Denali Therapeutics Inc. announced new interim results from the ongoing open-label, single-arm Phase 1/2 study of DNL310 (ETV:IDS) in children with MPS II (Hunter syndrome). Among the 13 participants who reached two years of treatment at the time of the interim analysis, a mean reduction of 64% (p<0.001) from baseline in serum neurofilament light (NfL) was observed. The U.S. Food and Drug Administration (FDA) 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.

DNL310 is an investigational brain-penetrant enzyme replacement therapy designed to address the behavioral, cognitive, and physical manifestations of MPS II. The global Phase 2/3 COMPASS study is ongoing. Denali was the first to publish research on biomarkers downstream of heparan sulfate, including biomarkers of lysosomal and neuronal health, in MPS II1 and has continued to explore biomarkers in the DNL310 clinical development program.

Additional interim data from the Phase 1/2 study of DNL310 will be highlighted in an oral presentation at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2023 in Jerusalem, Israel, August 29 – September 1, 2023. Webinar for analysts and investors at 8:30 a.m. Eastern Time. Denali will host a webinar for analysts and investors to present the interim NfL data from the Phase 1/2 study of DNL310.

The webinar will begin at approximately 8:30 a.m. Eastern Time on Tuesday, June 20, 2023, and will be available on Denali’s corporate website on the Events page under the Investor & Media Relations section. DNL310 is an investigational 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. In March 2021, 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.

Denali most recently reported interim Phase 1/2 results demonstrating positive changes across measures of exploratory clinical outcomes including VABS-II (adaptive behavior) and BSID-III (cognitive capabilities) scores and global impression scales over 49 weeks of treatment with DNL310. In addition, the interim data also suggested that DNL310 improved hearing, as assessed by auditory brainstem response testing. Additional biomarker data out to 49 weeks continued to demonstrate that DNL310 enabled rapid and sustained normalization of CSF heparan sulfate to normal healthy levels and improvement in lysosomal function biomarkers.

Reduction in urine heparan sulfate and dermatan sulfate after switch from standard of care to DNL310 suggested additional sustained peripheral activity of DNL310. The safety profile of DNL310, with up to two years of treatment, remained consistent with standard of care. Based on supportive clinical and preclinical data to date, Denali is conducting the Phase 2/3 COMPASS study, which is expected to enroll 54 participants with MPS II with and without neuronopathic disease.

The participants will be randomized 2:1 to receive either DNL310 or idursulfase, respectively. Cohort A will include children ages 2 to 6 with neuronopathic disease; cohort B will include children ages 6 to 17 without neuronopathic disease. The Phase 2/3 COMPASS study is being conducted globally in North America, South America, and Europe.

Upon completion of the ongoing Phase 1/2 study, and together with data from the global COMPASS study, this combined data package is intended to support registration. Families interested in learning more about Denali’s efforts related to the discovery and development of therapeutics for the potential treatment of Hunter syndrome are invited to visit EngageHunter.com, the Denali Hunter syndrome community engagement website, an online destination for information on Denali’s scientific approach in Hunter syndrome research and Denali’s clinical trials. DNL310 is an investigational product candidate and has not been approved by any health authority.