SOUTH SAN FRANCISCO, Calif.—Denali Therapeutics Inc. has reported some positive interim results from the company’s ongoing Phase 1/2 study evaluating ETV:IDS (DNL310) as a potential brain-penetrant enzyme replacement therapy for treating both central nervous system (CNS) and peripheral manifestations of Hunter syndrome (MPS II). The data was presented today during a late-breaker session at WORLDSymposium.
An interim analysis included data on five patients enrolled in Cohort A in the Phase 1/2 study, who all received three months of weekly intravenous doses of DNL310 after switching from idursulfase enzyme replacement therapy on study Day 1. The normal levels of heparan sulfate — a glycosaminoglycan (GAG) — in cerebrospinal fluid (CSF) that were seen after four weeks of dosing in four of five patients were sustained after three months of dosing (mean 85% reduction across Cohort A; p<0.001). Heparan sulfate levels were further reduced, and approached normal levels in the fifth patient (from 25% to 73% reduction from one to three months, respectively).
Reductions in downstream exploratory CSF biomarkers, GM3 and BMP (lysosomal lipids) — of 39% and 15%, respectively — were observed after eight weeks of dosing with DNL310, consistent with improvement in lysosomal function. Reductions in urine heparan sulfate and dermatan sulfate (of 76% and 82%, respectively), following a switch from idursulfase, were observed after eight weeks of dosing of DNL310. These results support the potential for improved peripheral effects, relative to the standard of care.
“We are encouraged by these new Phase 1/2 data, which continue to support the overall safety profile and biomarker effects of DNL310 as an investigational treatment in Hunter syndrome,” said Dr. Carole Ho, chief medical officer of Denali. “Importantly, at dose levels resulting in robust and durable biomarker response, DNL310 appears generally well tolerated and consistent with standard of care ERT.
“We are pleased to observe that early biomarker effects initially seen after four weeks of treatment with DNL310 were sustained after three months of dosing. We are also encouraged by the findings related to exploratory lipid biomarkers which indicate, for the first time, improvement in lysosomal function,” Ho continued. “Taken together, these data support our previously announced decision to expand and advance clinical studies with DNL310 as a potential treatment for both body and brain in patients with Hunter syndrome.”
DNL310 was generally well tolerated with no dose reductions, and all five patients continue in the study. The most frequently observed adverse events were mild or moderate infusion-related reactions in three of five patients, which is consistent with other enzyme replacement therapies. Based on three-month clinical data, doses of DNL310 ranging from 3 mg/kg to 30 mg/kg are generally well tolerated, and this will provide flexibility for dose selection in clinical studies.
Denali also presented preclinical research at WORLDSymposium on a mouse model of Hunter syndrome showing that DNL310 treatment reduces CSF GAGs, and that these reductions are correlated with GAG reductions in the brain. Reduction in CSF GAG levels was associated with subsequent improvements in lysosomal function, neurodegeneration biomarkers, neurobehavioral outcomes, and correction of skeletal disease manifestations in the mouse model.
“The magnitude and durability of biomarker response and tolerability seen with DNL310 provide strong support for the potential application of our Transport Vehicle (TV) technology to deliver enzymes and other therapeutic modalities to the brain,” added Dr. Ryan Watts, CEO of Denali. “Compared to other investigational BBB transport technologies, we have engineered specific molecular properties into our TV technology for better brain uptake and biodistribution of the therapeutic cargo to relevant cell types.”
“The DNL310 Phase 1/2 results also support the potential for systemic administration of TV-enabled therapeutics to address peripheral disease. Taken together, these data increase our confidence that DNL310 may ultimately prove to be an impactful therapy for Hunter syndrome patients and their families and that we can apply our TV technology more broadly to defeat degeneration and address other diseases with brain manifestations,” Watts concluded.