DNL151 (BIIB122) Phase 1 and 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

Denali Therapeutics, with Biogen as partner. First topline data were announced on 1 May 2021 (International Association of Parkinsonism and Related Disorders congress). The full paper is by Danielle Jennings and colleagues, Movement Disorders, February 2023.

What happened

Two placebo-controlled, double-blind studies of the tablet DNL151 (later BIIB122), 28 days of dosing each:

• Phase 1, healthy volunteers (NCT04557800): 186 randomised, 184 treated (145 on drug, 39 on placebo), at single doses and daily doses of 15 to 300 mg, plus twice-daily doses up to 400 mg for 14 days.
• Phase 1b (NCT04056689), people with mild to moderate Parkinson's, with or without a LRRK2 mutation: 36 (26 drug, 10 placebo) at 80, 130 or 300 mg a day.
• Targets. Reductions from baseline of up to 98% in blood LRRK2 phosphorylation (pS935), up to 93% in phospho-Rab10 in immune cells, up to 50% in spinal-fluid total LRRK2, and up to 74% in urine BMP, a lysosome lipid marker (landmark 231).
• Brain penetration. Spinal-fluid drug levels were close to the unbound level in blood.
• Safety. No serious adverse events. Most side effects were mild. Two volunteers stopped for nausea and headache and two patients stopped on day 1 with low blood pressure; all resolved. The company reported no clinically meaningful lung or kidney function changes.

Why it moved us toward a cure

It followed the first LRRK2 inhibitor in people, DNL201 (landmark 200), with a successor drug (Alzforum and Denali say it replaced DNL201 for better pharmacokinetics). It showed that a chosen dose could hit the target of the gene found in landmark 7 without the lung problems feared. The Phase 2b that followed is landmark 145.

Outcome

Advanced as a safety and target-engagement step. It did not test whether the disease slowed; LUMA, the Phase 2b it led to, failed in 2026 (landmark 145). The step itself still stands, so the outcome stays Advanced.

Sources

• Jennings et al., Mov Disord 2023;38(3):386–398, DOI 10.1002/mds.29297 (abstract read via Leiden University repository)
• Denali release, 1 May 2021 (BioSpace)
• West & Schwarzschild editorial, Mov Disord 2023, DOI 10.1002/mds.29343
• NCT04557800 · NCT04056689 · NCT05418673 (read via API, 19 Oct 2026)
• Not yet verified: how the LUMA dose of 225 mg was chosen; the number of LRRK2 carriers in Phase 1b (not stated in the release or abstract); the exact dose ranges used in the paper.