TMC1

Marcela Ruth Romero/Getty Images The treatment, called DB-OTO, is one of several early-stage gene therapies being developed to treat relatively straight-forward causes of genetic deafness. Regeneron’s gene therapy DB-OTO has restored partial hearing in 10 of 12 children with profound otoferlin-related deafness, a genetic condition researchers say is a perfect match for gene therapy. The Phase I/II data, shared Monday afternoon at the Association for Research in Otolaryngology’s (ARO) 48th Annual MidWinter Meeting in Orlando, reinforce the trial’s preliminary findings of restored hearing in two children that made a splash at last year’s American Society of Gene & Cell Therapy annual meeting. “It’s a status update, a kind of proof of concept,” Jeffrey Holt, an otolaryngology researcher at Harvard Medical School who viewed Regeneron’s data and attended the ARO talk, told BioSpace in an interview . He pointed to otoferlin’s biology as a key to the therapy’s preliminary success, given that mutations in the underlying gene cause deafness without harming the ear’s architecture or cells. “It’s a rare consensus in the field, among scientists and investors, that this genetic target [otoferlin] was the low hanging fruit, the best to go after,” Holt said. Mutations in the otoferlin protein, which connects sensations in the inner ear to the eighth cranial nerve connecting to the brain, allow outside auditory signals to get transmitted. With the protein mutated, the signal goes nowhere, but the underlying architecture of the ear is otherwise intact. “Everything else can go right in these kids’ ears, but when it comes time to send information to the nerve, you fail at the last step to send a signal to the brain,” Regeneron vice president and the company’s Auditory Global Program head Jonathon Whitton, told BioSpace . This is where DB-OTO gets to work. Regeneron acquired the gene therapy when it bought its longtime development partner Decibel Therapeutics for $109 million in 2023. DB-OTO’s payload is a cDNA molecule coding for the normal otoferlin protein sequence, which creates an episome, or “protein factory” in the cell, producing protein continuously at a certain level, in the specific cell type. Because the cells that the gene therapy targets, inner hair cells, do not divide—in fact, humans are born with the full number of cells they will have for their whole lives—the treatment in theory does not need to be repeated. “At least for right now,” said Whitton. In the Phase I/II CHORD trial, Regeneron treated 12 children, most younger than four years of age, although two participants were 16 years old at the time of treatment. Nine of the patients received the DB-OTO treatment in one ear, while the other three, all of whom were about one year old, were treated in both ears. Ten of the patients before the trial could only hear sounds of around 100-120 decibels, and all of those patients showed at least some improvement after 12 weeks. Five of those patients were assessed again at 24 weeks and of those five, three could hear sounds as quiet as 40 decibels after the treatment. None of the 12 patients showed adverse effects from the DB-OTO treatment. Regeneron shared video footage of a toddler who had received the treatment, responding to auditory cues, like being asked to hug their stuffed animal “Snap Snap,” or reading from a book and responding to questions like, “What sound does a duck make?” Whitton also shared an anecdote from one of the teenagers. The patient, who could hear using a cochlear implant, told an investigator that they were in the shower and were perceiving something that was totally unfamiliar to them: it was the first time they’d ever heard water in their life—because they took out their implant to shower. According to Whitton, the gene therapy can be administered by clinicians using the same tools used to set up cochlear implants. Whitton said that Regeneron has no timeline for pushing into new clinical trials or applying for approval with the FDA, stating that the company is working with regulators to outline a path forward and “trying to push forward internally.” Regeneron is one of at least five companies targeting otoferlin-related deafness with a gene therapy. In 2022, Eli Lilly purchased Akuous Inc. for $487 million to scoop up that company’s inner ear condition–targeting therapies. Sensorion, based in Montpellier, France, announced promising Phase I/II data from its own otoferlin-related deafness gene therapy late last year. Another company based in China, Refreshgene Therapeutics, also restored hearing in children with otoferlin-related deafness in 2023 with a gene therapy. Holt was optimistic about the future potential of sensory disorder-treating gene therapies. He cautioned that otoferlin-related deafness “occurs in about 10-20,000 people in the U.S.—a small fraction of the 30 million people with hearing loss in the US.” But he listed a few potential next targets such as TMC1, a deafness-causing mutation with similar prevalence to otoferlin-mutations, and stereocilin, another inner ear protein whose mutations cause about 120,000 cases of deafness in the U.S. Whitton said that besides otoferlin, Regeneron is continuing its work on GJB2-related hearing loss, which affects about 1,400 children in the U.S. every year.

