Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 127

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 127
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 of Parkinson’s disease, with royalty amounts varying based on the scope of the label.

In December 2024, we announced that dosing had commenced in the Phase 2a study, called BEACON, which is expected to enroll approximately 50 participants into a double-blind treatment period of three months followed by an open label extension.

2025 expected progress and milestones:

•Complete enrollment of the Phase 2b LUMA study in early-stage PD

•Continue enrollment in the Phase 2a study in PD related to pathogenic variants of LRRK2

Other LRRK2 Compounds

Genetic and functional studies have linked LRRK2 and other proteins that modulate lysosomal function to Crohn's disease. Excessive LRRK2 activity leads to a reduction in lysosomal function, which contributes to the inflammation and intestinal dyshomeostasis that are characteristic of this disorder. We have discovered potent and selective small molecule inhibitors of LRRK2 and have selected a lead clinical candidate (DNL975) for treatment of Crohn's disease. As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Biogen on the Peripheral LRRK2 program.

DNL343 eIF2B Activator Program for ALS

DNL343 is a novel small molecule investigational therapeutic that targets eIF2B, a central regulator of the integrated stress response ("ISR"). The ISR appears to be overactive in ALS, leading to the formation of stress granules containing TDP-43. The buildup of TDP-43 is harmful and leads to neuronal degeneration. In preclinical data, inhibition of the ISR by DNL343 dissolves TDP-43 containing stress granules and decreases biomarkers of the ISR. Early clinical studies demonstrated that once-daily oral dosing with DNL343 was generally well tolerated and exhibited extensive penetration of CSF. In addition, robust inhibition of biomarkers associated with the ISR pathway was observed in blood samples from study participants. 

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In May 2023, the first participant with ALS was dosed with DNL343 (Regimen G) in the Phase 2/3 HEALEY ALS Platform Trial led by the Sean M. Healey & AMG Center for ALS ("Healey Center") at Massachusetts General Hospital ("MGH") in collaboration with the Northeast ALS Consortium ("NEALS") clinical trial network. The HEALEY ALS Platform Trial is a large-scale collaborative effort made possible by contributions from