Dear readers,
Happy March! This newsletter believes in the good word of Punxsutawney Phil, who declared six more weeks of winter five weeks ago. By my math, that puts us right on the cusp of spring. When asked to comment on the current and future landscape of the pharma and biotech industries, Phil gazed off into the distance for several seconds before returning to his burrow. Not sure what to make of that. Let’s get into this week’s story.
This week’s edition focuses on some news out of Regeneron from late last month, announcing results from a phase 1/2 trial for a gene therapy treating a rare form of hearing loss in children. Regeneron has had their metaphorical ear to the ground for therapies to treat hearing loss for a while now, most notably acquiring their Boston-based collaborator Decibel Therapeutics in 2023. These results mark some significant progress for restoration of hearing using gene therapy.
The hearing loss that this treatment aims to address is called DFNB9, a congenital disorder caused by a malfunctioning otoferlin protein. When functioning properly, the otoferlin protein plays a major role in the inner ear’s hair cells, acting to regulate and facilitate stimulation of auditory nerve fibers. In cases of DFNB9, the mutated otoferlin protein doesn’t perform these functions properly. Because otoferlin plays a critical role in several processes at the inner hair cell ribbon synapses, dysfunctional otoferlin proteins disrupt sound signal transmission to the auditory nerve, resulting in hearing loss even without any other structural deficiencies. For more details on the mechanism here, this commentary summarizes otoferlin’s role in hearing and explores how otoferlin is implicated in heat-dependent hearing loss.
Regeneron’s treatment, known as DB-OTO, is a gene therapy that aims to deliver a working copy of the OTOF gene that codes the otoferlin protein. The gene therapy introduces a modified virus that carries the correct sequence of the OTOF gene and is able to target specific cell types to only introduce the new sequence to the relevant cells. This approach is known as adeno-associated virus (AAV) vector gene therapy and has already achieved clinical success in several other FDA-approved treatments. So if all goes according to plan, a working copy of OTOF should be introduced to the inner hair cells via an AAV vector, leading to production of functioning otoferlin proteins, which will facilitate sound transmission to the brain, and allow hearing! So how’d this work out in practice?
Well, swimmingly well. The Regeneron trial reported significant hearing improvements for 10 of the 11 children in the trial, with three achieving “nearly normal” or “normal” levels of hearing. Safety data shows that DB-OTO was well-tolerated and that there were no serious adverse events for all participants in the trial.
Regeneron isn’t alone here in their quest to develop gene therapies for otoferlin-related hearing loss. Eli Lilly shared data early last year showing promising results for their investigational therapy, known affectionately as AK-OTOF. While the two approaches share some similarities (both are trying to insert a functioning copy of the OTOF gene to cells in the inner ear), they differ in both the surgical approach that is used to introduce the virus to the ear and in the molecular mechanism behind the insertion.
With brevity in mind, this concludes this edition of the newsletter. For those whose thirst for learning about otoferlin-related hearing loss has not yet been quenched, I invite you to take a look at some of the links below.
Have a blissful and riveting rest of the week!
Tommer
Referenced Literature:
Great read Tommer