With the J.P. Morgan Healthcare Conference in full swing, companies did not waste time in announcing deals and providing updates to their pipelines. BioSpace takes a look at some of the announcements made on day one of the annual conference in the Bay Area. With the J.P. Morgan Healthcare Conference in full swing, companies did not waste time in announcing deals and providing updates to their pipelines. BioSpace takes a look at some of the announcements made on day one of the annual conference in the Bay Area. Guardant Health – California-based Guardant Health, Inc. kicked off J.P. Morgan with an announcement it forged a strategic collaboration with Amgen to develop a blood-based companion diagnostic test for Amgen’s AMG 510, an investigational oral therapy that inhibits KRAS G12C mutant protein. Under the agreement, Guardant Health plans to pursue pre-market approval for the device dubbed Guardant360 CDx in the United States, Europe and Japan for use with AMG 510 in metastatic non-small cell lung cancer (NSCLC) patients with the KRAS G12C mutation. Amgen is currently enrolling patients in a potentially registrational Phase II study with AMG 510. The FDA granted Orphan Drug Designation to AMG 510 for previously treated metastatic NSCLC and colorectal cancer with KRAS G12C mutation and Fast Track Designation for previously treated metastatic NSCLC with KRAS G12C mutation. AMG 510, a first-in-class KRAS G12C inhibitor, is designed to selectively and irreversibly target a specific mutant form of KRAS called G12C that is present in nearly 13% of all NSCLC patients. AmirAli Talasaz, president of Guardant Health, said that “development of Guardant360 CDx will lead to consistently delivered guideline-complete genotyping results along with other important genomic information to patients and their providers through blood, which will ultimately increase the number of patients who are identified as eligible for targeted therapies, including AMG 510, and thus improve access to these potentially life-changing treatments.” BridgeBio Pharma – San Francisco-based BridgeBio added an additional four assets to its pipeline, bringing the company’s total to more than 20 developmental medications. The four new assets are aimed at the areas of cardiovascular and renal disease, gene therapy, and ophthalmology. Encaleret is a small molecule antagonist of the calcium-sensing receptor targeting conditions related to hypoparathyroidism including Autosomal Dominant Hypocalcemia Type 1 (ADH1). BridgeBio completed the submission of an Investigational New Drug Application to the U.S. Food and Drug Administration and plans a Phase IIb study in ADH1 early 2020. For retinal diseases, BridgeBio is focused on BBP-551, a novel treatment for the genetically determined retinal diseases phenotypically classified as Retinitis Pigmentosa and Leber’s Congenital Amaurosis. BBP-551 has been granted Orphan Drug Designation in the United States and European Union and Fast Track Designation in the United States. BBP-815 is an AAV gene therapy for the treatment for nonsyndromic hearing loss caused by recessive mutations in the TMC1 gene. By replacing the dysfunctional TMC1 protein using AAV gene therapy, BBP-815 is aiming to repair the deficient inner ear sensory cells at the source of this disease. BBP-472 is a novel treatment designed to balance kinase signaling in the brain for the treatment of children with autism-spectrum disorders characterized by loss of the PTEN protein. This program, currently in the lead-finding phase, is focused on advancing a brain-permeable inhibitor of PI3KB, a kinase shown to signal unabatedly in the absence of PTEN. Oyster Point – Oyster Point Pharma, Inc. announced positive top-line results from its Phase II MYSTIC study in Dry Eye Disease. The study focused on the company’s OC-01 nasal spray, which showed a statistically significant improvement in Schirmer’s score at Day 84 in both doses tested compared to control. OC-01 nasal spray is a preservative-free, aqueous, nicotinic agonist nasal spray designed to activate the trigeminal parasympathetic pathway to stimulate natural tear production, the company announced. The study demonstrated that OC-01 nasal spray was well-tolerated at the two dose levels tested. Adaptimmune – At the J.P. Morgan Healthcare Conference, Adaptimmune Therapeutics plc announced two confirmed partial responses in a liver cancer patient and melanoma patient who were both treated with the company’s SPEAR-T platform for solid tumors. Additionally, Adaptimmune said it observed two partial responses in a patient with gastroesophageal junction cancer and one in a patient with head and neck cancer. The company said these data further confirm the potential of its SPEAR T-cell platform for patients with multiple solid tumors. Data were previously reported showing compelling efficacy with ADP-A2M4 in synovial sarcoma. Adrian Rawcliffe, chief executive officer of Adaptimmune, said the responses it has seen in its platform demonstrates that the SPEAR T-cell program can overcome the challenges of treating a range of solid tumors with a T-cell therapy product. He expressed the fact that these results are still early and more data is needed to support the research. However, he noted that the data is a “critical demonstration of the value of our SPEAR T-cell therapies for people with cancer and a validation of the importance of our proprietary affinity engineering.” Eagle Pharmaceuticals – New Jersey-based Eagle Pharmaceuticals announced it agreed to terms with the University of Pennsylvania for the development of dantrolene sodium for the potential treatment of people living with Alzheimer’s disease. Last year, a proof-of-concept study showed that intranasal administration of dantrolene sodium provided therapeutic effects on memory and cognition in a mouse model of Alzheimer’s. Eagle believes that the homeostatic balance of calcium inside cells is essential for the proper function of the nervous system. hbspt.forms.create({ portalId: "4413123", formId: "c4dda430-e2b0-4083-86f3-ccce0c1d4479" });