Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Denali Therapeutics Inc.
DNL151 is an orally available, brain-penetrant inhibitor of the leucine-rich repeat kinase 2 (LRRK2). It is a backup to Denali’s lead LRRK2 inhibitor, DNL201; both drugs are in early clinical development for Parkinson’s disease.
LRRK2, also known as Dardarin, is a large, multidomain protein containing serine and threonine kinase activity. Kinase-activating mutations in the LRRK2 gene are the most frequent cause of inherited PD (reviewed in Schneider and Alcalay, 2020). Other variants in the gene are associated with higher risk of sporadic PD, and there is some evidence for LRRK2 kinase activation in idiopathic PD (Di Maio et al., 2018). Increased LRRK2 kinase activity impairs vesicle trafficking and lysosome function, and promotes neuroinflammation, processes that contribute to PD pathology (see review by Taylor and Alessi, 2020; Shutinoski et al., 2019; Sept 2018 news). Several companies are pursing LRRK2 inhibitors for treating PD; Denali was the first to begin clinical testing.
No preclinical data has been published on DNL201. However, reducing LRRK2 activity using other inhibitors or by genetic knockdown in rodent models of PD has been reported to reduce α-synuclein aggregation, neuroinflammation, and dopaminergic neuron loss (Daher et al., 2014; Daher et al., 2015).
Besides brain, LRRK2 is highly expressed in the lungs, kidneys, and spleen. Knockout or systemic inhibition of LRRK2 was found to change lung morphology in rats or macaque monkeys, possibly by affecting lysosomal function (Fuji et al., 2015). This raised safety concerns of systemic LRRK2 inhibition. Recent data confirmed that three different inhibitors caused an accumulation of large vacuoles in lung cells of treated monkeys; this response did not compromise lung function after two weeks of treatment, and the changes reversed after the drugs were stopped (Baptista et al., 2020).
In December 2017, Denali began Phase 1 dosing of DNL151 (press release). A January 2020 press release announced that DNL151 met biomarker and safety goals after evaluation in 153 healthy volunteers. The majority of participants had no or mild AEs at all doses tested. DNL151 dose-dependently reduced LRRK2 kinase activity by up to 80 percent, based on measuring phosphorylation of LRRK2 and its substrate pRab10 in blood. Urine levels of the lipid BMP, a marker of lysosome dysfunction, were reduced, as well. Based on these safety, target, and pathway engagement data, the trial was expanded to higher doses (see company presentation, slide 13).
In July 2019, the company began a Phase 1b safety study in 34 people with Parkinson’s disease. Participants with or without an LRRK2 mutation will be randomized to a low, middle, or high dose of DNL151 or placebo, taken daily for 28 days. The primary outcome comprises adverse events and laboratory tests, vital signs, electrocardiogram, or neurological exam. Secondary outcomes include plasma pharmacokinetics, drug concentration in the CSF, and LRRK2 and Rab10 phosphorylation in blood. The trial is expected to run through June 2020.
In April 2020, Denali acknowledged recruitment delays due to the COVID-19 pandemic, and announced that this trial has been paused temporarily. Denali still intends to evaluate all data gathered by mid-2020 and select either DNL201 or DNL151 to advance into Phase 2/3 (press release).
For details on DNL151 trials, see clinicaltrials.gov.
Last Updated: 19 May 2020
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- Sigh of Relief? Lung Effects of LRRK2 Inhibitors are Mild.
- LRRK2 Mutation Fires Up Immune Response, Harms Brain
- Does LRRK2 Sweep α-Synuclein from the Cell?
- Parkinson’s Treatments Go After Genetic Targets
- LRRK2 Interactions Identify New Parkinson’s Genes, Implicate Autophagy
- Rethinking LRRK2 Toxicity: It’s How Much Is Present, Not What It Does
- Evidence Piles Up for Lysosomal Dysfunction in Parkinson’s
- More Than a LRRK: PD Field Thinks Big With Genetic Cohort
- α-Synuclein Conspires With LRRK2 to Corrupt Neurons
- More Than a Lark? PD Mutations Increase Kinase Activity
- Not Just a Family Affair: Dardarin Mutations Predict Sporadic PD
- PARK8 is Cloned: Introducing…"Dardarin"
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