Denali Therapeutics (DNLI) investor relations material

FDA Approval and Clinical Significance

• AVLAYAH received accelerated FDA approval as the first enzyme replacement therapy designed to cross the blood-brain barrier for Hunter syndrome, addressing both systemic and neurological disease manifestations in pediatric patients prior to advanced impairment.

• Approval is based on a 91% mean reduction and normalization of cerebrospinal fluid heparan sulfate, a key biomarker, with robust clinical data from phase I/II studies.

• AVLAYAH is the first FDA-approved therapy leveraging transferrin receptor-mediated delivery to cross the blood-brain barrier, utilizing a proprietary TransportVehicle platform.

• The approval sets a regulatory precedent for future therapies targeting lysosomal storage disorders and validates the TransportVehicle platform.

• A Rare Pediatric Disease Priority Review Voucher was awarded in connection with approval.

Clinical Data and Study Results

• Phase I/II studies included 47 pediatric patients, both ERT-naïve and previously treated, aged 0.3–13 years, showing normalization of CNS and peripheral biomarkers over a median of 2 years.

• 91–93% of treated patients achieved CSF heparan sulfate levels within the normal range by week 24, with improvements in urine GAGs.

• Functional outcomes included improvements in adaptive behavior, cognitive skills, and hearing thresholds.

• The most common adverse events were infusion-related reactions, mostly mild to moderate, with other side effects including anemia, membranous nephropathy, and infections.

• The COMPASS Phase II/III confirmatory study is ongoing, designed as a head-to-head trial versus standard ERT, to support full approval and label expansion.

Mechanism of Action and Platform Technology

• AVLAYAH consists of the IDS enzyme fused to a proprietary TransportVehicle platform, enabling delivery across the blood-brain barrier via transferrin receptor binding.

• The platform allows for widespread distribution of therapeutic molecules in the brain and peripheral tissues, with significantly increased brain exposure in preclinical models.

• AVLAYAH is administered intravenously once weekly.

• Five TransportVehicle-enabled programs are currently in clinical development.

• The approval establishes a foundation for a lysosomal storage disorder franchise and supports future pipeline expansion.