FDA Grants Breakthrough Therapy Status to Denali's Tividenofusp Alfa for Hunter Syndrome

Denali Therapeutics Inc., located in South San Francisco, has announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for tividenofusp alfa (DNL310). This investigational treatment is designed for individuals suffering from Hunter syndrome, also known as MPS II. Previously, the FDA had awarded tividenofusp alfa several other designations, including Fast Track, Orphan Drug, and Rare Pediatric Disease Designation.

Hunter syndrome is a rare, genetic disorder predominantly affecting males, characterized by physical, cognitive, and behavioral symptoms due to a deficiency in the iduronate-2-sulfatase (IDS) enzyme. This deficiency stems from mutations in the IDS gene, leading to an accumulation of glycosaminoglycans (GAGs) within lysosomes, which are responsible for breaking down various materials in the body. The disorder manifests as early as age two, with symptoms such as organ dysfunction, joint stiffness, hearing loss, and impaired growth. Moreover, neurocognitive symptoms, including impaired development, are common. Currently, enzyme replacement therapy is the standard treatment, which partly addresses physical symptoms but fails to cross the blood-brain barrier, leaving cognitive and behavioral symptoms untreated. Therefore, there is a significant unmet need for therapies that address the comprehensive effects of the disease.

Tividenofusp alfa is a novel therapeutic candidate made from iduronate 2-sulfatase fused to Denali's proprietary Enzyme TransportVehicle™. This design allows active transport into the brain and distribution throughout the body, aiming to alleviate the behavioral, cognitive, and physical symptoms associated with Hunter syndrome. Denali plans to submit a Biologics License Application for this treatment in early 2025, seeking FDA review through the accelerated approval pathway.

The FDA's Breakthrough Therapy Designation is intended to expedite the development and review of drugs that show potential to significantly improve treatment over existing options for serious or life-threatening conditions. This designation offers Denali the benefit of more comprehensive guidance from the FDA, including involvement of senior reviewers, alongside eligibility for rolling and priority reviews of its marketing application.

Dr. Carole Ho, Chief Medical Officer of Denali Therapeutics, noted that the Breakthrough Therapy Designation is a substantial milestone in developing tividenofusp alfa. She highlighted the encouraging results from an open-label Phase 1/2 study, which demonstrated promising outcomes based on surrogate endpoints and early signs of improved clinical results for participants. She expressed gratitude to the FDA for acknowledging the potential of the treatment as a meaningful option for the Hunter syndrome community. Dr. Ho emphasized Denali’s commitment to working closely with the FDA to make this therapy accessible to patients as swiftly as possible.

Denali Therapeutics is a biopharmaceutical company focused on creating treatments for neurodegenerative and lysosomal storage diseases. They specialize in developing product candidates engineered to cross the blood-brain barrier to treat these conditions. Denali's approach involves meticulous assessment of genetically validated targets, engineering mechanisms for delivery across the blood-brain barrier, and proving development through biomarkers that show target engagement and pathway manipulation.

As Denali progresses with tividenofusp alfa, they remain focused on their mission to deliver innovative treatments that address the needs of individuals with serious genetic and neurodegenerative diseases.