Rare Daily Staff
Denali Therapeutics reported positive interim data from a phase 1/2 study evaluating its experimental therapy DNL310, a brain-penetrant enzyme replacement therapy intended to treat both central nervous system and peripheral manifestations of the lysosomal storage disorder Hunter syndrome.
The interim results are being presented at MPS 2021, the 16th International Symposium on MPS and Related Diseases.
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 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, which is engineered to cross the BBB via receptor-mediated transcytosis into the brain.
The BBB is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the BBB has posed significant challenges to drug development for CNS diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali’s Transport Vehicle platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the BBB after intravenous administration.
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; six-month and up to three-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, with rapid response observed in most patients 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 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 and Parent Global Impression of Change, 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 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 four-and-a-half- to six-month period in patients who subsequently enrolled in Cohort A of the phase 1/2 study. During the six-month treatment period of the phase 1/2 study, mean levels of serum and CSF Nf-L in Cohort A 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. Infusion-related reactions occurred in 12 of 17 patients: the majority had mild or moderate infusion-related reactions, and one patient had severe infusion-related reactions. A total of three serious adverse events were reported: one previously reported serious adverse event for a patient enrolled in Cohort A based on a mild IRR, and 2 serious adverse events in a patient enrolled in Cohort B based on severe infusion-related reactions. 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.
“The longer-term safety data and six-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, 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.”
Ho added that it is the first time the company is 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, the company said it is accelerating its 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.
Photo: Carole Ho, Denali’s chief medical officer