New gene therapy trial results have shown dramatic and sustained improvements in hearing and speech perception in children with profound genetic hearing loss. 

The updated data for Regeneron Pharmaceuticals’ investigational gene therapy DB-OTO for profound genetic hearing loss due to variants of the otoferlin (OTOF) gene were published in The New England Journal of Medicine and presented at the annual American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNSF) meeting.  

These latest results from the CHORD trial show 11 out of 12 participants have experienced clinically meaningful hearing improvements, including three who achieved normal hearing levels.  

Additionally, eight participants with longer follow-up showed stability or continued improvement in their hearing, and among three who completed speech assessments, all showed significant improvement. 

“Until now, genetic OTOF-related hearing loss was considered permanent, which is why many of us have dedicated our careers to this field,” said Lawrence Lustig, Chair of the Department of Otolaryngology-Head and Neck Surgery at the Columbia University College of Physicians and Surgeons and a trial investigator.  

“This registrational data set showcases consistent, rapid and robust responses to DB-OTO, and for those followed to later timepoints, we’ve seen hearing stability as well as continued improvement in understanding of speech. These results are even more poignant when viewed by the families – as one of the parents said, their situation is now ‘unimaginable’ from one year ago. This truly represents a new era in the treatment of hearing loss.” 

Results of the CHORD trial

The CHORD trial evaluated paediatric participants with profound hearing loss due to variants of the OTOF gene that received a single administration of DB-OTO via intracochlear infusion.  

Among 12 participants (aged 10 months to 16 years), nine received the gene therapy unilaterally (in one ear) and three received it bilaterally (in both ears). The surgical procedure to administer DB-OTO leverages an approach similar to cochlear implantation, which enables use in young infants. 

Nearly all participants (11 of 12; 14 of 15 treated ears) demonstrated improved hearing, responding within weeks of treatment. The trial met the primary endpoint with nine participants experiencing hearing improvements at a threshold of ≤70 decibel hearing level (dBHL) as assessed by behavioural pure tone audiometry (PTA) at week 24.  

This threshold corresponds to a clinical standard that typically does not require cochlear implantation and enables natural acoustic hearing. Notably, six could hear soft speech without assistive devices, and three were further able to detect whispers (achieving normal hearing sensitivity).  

One participant who did not meet the primary PTA endpoint at week 24 further improved to achieve “nearly normal” hearing sensitivity at week 48. Nine participants also demonstrated an auditory brainstem response (ABR) at ≤90 decibels (dB), achieving the trial’s key secondary endpoint. 

Hearing improvements remained stable or continued to improve in eight participants who had follow-up visits of ≥36 weeks (up to 72 weeks). Speech development was also assessed in the three participants who were followed at least 48 weeks and all showed significant improvements. One of these participants demonstrated the ability to identify one- and two-syllable words with no visual cues and could respond to distant sounds and speech in noisy environments. 

Across all 12 participants, both the surgical procedure and DB-OTO were well tolerated, and there were no DB-OTO-related adverse findings reported.

Diana Turner, Deputy Editor, DDW