Regeneron’s DB-OTO: Overcoming Clinical and Manufacturing Hurdles in Gene Therapy for Hearing Loss

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, the performative potential of DB-OTO, and the company’s work with regulatory authorities.

Pharmaceutical Executive: What are the biggest regulatory hurdles that Regeneron anticipates in bringing DB-OTO to market, and how is the company preparing to address them?

Jonathon Whitton: DB-OTO is an AAV-based gene therapy. For these therapies, there are a couple of major areas to consider, one being the clinical plan. For example, a clinical study will generate data, and we spend most of our time discussing the clinical data because it is exciting—we're talking about results in patients and their impact.

Manufacturing is equally important. Many advanced therapies have complex manufacturing processes, requiring careful planning to ensure that all systems are in place before moving toward approval and commercialization. As a result, manufacturing must remain a significant focus. While we don’t discuss it as often, we have dedicated substantial efforts to ensuring the company is prepared from a manufacturing standpoint.

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.