Denali Therapeutics Pushes Forward with Blood-Brain Barrier-Crossing Drug for Hunter Syndrome

Denali Therapeutics, a biotechnology company focused on neurodegenerative diseases, has initiated a rolling Biologics License Application (BLA) for accelerated approval of tividenofusp alfa (DNL310), a potential treatment for Hunter syndrome. This move marks a significant milestone for the company, which has faced challenges in its decade-long journey to bring a product to market.

A Decade-Long Journey to Tackle Neuroscience's Toughest Challenge

Founded in 2015 with a record-breaking $215 million in first-round venture financing, Denali set out to develop new approaches for neurodegenerative diseases. The company's initial focus was on small molecules, but after several setbacks, including failed trials in Alzheimer's and ALS, Denali shifted its strategy to large molecules and engineered enzymes.

Carole Ho, Denali's chief medical officer and head of development, explained the company's approach: "When we came out of stealth in 2015, we raised a significant amount of money. And there was a question: What were we doing differently?" The answer lies in Denali's focus on crossing the blood-brain barrier (BBB), a longstanding challenge in neurology.

DNL310: A Breakthrough in Hunter Syndrome Treatment

DNL310, an enzyme replacement therapy, represents the culmination of Denali's efforts to overcome the BBB challenge. The drug utilizes a specialized transport vehicle to deliver the treatment across the blood-brain barrier. This innovative approach has garnered significant attention from regulators, with DNL310 securing FDA Breakthrough Therapy Designation in January, adding to its existing Fast Track Designation, Orphan Drug Designation, and Rare Pediatric Disease Designation.

Hunter syndrome, a rare genetic disorder primarily affecting boys, results from a deficiency in the iduronate 2-sulfatase (IDS) enzyme. DNL310 aims to replace this missing enzyme, potentially addressing both physical and mental developmental issues associated with the condition.

Recent Phase I/II trial results for DNL310 have shown promising outcomes, with improvements reported in hearing, cognition, and adaptive behavior, along with a "generally well-tolerated" safety profile over four years of treatment.

Shifting Focus and Future Prospects

While Denali continues to develop treatments for Parkinson's disease, including the LRRK2-targeting small molecule DNL151 in partnership with Biogen, the company has moved away from its earlier focus on Alzheimer's and ALS. Ho noted that these areas have been "moved to the back burner," with no current candidate molecules in the pipeline for either disease.

As Denali awaits regulatory review of DNL310, the company hopes to launch the treatment in late 2025 or early 2026. This milestone could potentially validate Denali's approach to crossing the blood-brain barrier and pave the way for future therapies targeting neurological disorders.