|Denali Therapeutics Announces Positive Interim Data from Phase 1/2 Study with ETV:IDS (DNL310) in Patients with the Lysosomal Storage Disease Hunter Syndrome (MPS II)|
|By: GlobenewsWire - 25 Jul 2021||Back to overview list
SOUTH SAN FRANCISCO, Calif., July 25, 2021 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases, today announced additional positive interim data from a Phase 1/2 study evaluating ETV:IDS (DNL310), an investigational brain-penetrant enzyme replacement therapy intended to treat both central nervous system (CNS) and peripheral manifestations of Hunter syndrome (MPS II). The interim results being presented today at MPS 2021, the 16th International Symposium on MPS and Related Diseases, include safety data up to Weeks 43 and 25 from Cohorts A and B, respectively, 6-month biomarker data from Cohort A and up to 3-month biomarker data from Cohort B. Denali Management will host a webinar today for analysts and investors beginning at approximately 11:30 a.m. Eastern Time.
“The longer-term safety data and 6-month biomarker data on DNL310 from Cohort A continue to demonstrate durability of effect with CNS impact, improved peripheral activity after switching from standard of care, and a safety profile consistent with standard of care enzyme replacement therapy,” said Carole Ho, M.D., Denali’s Chief Medical Officer. “We are also encouraged by initial indications of improved clinical symptoms and function reported by investigators and parents in all five patients enrolled in Cohort A. In addition, this is the first time we are sharing data from Cohort B, which is designed to inform dose selection, and exploratory biomarker data demonstrate activity of DNL310 across all dose regimens. Based on these data, we are accelerating our efforts to initiate a pivotal Phase 2/3 study of DNL310 in the first half of 2022 and to begin enrolling Cohort C in the Phase 1/2 study to further investigate clinical endpoints.”
This interim analysis of the Phase 1/2 study included data on five patients enrolled in Cohort A and 12 patients enrolled in Cohort B. All patients have neuronopathic MPS II disease except for one patient with non-neuronopathic MPS II disease in Cohort B. The median age of patients is 6 years in both cohorts, with the youngest patients aged 5 and 2 in Cohorts A and B, respectively. All patients received weekly intravenous doses of DNL310 after switching from idursulfase enzyme replacement therapy on Day 1 of the study. Data being presented include safety data up to Weeks 43 and 25 from Cohorts A and B, respectively; 6-month and up to 3-month biomarker data from Cohorts A and B, respectively; and exploratory clinical Global Impression of Change data from Cohort A up to Week 24.
Results across Cohorts A and B showed that, following the switch from idursulfase to DNL310, the levels of heparan sulfate in cerebrospinal fluid (CSF) normalized in all patients analyzed (n=15), with rapid response observed in most patients (n=12) by Week 7, which is consistent with crossing of the BBB by DNL310 and activity in tissues of the CNS. Rapid normalization of CSF heparan sulfate at low dose regimens suggest that BBB crossing with Denali’s Transport Vehicle (TV) was robust and efficient. Furthermore, the observed decline in urine and serum heparan sulfate was consistent with improved peripheral activity with DNL310.
Exploratory clinical data suggest improved clinical symptoms and function for all five patients enrolled in Cohort A as reported by investigators and parents. Based on Global Impression of Change scales [Clinician Global Impression of Change (CGI-C) and Parent Global Impression of Change (PGI-C)], which are standardized assessment scales used to measure change, the data showed clinical improvement in overall MPS II symptoms, cognitive abilities, behavior, and physical abilities.
Exploratory lysosomal lipid data showed reductions, which are consistent with improved lysosomal function: 10 of 15 patients across Cohorts A and B had normal GM3 ganglioside levels, including patients on low dose regimens and with shorter duration of treatment. In addition, reductions in levels of bis(monoacyl glycerol)-phosphate (BMP) and a potential reduction in levels of glucosylceramide (GlcCer) were observed in Cohort A at Week 24.
High within patient variability in levels of neurofilament (Nf-L), an exploratory biomarker of neuronal structure, was observed pre- and post-treatment. Data from an ongoing observational natural history study conducted by Denali showed a marked increase in mean levels of serum Nf-L over a 4.5- to 6-month period in patients (n=3) who subsequently enrolled in Cohort A of the Phase 1/2 study. During the 6-month treatment period of the Phase 1/2 study, mean levels of serum and CSF Nf-L in Cohort A (n=5) showed a modest increase. Denali believes that the utility of Nf-L as a treatment response biomarker in MPS II will require further investigation.
The safety profile of DNL310 remained consistent with standard of care enzyme replacement therapy. DNL310 was generally well tolerated with the most common treatment-emergent adverse events being infusion-related reactions (IRRs). IRRs occurred in 12 of 17 (71%) patients: the majority had mild (n=5) or moderate (n=6) IRRs, and 1 patient had severe IRRs. A total of 3 serious adverse events (SAEs) were reported: 1 previously reported SAE for a patient enrolled in Cohort A based on a mild IRR, and 2 SAEs in a patient enrolled in Cohort B based on severe IRRs. The SAEs resolved, and both patients are continuing in the study. All other treatment-emergent adverse events were mild or moderate.
The study continues without modification following recommendation by an independent data monitoring committee on July 9, 2021.
“DNL310 is our lead program enabled by our blood-brain barrier Transport Vehicle platform, and these data continue to validate the platform’s potential as we advance additional TV-enabled programs toward the clinic,” said Ryan Watts, Ph.D., Denali’s Chief Executive Officer. “Our DNL310 program exemplifies application of Denali’s core scientific principles to increase likelihood of success by targeting degenogenes, engineering therapeutics to cross the blood-brain barrier, and using biomarkers to inform development. We are encouraged by these interim data and we look forward to continued collaboration with the community to advance MPS II research and DNL310 as a potential treatment for affected individuals and their families.”
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.
Denali Webinar for Analysts and Investors
About DNL310 and Hunter Syndrome (MPS II)
About Denali’s TV Platform
About the EngageHunter.com Website
About Denali Therapeutics
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