Regeneron has posted updated clinical data on DB-OTO, providing more evidence of the gene therapy’s potential to treat a rare genetic form of deafness as it plans for a potential FDA filing later this year.
In February, the biotech reported improvements in 10 of 11 children who received DB-OTO. The AAV gene therapy, which Regeneron acquired in its $109 million Decibel Therapeutics buyout, is designed to address a mutation that leaves children lacking a protein critical to synaptic transmission by hair cells of the ear.
Regeneron shared updated data from its phase 1/2 CHORD trial on Sunday at a meeting of the American Academy of Otolaryngology. The data set includes 12 patients, three of whom received DB-OTO in both ears. After 24 weeks, nine of the patients met the primary endpoint efficacy threshold. Hearing gains below the threshold were seen in a further two patients. One child didn’t respond to the treatment.
The nonresponder received a cochlear implant, the current standard treatment option for kids with the condition. Lawrence Lustig, M.D., chair of the Department of Otolaryngology—Head and Neck Surgery at Columbia University, outlined one way DB-OTO may improve on the existing treatment.
“With cochlear implants, you turn it on, everything's mechanical, robotic-like. Over time, that becomes the new normal, patients adapt to it and can hear pretty well,” Lustig said. “This [gene therapy] essentially is basically turning on the natural sound mechanism of the ear.”
All the children in the study are too young for music appreciation assessments, one of the ways doctors evaluate the quality of hearing treatments, but all the patients who have had speech testing have shown improvements. Lustig said the kids’ hearing should be shown to be equivalent to that of people without the condition once they are old enough for assessments of the naturalness of the sound they hear.
Children who receive cochlear implants by 18 months of age and undergo appropriate speech and language therapy achieve normal or near-normal development milestones. However, speech outcomes are delayed when kids receive implants aged 3 or 4 years.
“That's exactly what we saw in our one 4-year-old who was dosed,” Lustig said. “The time frame in which it happened is shocking to us, how quickly it has happened in 24 weeks. They seemed to be coming up to speed quicker than they would have with a cochlear implant.”
The durability of the effects remains an open question given how little time has passed since the first patients received DB-OTO. Lustig said some patients that were in the severe range after 24 weeks continued to improve over time and surpassed the primary endpoint by Week 48.
Yet the researchers also tracked declining high-frequency hearing in two patients, albeit at a level that didn’t affect speech perception. Lustig said the decline could reflect variability in the uptake of the AAV between hair cells or damage from the procedure. Studies of other therapies have seen similar declines, Lustig said. A spokesperson for Regeneron said one of the participants experienced ear infections, which were treated with steroids and some hearing was recovered.
"Stemming from this learning, the other participant who started to experience a decline in hearing (and did not have any outward confirmation of an infection/inflammation) but was also treated with steroids and some hearing was also recovered. That said, we have reason to believe these were environmental factors post-procedure," the spokesperson said.
Lustig explained the procedure “is nearly identical to what we do for a cochlear implant.” Some patients had transient dizziness for a couple of days after the procedure, Lustig said, but no participants had any long-term vestibular problems. One-quarter of the 67 adverse events that were reported as starting or worsening during or after were linked to the procedure.
The procedure was uneventful in the one patient who didn’t respond to DB-OTO. While the patient’s immune response may indicate insufficient delivery, the researchers are yet to find an explanation for the absence of hearing improvements.
The study suggests DB-OTO could help most patients. Between 30 and 50 kids per year have the form of generic deafness targeted by DB-OTO. While that limits the impact of the treatment, Lustig sees the gene therapy as a proof of concept that could unleash investment in other programs.
“I think this is going to attract a lot of seed money into the field and help drive therapy for a number of other forms of genetic deafness. That's really exciting,” Lustig said.
The U.S. biopharma said that an application for DB-OTO "is planned for later this year," pending discussions with the FDA.