DNL201 Phase 1/1b

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Danielle Jennings, Denali Therapeutics colleagues (Science Translational Medicine 2022;14:eabj2658). The registered studies ran from 2017 to 2019; 2022 is the publication year.

What happened

DNL201 is an ATP-competitive small-molecule LRRK2 kinase inhibitor. In cells it lowered phosphorylation of LRRK2 (pS935) and of Rab10 (landmark 37) and improved lysosome function in mouse astrocytes and fibroblasts from patients with Gaucher disease. Chronic dosing in cynomolgus macaques at relevant doses had no adverse findings (the lung issue is in landmark 199). Phase 1 (NCT04551534) enrolled 122 healthy volunteers and Phase 1b (NCT03710707) 28 patients with Parkinson's in the paper (29 on the registry). Alzforum reports the urine lysosome marker BMP fell about 75% in healthy volunteers and about 60% in patients on the high dose, and blood phospho-Rab10 fell about 80%. It inhibited LRRK2, was well tolerated at doses showing pathway engagement and changed downstream lysosomal markers. Spinal-fluid penetration was robust. Efficacy was not tested.

Why it moved us toward a cure

It turned the 2004 gene discovery (landmark 7) into a human drug-effect test, showing both target and lysosomal biomarker engagement. This directly led to the later Phase 2b trial (landmark 145), which should list this as a parent.

Outcome

Superseded. Alzforum says Denali dropped DNL201 for DNL151 (BIIB122), which the company says has better pharmacokinetics; Denali's August 2020 release moved DNL151 into late-stage studies. One news item claimed liver safety as the reason; no primary source supports that. The successor's Phase 2b later failed (landmark 145), which does not change this file's status.

Sources

• Jennings et al., Sci Transl Med 2022;14:eabj2658, DOI 10.1126/scitranslmed.abj2658
• Alzforum, "LRRK2 Inhibitor Hits Target, Appears Safe for Parkinson's" · Denali Q2 2023 release
• NCT04551534 · NCT03710707 (read via API, 19 Oct 2026)
• Not yet verified: dose levels (Alzforum gives 25–100 mg twice daily for 10 days in volunteers and 30 or 50 mg three times daily in patients); the real reason DNL201 was dropped.