Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 116

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 116
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 the same receptor mediated transcytosis pathway utilizing TfR. In fact, in the open-label Phase 1/2 study, we have observed that treatment with tividenofusp alfa is associated with further reductions in levels of urine heparan sulfate (a key biomarker used clinically to monitor treatment effect in the periphery) beyond those achieved with standard of care as well as normal liver volume irrespective of prior enzyme replacement therapy exposure in participants with MPS II. 

In addition to our MPS II and MPS IIIA programs, we are conducting a Phase 1/2 study for FTD-GRN with TAK-594/DNL593 (PTV:PGRN), which has a similar mechanism of action in replacing deficient enzyme activity to improve lysosomal function. Our next two ETV-enabled programs advancing to the clinic are DNL952 (ETV:GAA) for Pompe disease and DNL111 (ETV:Gcase) for Parkinson’s disease and Gaucher disease. DNL622 (ETV:IDUA) is also in IND-enabling stage for Hurler syndrome (MPS I). We have built clinical manufacturing capabilities for our TV-enabled programs and continue to expand our commercial capabilities in lysosomal storage diseases. Launching in rare indications first gives us the opportunity to build and establish our commercial organization so that we are poised for success in larger indications over time.

Figure 3: Our ETV franchise is intended to deliver the next generation of enzyme replacement therapies designed to treat CNS and somatic manifestations of lysosomal storage diseases and other serious genetic diseases. 

Our ETV franchise lays the foundation for value creation to fuel expansion of our TV portfolio utilizing our ATV and OTV platforms. In preclinical studies, broader brain biodistribution of ATV and OTV-enabled antibodies and oligonucleotides are achieved compared to non-TV-enabled standard antibodies and oligonucleotides (Figure 4). We have further engineered these platforms to optimize certain pharmacokinetic, pharmacodynamic, and safety properties. For example, our ATV:Abeta construct contains a "cisLALA" mutation that confers the ability to toggle effector function "on-or-off" such that immune cells are activated only when ATV:Abeta is bound to amyloid beta ("Abeta") plaque and not when bound to TfR. This feature addresses a known safety liability of utilizing TfR associated with depletion of reticulocytes (immature red blood cells) in the bone marrow where transferrin receptor is highly expressed. With