Denali Therapeutics Plans Accelerated Approval Filing for Tividenofusp Alfa in MPS II
核心洞察
Denali Therapeutics plans to submit a Biologics License Application (BLA) to the FDA in early 2025 for tividenofusp alfa (DNL310) to treat Mucopolysaccharidosis type II (MPS II (搜索)).
The FDA has indicated that cerebrospinal fluid heparan sulfate (CSF HS (搜索)) can serve as a surrogate biomarker to support accelerated approval of tividenofusp alfa in MPS II (搜索).
Phase 1/2 data presented at SSIEM 2024 showed a 90% mean reduction in CSF HS (搜索) and improvements in clinical outcomes with tividenofusp alfa treatment in MPS II (搜索) patients.
Denali Therapeutics is set to file for accelerated approval of tividenofusp alfa (DNL310) for the treatment of Mucopolysaccharidosis type II (MPS II (搜索)), also known as Hunter syndrome (搜索). This decision follows a successful meeting with the FDA's Center for Drug Evaluation and Research (CDER), where an agreement was reached regarding the use of cerebrospinal fluid heparan sulfate (CSF HS (搜索)) as a surrogate biomarker to predict clinical benefit. The company plans to submit a biologics license application (BLA) in early 2025 under the accelerated approval pathway.
Tividenofusp alfa is a fusion protein designed to cross the blood-brain barrier (BBB) using Denali’s Enzyme Transport Vehicle (ETV) technology. It aims to deliver iduronate-2-sulfatase (IDS) into the brain to address the cognitive and behavioral symptoms of MPS II (搜索), which current enzyme replacement therapies cannot effectively target due to their inability to cross the BBB.
Phase 1/2 Data Highlights
Interim data from the Phase 1/2 study, presented at the Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM 2024), showcased the potential of tividenofusp alfa. The study included 37 participants and evaluated treatment duration up to 129 weeks. Key findings include:
- CSF HS Reduction: A 90% mean reduction in CSF HS from baseline at Week 24, with most participants achieving normal or near-normal levels, sustained through Week 104.
- Urine GAGs Normalization: The proportion of participants with normal total urine glycosaminoglycans (GAGs) increased from 5% at baseline to 77% at Week 24, sustained through Week 129.
- Serum NfL Reduction: Significant and sustained reduction of serum neurofilament light (NfL) from baseline, suggesting reduced neuronal injury.
- Clinical Improvements: Improvement or stabilization in adaptive behavior and cognitive scores, hearing, liver volume, and growth outcomes.
- Safety Profile: Tividenofusp alfa was generally well-tolerated.
COMPASS Study and Future Plans
Denali is currently enrolling patients in the Phase 2/3 COMPASS study, a global trial assessing tividenofusp alfa against idursulfase. The study aims to enroll 54 participants with MPS II (搜索), both with and without neuronopathic disease. According to clinicaltrials.gov, the study is expected to complete in 2025. Full approval of tividenofusp alfa is contingent upon the completion of the COMPASS study.
Expert Commentary
"The Phase 1/2 data show that treatment with tividenofusp alfa produces robust and durable effects, with normalization of key disease biomarkers and improvement or stabilization in associated CNS and somatic clinical endpoints," said Barbara Burton, MD, Professor of Pediatrics, Genetics, Genomics and Metabolism at Feinberg School of Medicine in Chicago. "The totality of data support Denali's plans to file for accelerated approval of tividenofusp alfa with the potential to address a critical unmet need for CNS-penetrant therapies in MPS II (搜索)."
Carole Ho, MD, Chief Medical Officer of Denali, stated, "We thank CDER for a positive and collaborative discussion and their guidance on CSF HS (搜索) as a surrogate biomarker, which we see as a significant step towards accelerating development of medicines for individuals and families living with MPS II (搜索)."