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Latest DB-OTO Results Show Dramatically Improved Hearing to Normal Levels in a Child with Profound Genetic Deafness Within 24 Weeks and Initial Hearing Improvements in a Second Child at Six Weeks

May 8, 2024 – Biotechnology, Clinical Trials – Regeneron Pharmaceuticals, cell and gene therapies, clinical trials, genetic deafness

Preliminary data detailed in an ASGCT oral presentation include results for one of the youngest children in the world to receive a gene therapy for genetic deafness
Ongoing phase 1/2 CHORD trial is currently enrolling infants and children in the US, UK and Spain.

8 May 2024 — New York, US — Regeneron Pharmaceuticals today announced that the investigational gene therapy DB-OTO improved hearing to normal levels in one child (dosed at 11 months of age) within 24 weeks, and initial hearing improvements were observed in a second child (dosed at four years of age) at a six-week assessment. Both children were born with profound genetic deafness due to variants of the otoferlin gene, and the child dosed at 11 months of age is one of the youngest in the world to receive a gene therapy for genetic deafness. The results are from the ongoing phase 1/2 CHORD trial, which is currently enrolling infants and children and were detailed during an oral presentation at the American Society of Gene and Cell Therapy (ASGCT) annual conference.

“The opportunity of providing the full complexity and spectrum of sound in children born with profound genetic deafness is a phenomenon I did not expect to see in my lifetime,” said Lawrence R Lustig MD, chair of Columbia University’s Department of Otolaryngology – Head & Neck Surgery and a clinical trial investigator. “These impressive results showcase the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related deafness, and we are excited to see how this translates into an individual’s development, especially since early intervention is associated with better outcomes for speech development. With the DB-OTO CHORD trial now enrolling participants in sites across the US and Europe, we’re part of the beginning of a new era of gene therapy research that looks to create treatment options that address the root cause of profound genetic deafness.”

In the trial, both children received a single intracochlear injection of DB-OTO in one ear. The surgical procedure leverages the same approach used for cochlear implants, which is amenable for use in young infants. Hearing improvements were assessed by pure tone audiometry (PTA) and auditory brainstem response (ABR). PTA is considered by auditory experts to be the gold standard measurement of hearing and is measured through behavioural confirmation of sound (eg, turning head towards sound) emitted at different intensity levels (measured in decibels or dB). ABR corroborates these behavioural responses, serving as an objective confirmation of hearing function, by measuring electrical brainstem responses to sound emitted at different dBs.

At baseline, both participants had no behavioural (PTA) or electrophysiological (ABR) responses at maximum sound levels (≥100dB). Following treatment with DB-OTO, both children showed auditory responses at the first efficacy assessment of four weeks.

As presented at ASGCT, the first participant dosed in the trial was 16 months of age at the 24-week assessment and showed:

Improvement of hearing to normal levels across key speech frequencies, with an average 84dB improvement from baseline and one frequency measure reaching 10dB in hearing level per PTA. Across all tested frequencies, an average 80dB improvement from baseline was observed
Positive ABR responses, with best frequency reaching 45dB.

The second participant dosed in the trial was four years of age at the six-week assessment and experienced consistent results to the first participant at the same timepoint, including:

Initial improvement of hearing with responses to loud sounds, which was observed across key speech frequencies, with an average 19dB improvement from baseline and one frequency measure reaching 80dB in hearing level per PTA. Across all tested frequencies, an average 16dB improvement from baseline was observed
Positive ABR responses, with best frequency reaching 75dB.

Both the surgical procedure (delivery and post-operation) and DB-OTO were well tolerated, and there were no related adverse events or serious adverse events following treatment.

DB-OTO received Orphan Drug, Rare Paediatric Disease and Fast Track Designations from the US Food and Drug Administration (FDA) and Orphan Drug Designation was granted by the European Medicines Agency (EMA). The potential use of DB-OTO for otoferlin-related hearing loss is currently under clinical investigation, and its safety and efficacy have not been evaluated by any regulatory authority.

About the CHORD Trial
The CHORD trial (NCT# 05788536) is a phase 1/2 first-in-human, multicentre, open-label trial to evaluate the safety, tolerability and preliminary efficacy of DB-OTO in infants, children and adolescents with otoferlin variants. Currently enrolling children across sites in the US, UK and Spain (<18 years of age; staggered by age in the US), CHORD is being conducted in two parts. In the initial dose-escalation cohort (Part A), participants will receive a single intracochlear injection of DB-OTO in one ear, while in expansion cohort (Part B), participants will receive simultaneous single intracochlear injections of DB-OTO in both ears at the selected dose from Part A.

About DB-OTO and the Regeneron Auditory Program
DB-OTO is an investigational cell-selective, adeno-associated virus (AAV) gene therapy designed to provide durable, physiological hearing to individuals with profound, congenital hearing loss caused by variants of the otoferlin gene. The treatment aims to deliver a working copy to replace the faulty otoferlin gene using a modified, non-pathogenic virus that is delivered via an injection into the cochlea under general anaesthesia (similar to the procedure used for cochlear implantation). In this gene therapy, the newly introduced otoferlin gene is under the control of a proprietary cell-specific Myo15 promoter, which is intended to restrict expression only to inner hair cells that normally express otoferlin.

The ongoing CHORD trial is Regeneron’s first clinical-stage auditory programme. In addition to DB-OTO, AAV.103 is also being investigated for people with GJB2-related hearing loss.

About Regeneron
Regeneron is a leading biotechnology company that invents, develops and commercialises life-transforming medicines for people with serious diseases. Founded and led by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous approved treatments and product candidates in development, most of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, neurological diseases, haematologic conditions, infectious diseases and rare diseases.

Regeneron pushes the boundaries of scientific discovery and accelerates drug development using our proprietary technologies, such as VelociSuite, which produces optimised fully human antibodies and new classes of bispecific antibodies. We are shaping the next frontier of medicine with data-powered insights from the Regeneron Genetics Center and pioneering genetic medicine platforms, enabling us to identify innovative targets and complementary approaches to potentially treat or cure diseases. For more information, please visit www.Regeneron.com.