AK-OTOF

Regeneron Pharmaceuticals announced further encouraging early results for its DB-OTO gene therapy for hearing loss, including 24-week data showing that the first treated patient – a 10-month-old infant – went from profound deafness at baseline to being able to detect sounds in the conversational range.The company also unveiled six-week results from a second patient who was treated at 4 years old and appears to be showing signs of a similar trajectory.The results, presented Wednesday at the American Society of Gene and Cell Therapy (ASGCT) meeting, are from Regeneron's ongoing Phase I/II CHORD trial evaluating DB-OTO as a treatment for profound hearing loss caused by mutations in the otoferlin gene.DB-OTO, a dual AAV1 vector designed for intracochlear delivery, aims to provide a full-length copy of the OTOF gene to hair cells in the inner ear. The therapy is surgically delivered using a well-established approach based on cochlear implantation, allowing direct infusion into the perilymph – the fluid-filled space of the inner ear.Preliminary data from the first patient were reported last October. The infant received a single unilateral dose of 7.2 x 1012 vector genomes of DB-OTO administered in the right ear, while a cochlear implant was placed in the left ear during the same surgical procedure.At the 24-week mark, no serious adverse events related to DB-OTO were reported. Researchers were also concerned with not damaging vestibular organs, which help people keep their balance, during surgical delivery of the therapy in the inner ear. Regeneron says vestibular function has remained normal.Unlocking auditory functionResults also showed progress in hearing ability through week 24 in the ear treated with DB-OTO. Auditory brainstem response (ABR) indicated improvement in hearing at different sound levels ranging from 45 to 85 dB, whereas before treatment, there was no response to sound at 100 dB. Additionally, an audiogram demonstrated improvement in hearing levels to within normal hearing thresholds compared to the beginning of the study, while there was no improvement in hearing intensity observed in the untreated ear with cochlear implant turned off.The first patient "entered the study with profound deafness, a sort of a level at which you couldn't even hear [a] chainsaw," explained Johnathon Whitton, who heads the Auditory Global Program at Regeneron, in an interview with FirstWord. But after treatment, "we saw responses that are in the normal sensitivity range, which is just remarkable."Corroborating the tests, parents also reported improved auditory behaviour and voice quality when the cochlear implant in the untreated ear was turned off.In a second patient, a 4-year-old child who received the same unilateral dose of DB-OTO, preliminary data demonstrated ABR and audiogram improvement through week six in the treated ear compared to baseline. No DB-OTO-related adverse events or vestibular abnormalities were observed here either."It looks very similar basically to what we saw on the first patient at that time point, so I think we're seeing something consistent starting to play out," Whitton commented.End-of-2025 filing targetRegeneron is now engaging with regulators to align on the necessary data requirements and expedite patient enrollment in the ongoing trial, targeting a filing for the end of next year. "We believe and it's a moral obligation to push as aggressively as possible now given…that very promising early efficacy data," Christos Kyratsous, co-head of Regeneron Genetic Medicines, told FirstWord.Regeneron acquired DB-OTO through its purchase of Decibel Therapeutics last year for $109 million or up to approximately $213 million if contingent value right (CVR) milestones are achieved. Alongside DB-OTO, Regeneron is also advancing other gene therapy programmes, including AAV.103 for GJB2-related hearing loss and AAV.104 for stereocilin-related hearing loss.Regeneron's efforts are part of a broader push to develop gene therapies for genetic hearing loss. Eli Lilly earlier this year reported that an 11-year-old boy born with hearing loss due to a mutation in the otoferlin gene was able to hear across all tested frequencies after being treated with a single dose of AK-OTOF, while another group involving Refreshgene Therapeutics posted positive data for the gene therapy AAV1-hOTOF.