Denali Therapeutics Plans Accelerated FDA Filing for Tividenofusp Alfa in MPS II Treatment

Denali Therapeutics Inc. (Nasdaq: DNLI) recently announced a significant step forward in their development of tividenofusp alfa (DNL310) for treating MPS II, also known as Hunter syndrome. Following a productive meeting with the Center for Drug Evaluation and Research (CDER) division of the U.S. Food and Drug Administration (FDA), Denali has been provided with a clear path to file for accelerated approval of tividenofusp alfa. The discussions confirmed that cerebrospinal fluid heparan sulfate (CSF HS) can be used as a surrogate endpoint likely to predict clinical benefit, supporting the accelerated approval process.

Denali plans to submit a biologics license application (BLA) in early 2025, incorporating preclinical and clinical data on biomarkers and safety. This milestone is considered a major step in the collective efforts of the patient community, academia, and industry to expedite the development of effective treatments for rare diseases like MPS II. Denali aims to convert the accelerated approval to full approval following the completion of their global Phase 2/3 COMPASS study.

New Phase 1/2 data will be presented at the upcoming SSIEM 2024 conference, showcasing robust and durable biomarker responses and positive clinical outcomes. Dr. Barbara Burton, a specialist in pediatrics, genetics, genomics, and metabolism, will present findings indicating significant improvements in key disease biomarkers and clinical endpoints. Data includes treatment effects observed in additional participants and over longer durations, with highlights such as a 90% mean reduction in CSF HS from baseline at Week 24 and sustained effects up to Week 104.

Participants also showed a marked increase in normal urine glycosaminoglycans (GAGs) from 5% at baseline to 77% at Week 24, with sustained results through Week 129. Serum neurofilament light (NfL) levels also significantly decreased, indicating reduced neuronal injury. Clinical outcomes showed improvements or stabilization in adaptive behavior, cognitive scores, hearing, liver volume, and growth. Tividenofusp alfa was generally well-tolerated, underlining its potential as a viable treatment for MPS II.

MPS II is a rare genetic disorder affecting over 2,000 individuals worldwide, predominantly males. The disease results from mutations in the iduronate-2-sulfatase (IDS) gene, leading to a deficiency in the enzyme responsible for breaking down certain glycosaminoglycans. This deficiency causes a buildup of GAGs in lysosomes, resulting in severe physical and neurocognitive symptoms. Current treatments partially address physical symptoms but fail to cross the blood-brain barrier (BBB), leaving cognitive and behavioral issues untreated.

Tividenofusp alfa is a fusion protein combining the IDS enzyme with Denali’s proprietary Enzyme Transport Vehicle (ETV), designed to cross the BBB and deliver IDS to the brain and other tissues. This innovative approach aims to address the full spectrum of MPS II symptoms. The FDA granted Fast Track designation to DNL310 in March 2021, and the European Medicines Agency followed suit with Priority Medicines designation in May 2022.

Denali is currently enrolling participants in their Phase 2/3 COMPASS study across multiple regions, including North America, South America, Europe, and Australia. This study aims to enroll 54 participants with and without neuronopathic disease, randomized to receive either tividenofusp alfa or idursulfase. The study includes children in two age cohorts to assess the treatment’s efficacy across different age groups.

Denali Therapeutics leverages its proprietary Transport Vehicle (TV) platform to overcome the challenges posed by the BBB, ensuring effective delivery of therapeutic molecules to the brain. This platform has demonstrated significantly improved brain exposure in preclinical models and is being validated through ongoing clinical programs. Denali’s broader portfolio targets neurodegenerative and lysosomal storage diseases, aiming to develop treatments that cross the BBB and demonstrate effectiveness through biomarker-guided development.