The 'little protein factory' that could: Regeneron gene therapy restores hearing in 2 children

If your child is in a clinical trial for what could be a groundbreaking treatment to restore hearing, as a parent, you’re going to notice the changes before a clinical investigator ever does. That’s what happened for patient 1, a baby with chubby arms and short, wispy blond hair, who was the first to receive Regeneron’s gene therapy for a type of genetic hearing loss in a phase 1/2 trial called CHORD.

Of course, Regeneron officially tested the patient’s hearing in the clinic, but for Jonathon Whitton, Ph.D., who is executive director and head of the company's Auditory Global Program, these stories are why he does what he does.

“The child was starting to respond to different types of sounds even before they came back to the clinic, at the four-week time point. And that's a beautiful thing,” Whitton said in an interview with Fierce Biotech. “The families are experiencing this sort of awakening of hearing in their child in the home environments. [It’s] obviously a very sort of intimate experience to have.”

Regeneron is presenting two case studies from the CHORD trial at the American Society of Gene and Cell Therapy (ASGCT) meeting in Baltimore today, which is testing DB-OTO in patients with profound hearing loss due to mutations of the otoferlin gene. Patients receive a cochlear implant in one ear and have DB-OTO administered in the other. The children then receive numerous hearing and brain tests following treatment, with a focus on the tones that are needed for speech.

The ASGCT presentation will show how, at three weeks, patient 1 began responding to sound, and, by six months, she was responding to meaningful sounds. At Week 24, the patient could hear sounds when the cochlear implant in her other ear was turned off. The patient, who enrolled in the trial at eight months old, continues to make progress, and use of the implant has tapered off.

Christos Kyratsous, Ph.D., co-head of Regeneron Genetic Medicines, says the DB-OTO program was conceived in a brainstorming session between Regeneron and Decibel Therapeutics about six years ago, where they considered what diseases they could make an impact in.

“It sounds like a miracle result,” he said. “We couldn't even imagine that you can do gene therapy for a year and restore hearing, right? And here we are, five, six years later, and you have a profound impact in the life of the child.”

A second 4-year-old patient has also had improvement at weeks 4 and 6 at all tested frequencies, similar to what was seen with patient 1 at those time points. Both patients tolerated DB-OTO well, with patient 1 experiencing common childhood respiratory illnesses during the testing period including an ear infection, which cleared up with standard care.

“Being able to go from an idea, getting the animal data, developing the clinical program, and getting actual clinical data in as little as five to six years—it's a miracle,” Kyratsous said. “This is a very rare thing in our industry, and being able to witness this whole thing is amazing.”


Getting the message

DB-OTO is a cell-selective AAV gene therapy for children with hearing loss stemming from a mutation to the otoferlin gene. The therapy came to Regeneron through the $109 million acquisition of Decibel last year. The two companies had been working together closely on DB-OTO since 2017, so the acquisition was a natural choice, says Kyratsous. Whitton himself came over in the deal, bringing continuity for the clinical program.

The otoferlin protein is expressed in the sensory hair cells of the ear, which have tiny cilia that move as vibrations come into the ear. These cells help signal between the auditory nerve and the hair cells, passing information from the ear to the brain. Children born with this type of genetic hearing loss have the hair cells and can detect the signal coming into the ear.

“But they can't get that message from the ear to the brain, basically, because otoferlin is critical to enable that communication,” Whitton explained.

That’s where DB-OTO comes in. The adeno-associated viral vector delivers the gene therapy to the ear to provide a payload of cDNA that expresses the protein in the hair cells that are missing it. The hypothesis was that if they provided the gene, patients could eventually begin to hear on their own.

No one had ever administered a treatment quite like this, Whitton said. So the Decibel and Regeneron team looked to the common procedure used for cochlear implants and essentially copycatted the surgery. This means that, as DB-OTO advances—and someday arrives on the market—otolaryngologists will already be familiar with the process.

“They already know how to do this surgery,” Whitton said. “What we've found is that you can take this new thing that you're doing, which is really sort of a game changer in the field, and couch it essentially with techniques that are very familiar to surgeons already.”

Another key finding was that the family reported that the patient’s voice is less “screechy” when the cochlear implant is not in use. This isn’t exactly a clinical endpoint, but Whitton said it’s a clue that DB-OTO could restore hearing in a more natural way than cochlear implants, which have long been used to restore hearing.

“We've never had an option which has the potential for what I'll call more natural hearing. That is, that your ear is actually providing the hearing to your brain, sending these types of signals,” Whitton said.

Cochlear implants, by contrast, work by skipping the ear entirely to directly stimulate the auditory nerve, thereby sending the messages directly to the brain. What results is what adults who get the devices later in life have called a very unnatural sound that takes some time to learn.

“We've never had a technology that could do this. So I think that was a very interesting observation from the parents. They're noticing differences, basically, in the quality of their child's voice when they do or don't have on the implant at the same time. That now they have a gene therapy working in the other ear,” Whitton said.

Regeneron does not yet know how long the effect will last, but “rigorous” preclinical tests were done to get a sense of durability, according to Whitton. Since those hair cells targeted by the gene therapy do not turn over during a person’s lifetime, they believe the effect should be persist once restored.

“The ones that you're born with are the ones you will have the rest of your life, so if we can create a little protein factory in those cells, make the protein that's missing, there's reason to believe that you could have long-term benefit,” Whitton said.

That’s what was shown in models, but clinical translation is never certain in biotech. Regeneron is continuing to enroll patients in the trial to find out more.