RARE Daily

Denali Reports Positive Early Data from Phase 1/2 Study in Hunter Syndrome

February 12, 2021

Rare Daily Staff

Denali Therapeutics reported positive interim results from its ongoing phase 1/2 study evaluating ETV:IDS (DNL310) as a potential brain-penetrant enzyme replacement therapy for treating the rare neurodegenerative condition Hunter syndrome.

Hunter syndrome is a lysosomal storage disorder caused by a mutation in the gene that encodes for the enzyme iduronate-2-sulfatase (IDS). The reduction or loss of IDS enzyme activity leads to accumulation of metabolic waste in cells, 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.

DNL310 is a fusion protein composed of IDS fused to Denali’s proprietary Enzyme Transport Vehicle (ETV), which is engineered to cross the blood-brain barrier into the brain. Denali previously announced human biomarker proof-of-concept for its TV technology from a five-patient Cohort A of an ongoing phase 1/2 study of DNL310 in patients with Hunter syndrome. The study is currently enrolling Cohort B, and a Cohort C is planned to further explore clinical endpoints. DNL310 is an investigational drug and is not approved by any health authority.

An interim analysis included data on a total of 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 Day 1 of the study. The data showed normal levels of heparan sulfate, a glycosaminoglycan (GAG), in cerebrospinal fluid that were seen after four weeks of dosing in four of five patients and were sustained after three months of dosing. It also showed heparan sulfate levels were significantly reduced and approached normal levels in the fifth patient (from 25 percent to 73 percent reduction from one to three months).

Reductions in downstream exploratory cerebrospinal fluid biomarkers, GM3 (39 percent) and lysosomal lipids (15 percent) were observed after eight weeks of dosing with DNL310, consistent with improvement in lysosomal function.

Reductions in urine heparan sulfate (76 percent) and dermatan sulfate (82 percent) following a switch from idursulfase were observed after eight weeks of dosing of DNL310, supporting potential for improved peripheral effects relative to standard of care.

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. 

“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,” said Ryan Watts, Denali’s CEO. “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.”

Photo: Ryan Watts, Denali’s CEO

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