Denali Therapeutics (DNLI) Study update summary

Enzyme transport vehicle program highlights

• Presented new data on tividenofusp alfa (TIVI), DNL126, and ETV-GAA at the WORLD Symposium, focusing on enzyme transport vehicle programs for rare lysosomal storage diseases.

• The Enzyme TransportVehicle platform leverages transferrin receptor-mediated delivery to enable brain and systemic biodistribution of biotherapeutics, supporting a pipeline of next-generation enzyme replacement therapies for serious genetic diseases.

• Data and plans presented at the 2026 WORLD Symposium reflect strong momentum and launch readiness for upcoming regulatory milestones.

• The proprietary TransportVehicle platform enables effective delivery of large therapeutic molecules across the blood-brain barrier, with clinical validation in multiple programs.

• The enzyme transport vehicle platform is being considered for expansion to other lysosomal storage diseases, leveraging its ability to target both CNS and peripheral tissues.

Clinical outcomes and biomarker insights

• TIVI phase 1/2 study in Hunter syndrome showed sustained reductions in CNS and peripheral biomarkers, normalization of CSF and urine heparan sulfate, improvements in cognition, behavior, hearing, and somatic symptoms, with a stable safety profile over long-term follow-up.

• DNL126 phase 1/2 study in MPS IIIA demonstrated an 80% mean reduction in CSF heparan sulfate, normalization of other biomarkers, improvement in mild hepatomegaly, and manageable safety with decreased infusion-related reactions over time.

• ETV-GAA (DNL952) preclinical data in Pompe disease mouse models showed superior reduction of glycogen accumulation in muscle and nervous system compared to standard of care, supporting advancement to clinical studies.

• Infusion-related reactions were the most common adverse event across programs but were generally mild, manageable, and decreased with optimized dosing regimens.

• No treatment-related serious TEAEs, deaths, or discontinuations were reported in DNL126 studies.

Study design and future directions

• TIVI phase 1/2 and COMPASS trials include a broad age range, with complementary data from very young patients in E2 and older patients in COMPASS, supporting global regulatory submissions.

• DNL126 efficacy cohorts use optimized slow dose escalation and weekly dosing, aiming for robust biomarker response and improved tolerability.

• Phase 3 design for DNL126 will use a baseline comparator rather than placebo, with a focus on rapid and efficient development; global confirmatory study planning is ongoing.

• Phase 1 clinical study of DNL952 (ETV-GAA) in late-onset Pompe disease is ongoing, with primary focus on safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic markers; data will inform dose selection for future trials.

• Results support continued evaluation of DNL126 in ongoing efficacy cohorts and the platform's expansion to other lysosomal storage diseases.