The first patient dosed was able to correctly identify words—such as mommy, cookies and airplane—at a conversational level without visual cues.\n Regeneron’s investigational gene therapy has been tied to notable hearing improvements in 10 of 11 children who were treated for a rare genetic condition that causes hearing loss.“You can see the efficacy very early on,” Regeneron’s senior vice president and co-head of genetic medicines, Christos Kyratsous, Ph.D., told Fierce Biotech in an interview. “We are actively talking to FDA and other agencies around the world to understand what the clinical data set [is] but also everything else that you need to put together for your package to eventually get a drug approved.”The findings come from a phase 1/2 trial, called CHORD, and build off earlier data demonstrating restored hearing for two patients who received the gene therapy. The latest data were shared Feb. 24 at the Association for Research in Otolaryngology’s 48th Annual MidWinter meeting in Orlando, Florida.Regeneron’s gene therapy, dubbed DB-OTO, is a cell-selective AAV gene therapy for children with hearing loss stemming from a mutation to the otoferlin gene. The company snapped up DB-OTO through its $109 million acquisition of Decibel Therapeutics in 2023.To date, 12 participants between the ages of 10 months and 16 years have received DB-OTO, with nine children receiving an intracochlear injection in one ear and three receiving the investigational treatment in both ears. The gene therapy is delivered via a surgical procedure that is similar to a cochlear implantation.Among 11 participants with at least one post-treatment assessment, 10 demonstrated a notable hearing improvement at various decibel levels, according to researchers. Furthermore, among five children with 24-week assessments, three experienced improvements that brought their hearing to “nearly normal” or “normal” levels.One participant has not experienced a change from baseline hearing at 24 weeks after dosing. The updated data cut includes safety data from all 12 patients, with Regeneron finding both the surgical procedure and DB-OTO to be well tolerated.No adverse events caused by DB-OTO have occurred, according to Regeneron. Five of 12 patients experienced transient post-surgical vestibular AEs—such as uncontrollable eye movements, nausea, dizziness and vomiting—which resolved within six days of dosing.Two serious treatment-emergent AEs were reported, neither of which Regeneron believes are tied to DB-OTO.The TEAEs occurred in separate patients, with one child experiencing a grade 3 case of mastoiditis—inflammation or infection of the mastoid bone—in the cochlear implant ear, which cleared after a course of antibiotics. The patient also had a recurrent upper respiratory tract infection and chronic inflammation in both ears.A different patient experienced grade 3-level walking instability, which went away within 24 hours and was attributed to a varicella vaccine reaction.To date, 53 TEAEs were reported in 10 of 12 patients receiving DB-OTO. When zooming in on the first patient dosed, new 72-week results show speech and development progress since receiving the therapy at 10 months of age. The child was able to correctly identify words—such as mommy, cookies and airplane—at a conversational level without visual cues, as measured by formal speech perception assessments.“She, at her baseline, could not hear at all,” Jonathon Whitton, Ph.D., Regeneron’s vice president and auditory global program head, told Fierce. “She received DB-OTO in one ear, and within a few weeks, she started responding to sounds.”Over the course of six months, the patient became able to hear certain whispers, according to Whitton, who said a 48-week assessment showed maintenance of “very good hearing sensitivity.”“We\'re entering a new era here,” Whitton, a pediatric audiologist, explained. “Previously, we usually didn\'t know what was causing the hearing loss when people came to the clinic. Now we can start to understand that.” Otoferlin-related hearing loss is an ultrarare condition that leads to a lack of a functional protein involved in the communication between the sensory cells of the inner ear and the auditory nerve. DB-OTO is designed to provide a payload of cDNA that expresses the protein in hair cells that are missing it, helping restore hearing.The FDA has recognized the gene therapy’s promise, granting DB-OTO orphan drug, rare pediatric disease, fast track and regenerative medicine advanced therapy designations.“This is the beginning of identifying ways to actually provide sort of elegant solutions to these individuals to potentially allow them to hear, and so I think that this is quite an exciting moment for the entire field,” Whitton said.While Regeneron isn’t sharing a specific time for a readout of the second part of the trial—an expansion in which participants receive simultaneous intracochlear injections of DB-OTO in both ears—Whitton said the company is in talks with regulatory agencies about whether CHORD could serve as a pivotal study. When asked how DB-OTO compares to Eli Lilly’s investigational gene therapy being assessed in a phase 1/2 trial for OTOF-mediated hearing loss, Regeneron\'s Whitton detailed differences in the delivery process.At the start of 2024, Eli Lilly shared data that tied its investigational therapy, known as AK-OTOF, to restored hearing in one child who had experienced hearing loss since birth. The Akouos delivery device, which is being developed in parallel for intracochlear administration, is made to deliver AK-OTOF throughout the cochlea.“There\'s a big difference in how the therapy is delivered to the ear,” Whitton said about AK-OTOF compared to DB-OTO. “They both involve a surgical delivery of the gene therapy directly to the inner ear. The surgical approach that they\'re taking is to go through the ear canal, basically, and so this is at least for the very young children in the study—this is a new procedure to do.”For its part, Regeneron decided to use the same surgical approach that is already used for children with cochlear implants so the company could enroll very young participants.“Intervention with congenital deafness is urgent, so we try to provide intervention as early as possible to maximize outcomes in these patients,” Whitton explained.While the two gene therapies are also molecularly different, Kyratsous said it’s still too soon to see how those differences will play out in the clinic. Even though the gene therapy field has seen various setbacks lately, Kyratsous said Regeneron remains dedicated to its therapies.“We truly believe in the power of these technologies—we believe in what they can do for patients,” he explained. “So, we are trying to adopt the long-term view, as we do for most of the technologies we are working on.”“This is just the beginning,” Whitton added. “We\'re actively working on additional targets to try to address other types of childhood hearing loss. We\'re also thinking about age-related hearing loss, noise-induced hearing loss—these are big public health concerns, and we want to help.”
