Denali Therapeutics Reports Phase 1/2 Study Results on Hunter Syndrome with Tividenofusp Alfa

SOUTH SAN FRANCISCO, CA, USA, February 06, 2025—Denali Therapeutics Inc. announced promising findings from their Phase 1/2 trial examining tividenofusp alfa (DNL310) in patients with Hunter syndrome (MPS II). Over a 24-week treatment period involving 47 participants, coupled with extended follow-up, the results underscore the potential of this investigational therapy. The data is presented at the 21st Annual WORLD Symposium™ in San Diego, highlighting Denali's intent to submit a biologics license application for expedited approval in early 2025, potentially making the therapy available to the Hunter syndrome community by late 2025 or early 2026.

Hunter syndrome is a rare genetic disorder that predominantly affects males, leading to a spectrum of physical, cognitive, and behavioral symptoms. The disorder arises due to mutations in the iduronate-2-sulfatase (IDS) gene, resulting in insufficient levels of the IDS enzyme. This deficiency causes glycosaminoglycans (GAGs) to accumulate in lysosomes, leading to various complications including organ dysfunction, joint stiffness, hearing loss, and neurocognitive deficits. Current treatment options, such as enzyme replacement therapy, primarily address physical symptoms and fail to penetrate the blood-brain barrier, leaving cognitive and behavioral symptoms largely untreated.

The recent data presented by Denali Therapeutics suggests that tividenofusp alfa may overcome these limitations. As a fusion of the iduronate 2-sulfatase enzyme with Denali's proprietary Enzyme Transport Vehicle™ (ETV), this therapy is specifically engineered to deliver the enzyme throughout the body and into the brain. The primary analysis from the study revealed substantial reductions in biomarkers associated with the disease, such as cerebrospinal fluid (CSF) and urine heparan sulfate, as well as neurofilament light (NfL), a marker of neurodegeneration. Clinically, participants experienced normalization of liver volume, improvement in hearing across all frequencies tested, and progress in adaptive behavior and cognition.

In terms of safety, tividenofusp alfa was generally well-tolerated by participants. Most treatment-related adverse events were mild or moderate, including reactions during infusion, anemia, vomiting, fever, respiratory infections, and skin rash. Serious adverse events were observed in three participants but were manageable, with resolution or stabilization upon continued treatment. Only one participant discontinued treatment due to a moderate infusion-related reaction and other non-treatment-related issues.

Denali also presented additional research at the WORLD Symposium™, highlighting unmet needs in the current management of Hunter syndrome. Dr. Barbara Burton from the Feinberg School of Medicine identified challenges in diagnosis and ongoing care, emphasizing the inadequacies of existing treatments for the disease's wide-ranging manifestations. Denali’s research further illustrated age-based elevations in CSF and urine biomarkers in Hunter syndrome patients compared to pediatric reference intervals.

The ongoing Phase 2/3 COMPASS study of tividenofusp alfa aims to support global approval, enrolling participants across North America, South America, and Europe. The study randomizes participants to receive either tividenofusp alfa or idursulfase. Enrollment for neuronopathic MPS II participants in Cohort A is complete, with additional participants being recruited following an increase in sample size. Cohort B continues to enroll individuals with non-neuronopathic MPS II.

Denali Therapeutics continues to advance its therapeutic portfolio, focusing on treatments for neurodegenerative and lysosomal storage diseases by harnessing the potential of genetically validated targets and innovative delivery mechanisms. Through rigorous biomarker analysis, Denali aims to develop therapies that effectively engage target pathways and improve patient outcomes.