Denali Therapeutics Announces New Interim Data from Phase 1/2 Study of DNL310 (ETV

IDS) in MPS II (Hunter Syndrome) at SSIEM 2023 - Seite 2

The interim Phase 1/2 data presented at SSIEM included new biomarker and safety data from additional participants receiving up to two years of treatment with DNL310 as well as previously presented clinical outcomes data for participants receiving one year of treatment. A summary of key results includes:

• Achievement of normal levels of CSF heparan sulfate, sustained over time, including in participants with high pre-existing anti-drug antibodies
• Sustained normal levels of CSF lysosomal lipids in most participants consistent with improved lysosomal function
• Robust reduction in serum neurofilament light (NfL), a marker of neuronal damage, reached statistical significance after 61 weeks and a 64% reduction after two years of treatment with DNL310
• Improvements in mean cognitive Bayley Scales of Infant and Toddler Development III (BSID-III) and Vineland Adaptive Behavior Scales II (VABS-II) raw scores, and auditory brainstem response (ABR) thresholds at week 49 of DNL310 treatment, suggest positive effects on cognition, adaptive behavior, and hearing
• DNL310 continues to be generally well tolerated
• The interim safety profile, clinical outcomes data, and biomarker effects, including normalization of CSF heparan sulfate and reduction in NfL, continue to support development of DNL310 in MPS II

"We are excited to share sustained effects on key disease biomarkers in MPS II with DNL310 treatment, now out to two years," said Carole Ho, MD, Chief Medical Officer of Denali. "Importantly, the robust reduction in serum levels of NfL suggests improvement in neuronal health, which is not addressed by current enzyme replacement therapies. We are encouraged to see positive changes across multiple clinical outcomes measures in the ongoing Phase 1/2 study. We look forward to continued partnership with the MPS community as we enroll the global Phase 2/3 COMPASS study in MPS II and plan for expanding the enzyme transport vehicle, including initiating clinical studies in other lysosomal storage diseases."

About MPS II (Hunter syndrome)

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. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of glycosaminoglycans (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 blood-brain barrier, 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.