Denali Therapeutics Reports Positive Three-Month Data from Phase 1/2 Study with ETV

IDS (DNL310) in Patients with Hunter Syndrome (MPS II) - Seite 3

About the DNL310 Development Program for the Potential Treatment of Hunter syndrome (MPS II)
Hunter syndrome (MPS II) is a rare neurodegenerative lysosomal storage disorder caused by a mutation 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 GAGs, 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 BBB. DNL310 is a 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. Denali previously announced human biomarker proof-of-concept for its TV technology from Cohort A (n=5) 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.

About Denali’s TV Platform 
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 TV 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. The TV technology is based on engineered Fc fragments that bind to specific natural transport receptors, such as transferrin receptor, which are expressed at the BBB and are delivered to the brain through receptor-mediated transcytosis. Denali research has shown that in animal models, antibodies and enzymes engineered with the TV technology have demonstrated more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Improved exposure and broad distribution in the brain may increase therapeutic efficacy by enabling widespread achievement of therapeutically relevant concentrations of product candidates. ETV:IDS (DNL310) is Denali’s lead TV-enabled program in Phase 1/2 development for the potential treatment of Hunter syndrome (MPS II).