Denali Announces Fast Track Designation to DNL310 for Hunter Syndrome

Denali Therapeutics announced the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to ETV:IDS (DNL310) for the treatment of patients with Hunter syndrome (MPS II). DNL310, Denali’s lead investigational brain-penetrant enzyme replacement therapy, is under evaluation in a Phase 1/2 study in patients with Hunter syndrome as a potential treatment for both central nervous system (CNS) and peripheral manifestations of the disease.

“Hunter syndrome is a devastating disease for which current approved treatments fail to effectively cross the blood-brain barrier and therefore do not address CNS symptoms,” said Carole Ho, M.D., Denali’s Chief Medical Officer. “Using Denali’s Transport Vehicle technology, we have designed DNL310 to treat both body and brain in Hunter syndrome after intravenous administration. Receiving Fast Track designation is an important milestone in the DNL310 development program, and we look forward to our continued collaboration with the FDA to bring safe and effective treatments to patients with Hunter syndrome.”

Fast Track is an FDA process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Denali expects that Fast Track designation may allow for early and frequent communication with the FDA regarding the development of DNL310 for the treatment of Hunter syndrome. This designation also enables rolling review, and potentially priority review, of the marketing application.

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 glycosaminoglycans (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 (ClinicalTrials.gov Identifier: NCT04251026). 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.

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 deliver TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the TV technology demonstrate 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).