Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 115

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 115
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 "on or off", the loss of reticulocytes (immature red blood cells) can be avoided, potentially limiting anemia, which is a known liability associated with targeting the transferrin receptor. Further, as the BBB receptor binding site is a short amino acid sequence integrated into the Fc, the TV maintains high fidelity to the natural protein and does not require appended sequences, thereby limiting risk of immunogenicity and infusion-related reactions ("IRRs"). In addition, Fc engineering enables modularity for the broadest utility to transport biologics including enzymes, oligonucleotides, and antibodies. 

Figure 2: Denali’s TV technology is modular and highly differentiated.

Our pipeline of TV-enabled programs currently includes three clinical-stage programs and more than ten programs in preclinical development. We achieved proof of concept with safety and pharmacokinetic and pharmacodynamic data from Phase 1/2 clinical studies in patients and healthy volunteers, as well as data from several preclinical studies in mouse and nonhuman primate models. Preclinical studies demonstrated robust and sustained pharmacodynamic effects in the brain after intravenous dosing of TV-enabled antibodies, enzymes, proteins, and oligonucleotides, while standard antibodies, enzymes, proteins and oligonucleotides had no or minimal pharmacodynamic effects. These data show that TV-enabled product candidates have the potential to achieve therapeutically relevant concentrations in the brain after systemic administration, making them potentially superior to traditional biologic therapeutics in targeting neurodegenerative diseases.

Our most advanced TV-enabled program is tividenofusp alfa (ETV:IDS) for which we plan to submit a BLA for the treatment of MPS II using the FDA's accelerated approval pathway in early 2025 and, pending approval, launch in late 2025 or early 2026. In addition, we will seek alignment with the FDA on an accelerated approval path for our second ETV clinical program, DNL126 (ETV:SGSH) for the treatment of MPS IIIA. Together, we expect these two programs to be the foundation of a broad franchise of TV-enabled enzyme replacement therapies for lysosomal storage diseases (Figure 3), which affect more than 30,000 people worldwide.

10

Current standard-of-care enzyme replacement therapy does not cross the BBB and therefore does not address debilitating and progressive CNS degeneration present in about two thirds of lysosomal storage diseases. In addition to enabling brain delivery of enzymes, ETV may enhance therapeutic enzyme delivery to peripheral organs and tissues through