DB-OTO and the Evolving Approach to Genetic Deafness in Children

Last month, Regeneron announced updated results from the Phase I/II CHORD trial in children with otoferlin-related hearing loss. Out of 11 children who received DB-OTO, 10 showed notable hearing improvements at different decibel levels, with some achieving nearly normal or normal hearing thresholds. Pharmaceutical Executive spoke with Jonathon Witton, AuD, PhD, VP, auditory global program head, in more detail about the trial results and the performative potential of DB-OTO.

Pharmaceutical Executive: Given the promising speech and hearing improvements observed in the CHORD trial, how does Regeneron envision DB-OTO reshaping the standard of care for patients with otoferlin-related hearing loss?

Jonathon Whitton: I'm a pediatric audiologist by training, and I’m also a neuroscientist. If we go back even just a couple of decades when I was still in the clinic, when we first identified a child who was born with deafness, they would go see their pediatrician. Ultimately, their family would come to the clinic, and by that point, the child was usually a few months old. We could run different clinical assessments, most of them physiologic at that time, to try to understand whether or not the child had any hearing ability. At that point, we might be able to explain to the family what we were seeing based on those results, but usually, we couldn’t tell them why.

The story of DB-OTO goes back to the late '90s when this specific gene, responsible for deafness in the condition we are treating, was first identified. As we started testing more and more children who were coming to the clinic, we realized that more than half of them had a genetic protein deficiency that was actually causing their hearing loss, and we could use a blood test or saliva test to make the molecular diagnosis for the exact cause of the hearing loss. That was the first step toward changing the standard of care.

Building off of that, DB-OTO has been in the works for around eight years now. Over the last 10 years, we’ve been able to design a more elegant solution for how we might provide hearing to children. Right now, we have prostheses. We fit children with devices such as hearing aids and cochlear implants. As I said, we previously didn’t know the underlying cause and were just trying to manage their symptoms.

The approach with DB-OTO is based on the idea that if there is a specific cell type in the inner ear responsible for producing a critical protein for hearing, we could develop a therapeutic to deliver DNA to the cell lacking that functional protein. Potentially, you could then go from having no hearing in the case of these children at their baseline to potentially having good hearing. That can be the therapeutic concept for other protein deficiencies that are causing deafness in these kids.

More than half of these children have a genetic cause for their hearing loss. I think when it comes to the big change, there's going to be an appreciation by clinicians in taking a further step in diagnosis for children who are born with deafness. Describing that they have deafness is not enough. We need to dig deeper and try to understand the underlying cause of their deafness. If no therapeutics are available, the patient may ultimately be managed in the same way, relying on a prosthesis to address symptoms. But if you start implementing therapeutics, the onus for the clinician is to try and figure out what exactly is going on. I think this will result in more molecular diagnoses of hearing loss in clinics around the world.

Next, there will be a change in our expectations for what could be possible for the patients. In the core trial of the first 12 patients, 10 out of the 11 patients with available efficacy data have shown notable improvement in their hearing ability. We have several who have hearing results that are normal or near normal in terms of sensitivity. This kind of change is a breakthrough. It changes your expectations for what could be possible.

Full Interview Summary: Regeneron envisions DB-OTO reshaping the standard of care for hearing loss by shifting from symptomatic management with prostheses, such as hearing aids and cochlear implants, to a molecularly targeted therapeutic approach. Historically, clinicians diagnosed hearing loss without understanding its genetic cause, but advances in genetic testing have revealed that over half of childhood hearing loss cases stem from genetic protein deficiencies. DB-OTO aims to correct this by delivering functional DNA to specific inner ear cells, enabling them to produce the missing protein, potentially restoring hearing to near-normal levels.

The transformative potential of DB-OTO is evident in early clinical trials, where 10 out of 11 patients demonstrated hearing improvements, with some achieving normal or near-normal sensitivity. This represents a paradigm shift—clinicians will now need to incorporate molecular diagnostics into routine care, ensuring that patients receive precise, targeted treatments rather than generalized symptom management.

Regeneron has secured multiple regulatory designations, including the FDA’s RMAT designation, which facilitates early and frequent discussions with regulators. These interactions are crucial in navigating the complexities of gene therapy development, accelerating timelines for approval and commercialization.

Challenges remain, particularly in clinical development and manufacturing. Ensuring scalable, high-quality production of gene therapies is as critical as generating robust clinical data. Regeneron has invested heavily in manufacturing capabilities to meet these demands.

Beyond clinical development, Regeneron actively engages with the hearing loss community, including advocacy groups, clinicians, and families. Insights from these discussions have highlighted practical concerns, such as ensuring continuous hearing for safety. This patient-centric approach shapes the development of DB-OTO and future gene therapies, with plans to expand treatments to broader populations, including adults with age-related and noise-induced hearing loss. Regeneron aims to pioneer gene therapy solutions for a currently untreatable public health challenge.