Denali Therapeutics Inc. (DNLI) has announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to tividenofusp alfa (DNL310) for the treatment of individuals with Hunter syndrome (MPS II). This designation, announced January 8, 2025, aims to expedite the development and review of the drug, which has shown promise in addressing both the neurological and physical symptoms of this rare genetic disorder. Denali expects to submit a Biologics License Application (BLA) in early 2025, seeking accelerated approval.
Clinical Significance
Hunter syndrome (MPS II) is a rare, X-linked recessive lysosomal storage disease caused by a deficiency in the iduronate-2-sulfatase (IDS) enzyme. This deficiency leads to the accumulation of glycosaminoglycans (GAGs) in cells, resulting in a range of physical, cognitive, and behavioral symptoms. Affecting primarily males, Hunter syndrome impacts over 2,000 individuals in commercially accessible regions. Current standard of care, enzyme replacement therapy, addresses physical symptoms but does not cross the blood-brain barrier, leaving cognitive and behavioral symptoms largely unaddressed.
Tividenofusp Alfa: A Novel Approach
Tividenofusp alfa (DNL310) is composed of iduronate 2-sulfatase (IDS) fused to Denali’s proprietary Enzyme Transport Vehicle (ETV), engineered for active transport into the brain and broad delivery throughout the body. This innovative approach aims to address the full spectrum of Hunter syndrome symptoms, including the neurocognitive deficits that current therapies cannot reach.
Carole Ho, M.D., Chief Medical Officer of Denali Therapeutics, stated, “FDA Breakthrough Therapy Designation is another significant achievement in the development of tividenofusp alfa, our first Enzyme TransportVehicle™ program, uniquely designed to optimize enzyme delivery to both brain and body, addressing the full spectrum of Hunter syndrome, a progressive and devastating disease.”
Promising Clinical Data
Data from the open-label Phase 1/2 study have demonstrated promising results, with positive effects on evidence-based surrogate endpoints and early signs of improved clinical outcomes in participants with Hunter syndrome. Notably, the treatment led to substantial and significant reductions to normal and near-normal levels in central nervous system and peripheral biomarkers of disease, including cerebrospinal fluid (CSF) and urine heparan sulfate, and neurofilament light (NfL), a well-established marker of neurodegeneration. Clinical outcomes included normal liver volume after 24 weeks, hearing threshold improvement in all tested frequencies, and skill gains in most participants on measures of adaptive behavior and cognition.
Ongoing Clinical Trial
Tividenofusp alfa is also being studied in the ongoing Phase 2/3 COMPASS trial (NCT05371613), a large-scale investigation comparing the agent against idursulfase for up to a 96-week treatment period. The trial, comprised of 54 individuals with MPS II, includes 2 cohorts based on patients’ age: cohort A (ages ≥2 to <6 years) and cohort B (≥6 to <26 years). The study uses change in cerebrospinal fluid heparan sulfate (HS) over a 24-week period as the primary outcome, with additional changes in the Vineland Adaptive Behavior Scale, Third Edition over 96 weeks as an additional key outcome.
Regulatory Pathway
The Breakthrough Therapy Designation provides Denali with more intensive FDA guidance, including involvement of senior reviewers, and eligibility for rolling review and priority review of the marketing application. Denali has announced the outcome of a meeting with the FDA providing a path to filing a biologics license application (BLA) for accelerated approval and subsequent conversion to full approval for the treatment of Hunter syndrome (MPS II).
