RARE Daily

Denali Reports Positive Interim Results for Experimental MPS II Therapy

June 20, 2023

Rare Daily Staff

Denali Therapeutics said interim results from the ongoing open-label, single-arm phase 1/2 study of DNL310 in children with the rare lysosomal storage disorder MPS II.

MPS II, also called Hunter syndrome, is a rare genetic disease that leads to behavioral, cognitive, and physical symptoms ultimately resulting in shortened lifespan. MPS II is caused by mutations in the iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of the IDS enzyme. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of glycosaminoglycans (GAGs) in lysosomes—the part of the cell that breaks down materials including GAGs. The current standard of care enzyme replacement therapy partially treats the physical symptoms but does not cross the blood-brain barrier, and as a result, cognitive and behavioral symptoms experienced by the majority of patients with MPS II are not addressed.

DNL310 is an experimental fusion protein composed of IDS fused to Denali’s proprietary ETV, which is engineered to cross the blood-brain barrier via receptor-mediated transcytosis into the brain. Preclinical studies demonstrate that DNL310 delivers IDS to lysosomes, where it is needed to break down GAGs. DNL310 is engineered for broad delivery of IDS into cells and tissues throughout the body, including the brain with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS II.

The U.S. Food and Drug Administration granted Fast Track designation to DNL310 for the treatment of patients with MPS II. In May 2022, the European Medicines Agency granted DNL310 Priority Medicines designation.

Among the 13 participants who reached two years of treatment at the time of the interim analysis, a mean reduction of 64 percent from baseline in serum neurofilament light (NfL) was observed. NfL is a protein that is released by neurons following axonal injury. The U.S. Food and Drug Administration recently recommended to Denali the assessment of NfL as an exploratory endpoint to assess its potential as a possible biomarker to assess diagnostic, prognostic, or therapeutic response in subjects with neuronopathic MPS II.

Denali was the first to publish research on biomarkers downstream of heparan sulfate, including biomarkers of lysosomal and neuronal health, in MPS II and has continued to explore biomarkers in the DNL310 clinical development program.

“The robust reduction and normalization of CSF heparan sulfate, and now the downstream reduction in NfL after treatment, are consistent with positive changes in clinical outcomes measures we have observed from interim analyses of the ongoing phase 1/2 study,” said Carole Ho, chief medical officer at Denali.

Photo: Carole Ho, chief medical officer at Denali

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