Denali Therapeutics Inc. announced new data presentations highlighting the broad potential of its BBB-crossing enzyme replacement therapies in development for the treatment of mucopolysaccharidoses (MPS). New clinical data on tividenofusp alfa (DNL310) in MPS II (Hunter syndrome) and mouse model data on DNL126 (ETV:SGSH) in MPS IIIA (Sanfilippo syndrome type A) are being presented this week at the 20th Annual WORLDSymposium? in San Diego, California.

In addition, new data on somatic outcomes from the same study of tividenofusp alfa will be presented for the first time by Barbara Burton, M.D., Professor of Pediatrics, Genetics, Genomics and Metabolism at Feinberg School of Medicine in Chicago. The Phase 1/2 results demonstrate normalization of enlarged liver and spleen volumes and maintenance of normal growth compared to healthy boys in almost all participants. New two-year peripheral biomarker data demonstrate high magnitude and sustained reduction of urine heparan sulfate and dermatan sulfate, including in participants who switched from standard-of-care enzyme replacement therapy to tividenofusp alfa, suggesting enhanced peripheral activity.

Tividenofusp alfa treatment continued to be generally well tolerated. New MPS IIIA mouse model data on DNL126 will also be presented at the conference showing improvements in lysosomal and microglial morphology, neurodegeneration, and cognitive function. Treatment with DNL126 resulted in lowered heparan sulfate accumulation in the brain and in cerebrospinal fluid and improved cognitive function in adult MPS IIIA mice.

A correlation between the levels of heparan sulfate and cognitive behavioral performance was observed. Denali also announced that dosing has begun in the Phase 1/2 study of DNL126 for the potential treatment of MPS IIIA. MPS II, also called Hunter syndrome, is a rare genetic disease that affects over 2,000 individuals, primarily males, world-wide, and leads to behavioral, cognitive, and physical symptoms ultimately resulting in shortened lifespan.

MPS II is caused by mutations in the iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of the IDS enzyme responsible for the breakdown of the glycosaminoglycans (GAGs) heparan and dermatan sulfate in lysosomes. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth leading to short stature, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of GAGs in lysosomes ?

the part of the cell that breaks down materials including GAGs. The current standard of care enzyme replacement therapy partially treats the physical symptoms but does not cross the BBB, and as a result, cognitive and behavioral symptoms experienced by the majority of patients with MPS II are not addressed. Therapies that address behavioral, cognitive, and physical manifestations of the disease are one of the greatest unmet needs for this community.

Tividenofusp alfa (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 and to enable broad delivery of IDS into cells and tissues throughout the body with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS II. In March 2021, the U.S. Food and Drug Administration granted Fast Track designation to DNL310 for the treatment of patients with MPS II. In May 2022, the European Medicines Agency granted DNL310 Priority Medicines designation.

DNL310 is an investigational product candidate and has not been approved by any Health Authority. Based on supportive clinical and preclinical data to date, Denali is enrolling the Phase 2/3 COMPASS study in North America, South America, and Europe. The Phase 2/3 COMPASS study is expected to enroll 54 participants with MPS II with and without neuronopathic disease.

The participants are randomized 2:1 to receive either tividenofusp alfa (DNL310) or idursulfase, respectively. Cohort A includes children ages 2 to 6 with neuronopathic disease; cohort B includes children ages 6 to 17 without neuronopathic disease. The Phase 2/3 COMPASS study is being conducted globally in North America, South America, and Europe.

Upon completion of the ongoing Phase 1/2 study, and together with data from the global COMPASS study, this combined data package is intended to support registration.