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Denali Reports Continued Progress in DNL310 Program for Hunter Syndrome

February 10, 2022

Denali Therapeutics, a biotech developing a portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases, reported new longer-term data from an ongoing phase 1/2 clinical trial of DNL310, an experimental brain-penetrant enzyme replacement therapy intended to treat both central nervous system and peripheral manifestations of MPS II, also called Hunter syndrome.   

Photo: Carole Ho, chief medical officer at Denali

Hunter syndrome (MPS II) is a rare neurodegenerative lysosomal storage disease caused by mutations in the gene that encodes for the enzyme iduronate-2-sulfatase (IDS). The resultant reduction or loss of IDS enzyme activity leads to accumulation of glycosaminoglycans, which causes lysosomal dysfunction and neurodegeneration as well as progressive damage to multiple organs including bone, cartilage, heart and lung. Current standard-of-care enzyme replacement treatment only partially improves the peripheral manifestations of MPS II and does not address neuronopathic manifestations of the disease as it does not sufficiently cross the blood-brain barrier (BBB). DNL310 is an investigational fusion protein composed of IDS fused to Denali’s proprietary Enzyme Transport Vehicle (ETV), which is engineered to cross the BBB via receptor-mediated transcytosis into the brain.

“The longer-term phase 1/2 data, now up to approximately one year for Cohort A and six months for Cohort B, support DNL310 as a differentiated enzyme replacement therapy that rapidly normalizes CSF heparan sulfate and maintains improvement in CSF biomarkers of lysosomal function with weekly intravenous dosing,” said Carole Ho, chief medical officer at Denali. “With additional patient data now available, we are also encouraged that we continue to see improvements in exploratory clinical outcomes in the majority of individuals as assessed after six months of open label DNL310 treatment.”

The phase 1/2 study data, presented at WORLDSymposium, include longer-term biomarker data up to Weeks 49 and 24 from Cohort A and B, respectively; clinical outcomes data across Cohorts A and B at Week 24; and safety data up to Weeks 56 and 39 from Cohorts A and B, respectively. 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 in Cohort A and 2 in Cohort B. All patients received weekly intravenous doses of DNL310 on Day 1 of the study after switching from idursulfase enzyme replacement therapy. The main differences between the cohorts include exploration of different dose levels and age groups, with younger patients eligible for Cohort B.

Across Cohorts A and B, all patients had normalized levels of heparan sulfate in cerebrospinal fluid (CSF) by Week 24 of treatment with DNL310, which were sustained in all 5 patients from Cohort A at Week 49. Rapid response was observed in most patients after 4 to 6 weekly intravenous doses of DNL310, including in patients on lower dose regimens of DNL310. These results are consistent with robust and efficient crossing of the BBB by DNL310 and durable activity in the CNS. Furthermore, the observed decline in urine heparan and dermatan sulfate, as well as CSF dermatan sulfate, was consistent with increased peripheral and central activity with DNL310 compared to standard-of-care, respectively.

Exploratory CSF lysosomal lipid biomarker data showed further reductions with longer duration of treatment with DNL310, consistent with improved lysosomal function. Across Cohorts A and B, CSF GM3 ganglioside levels decreased from baseline, with normalized CSF GM3 ganglioside levels apparent in all 5 patients in Cohort A at Week 49, and in 9 of 12 patients in Cohort B at Week 24 (3 of 15 total patients in Cohort B had not reached Week 24 at the time of the data cut in September 2021). In addition, available preliminary exploratory data on other biomarkers of lysosomal function demonstrated reductions in levels of glucosylceramide (GlcCer) across Cohorts A and B at Week 24 and reductions in levels of other lysosomal lipid biomarkers including bis(monoacycerol)-phosphate (BMP), GM2 and glucosylsphingosine in Cohort A at 24 weeks.

Exploratory clinical outcomes data at Week 24 from Cohort A, and now including Cohort B (3 of 15 total patients had not reached Week 24 at the time of the data cut in September 2021), suggest improved clinical symptoms and function in the majority of patients as reported by investigators and parents/caregivers. Based on Global Impression of Change scales [Clinician Global Impression of Change (CGI-C) and Parent/Caregiver Global Impression of Change (PGI-C)], which are standardized assessment scales used to measure change and modified to measure specific domains impacted by MPSII, the data showed clinical improvement in overall MPS II symptoms, cognitive abilities, and behavior from baseline.

The safety profile of DNL310, which now includes data up to Weeks 56 and 39 from Cohorts A and B, respectively, remains 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 15 of 20 patients: the majority had mild or moderate IRRs, and 1 patient had severe IRRs. Most IRRs occurred during the first 12 study weeks; IRR frequency decreased with chronic dosing, including in patients who dose escalated up to 30 mg/kg.

A total of four serious adverse events (SAEs) were reported: 1 previously reported SAE for a patient enrolled in Cohort A based on a mild IRR; 2 previously reported SAEs in a patient enrolled in Cohort B based on severe IRRs; and 1 SAE in a patient in Cohort B hospitalized for constipation. The SAEs resolved, and all three patients are continuing in the study. The study is continuing without modification following recommendation by an independent data monitoring committee in October 2021.

Based on the strength of the clinical and preclinical data to date, Denali plans to initiate a potentially registrational phase 2/3 trial with DNL310 with the goal of demonstrating efficacy and safety in participants with neuronopathic and non-neuronopathic MPS II. Dosing is expected to begin in the Phase 2/3 trial in the first half of 2022.

Author: Rare Daily Staff

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