability of such treatments down the line will spur universal newborn screening for this form of genetic hearing loss.

The gene therapy is administered through an intracochlear injection to the inner ear and uses a dual adeno-associated virus vector to deliver a full-length copy of the normal OTOF gene.

DB-OTO was developed by Decibel, which Regeneron bought in a deal valued at up to $213 million last year. The investigational treatment is part of a crowded field of emerging gene therapies for OTOF-related hearing loss. At this same meeting, researchers shared data on other investigational gene therapies for the condition, including a late-breaking abstract on Thursday from researchers at Fudan University in Shanghai, who reported that 10 out of 11 pediatric patients with OTOF-related hearing loss have experienced hearing recovery after getting another gene therapy.

Standard care for patients with this rare form of congenital hearing loss relies on cochlear implants, which are devices implanted into the ear that deliver sound by stimulating the auditory nerve. However, while cochlear implants can replicate sounds, they "don't have the full spectrum of frequencies that the human ear has," said Vassili Valayannopoulos, who was previously the head of clinical research and development at Decibel but now is clinical program lead of auditory sciences at Regeneron, a division that was established after the acquisition. 

That means patients with cochlear implants can struggle in noisy environments and with complex sounds, such as music, Valayannopoulos said in an interview. He added that it could be especially useful for young patients to participate in the DB-OTO clinical trial underway, since hearing is important for speech and language development.

The early data presented on DB-OTO at the meeting came from a first-in-human Phase I/II trial, called CHORD, which is taking place at multiple sites in the US, UK, and Spain. In this study, researchers are testing the safety, tolerability, and preliminary efficacy of the gene therapy in children and infants. Initially, in the dose-escalation portion of the open-label study, patients receive a single dose of the gene therapy in just one ear. Once a study dose is selected, patients in the second portion of the study will receive the gene therapy in both ears.

The first patient treated with DB-OTO received a dose of the gene therapy at 10 months old in her right ear, which had previously been untreated, while her left ear has a cochlear implant. She has experienced improvement in hearing through 24 weeks post-treatment; she achieved normal hearing for critical speech frequencies, and investigators characterized her as having normal to mild hearing loss overall. Improvements were measured by audiometric data, auditory skills testing, and outcomes reported by the subject's parents.

The second patient, who received DB-OTO at nearly 4 years old, also received the gene therapy in his right ear and has a cochlear implant in his left ear. The patient's hearing has been improving and researchers have detected his ability to respond to loud sounds, though his hearing has not reached normal levels. The patient has exhibited trends similar to those observed in the first patient at weeks four and six post-treatment.

"This patient appears to be progressing exactly on the track that patient 1 progressed," Lustig said. "We have every reason to hope that the child will continue to improve their hearing like we saw in the first patient."

Patients in the CHORD study will be monitored for 72 weeks as part of the trial and will be followed for three and a half years after the trial. So far, researchers have reported no adverse events related to DB-OTO.

Currently, in the US, patients must be at least 2 years old to join the trial, though investigators are working with regulators to enroll those at least 9 months old based on initial safety data, Lustig said. In the UK and Spain, patients under age 18 can join the trial. Altogether, researchers expect to enroll up to 22 patients in the CHORD trial.

"We hope that in the next year or so, we'll enroll the numbers that we need, so that we can move forward into the next step of our study," Valayannopoulos said.

If investigators see consistent efficacy and safety results in the CHORD trial, Regeneron plans to speak with regulators in the US and Europe to discuss a registrational path.

Moving beyond DB-OTO

Decibel was founded in 2015 to develop gene therapies that restore hearing, starting with deafness caused by alterations in OTOF. Under a 2017 collaboration, Regeneron made an equity investment in the then-startup. By the time Regeneron announced it would acquire Decibel last year, the companies were already codeveloping three gene therapy programs, including DB-OTO as Decibel's lead candidate and two preclinical assets focused on other forms of monogenic hearing loss caused by variants in the GJB2 and STRC genes.

Decibel is now part of Regeneron's genetic medicines group. "Last year's acquisition served to cement this longstanding collaboration," Aris Baras, senior VP and head of the Regeneron Genetics Center, said in an email. "Now that we are one united team, we continue to actively expand our expertise in cutting-edge genetic medicine approaches, which currently includes gene silencing, gene editing, and gene therapy technologies, with the potential to address many serious and hard-to-treat diseases."

Armed with early and promising results from the CHORD trial, Valayannopoulos said Regeneron is equipped to advance Decibel's other, earlier-stage development programs, potentially leveraging the same intracochlear injection system if it continues to prove safe.

It made sense to lead with a gene therapy for OTOF-related hearing loss, since, other than the lack of OTOF, the anatomy of the inner ear for most patients remains healthy and intact. "That's what made us, and other groups, believe that if we can restore this expression of otoferlin in the right type of cells in the inner ear, we might restore that connection," he said. It's also monogenic, impacts a limited number of cells, and has a consistent set of symptoms, mainly hearing loss, which don't cause additional issues in other places in the body.

In terms of the other development programs Regeneron is advancing, the company is currently doing preclinical studies of a gene therapy to treat GJB2-related hearing loss and is gathering data for an investigational new drug application. GJB2 deficiency is one of the most common causes of congenital hearing loss, and patients with it lack a protein expressed in certain inner ear cells that plays a critical role in hearing.

Regeneron plans to launch a clinical trial to test that candidate in 2025, Valayannopoulos said. 

Biopharmaceutical companies in the auditory disorders space have been "navigating uncharted waters" in these early studies, seeking to answer questions not just about their specific products but also generally about whether it's safe and effective to inject the treatment directly into the inner ear, Valayannopoulos noted. "Gene therapy for the inner ear is a new frontier," he said.