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.
DNL201 is an orally available, brain-penetrant inhibitor of the leucine-rich repeat kinase 2 (LRRK2). It is being developed to treat Parkinson’s disease.
Also known as Dardarin, LRRK2 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 is 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 reduces 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 about 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 2017 and 2018, Denali conducted a Phase 1 safety study of DNL201 in healthy volunteers. The trial was not registered. According to one company press release, the highest evaluated dose of DNL201 inhibited LRRK2 by 90 percent and 50 percent at peak and trough blood concentrations, respectively. Kinase activity was measured by phosphorylation of LRRK2 itself and a substrate, Rab10, in blood. The drug was detected in cerebrospinal fluid, indicating it entered the brain. In a second press release, Denali reported no serious adverse events in more than 100 healthy participants, including healthy elderly, in this single- and multiple-dose study.
In December 2018, Denali began a Phase 1b study in 29 people with Parkinson’s disease. Participants with or without an LRRK2 mutation were randomized to one of two doses of drug or placebo, taken twice daily for 28 days. The primary outcomes consisted of adverse events and abnormalities in laboratory tests, vital signs, electrocardiogram, or neurological exam. Secondary outcomes included plasma pharmacokinetics, drug concentration in CSF, and LRRK2 and Rab10 phosphorylation. The trial also measured levels of the lipid BMP in urine, a biomarker of lysosome function. It was completed in December 2019.
In a January 2020 press release, the company announced that both doses achieved more than 50 percent inhibition of LRRK2 and Rab10 phosphorylation in blood, and improved BMP in urine. At the low dose, most participants had no or mild adverse events. At the high dose, most experienced mild or moderate adverse events. One person had a dose reduction due to severe headache, and one withdrew due to headache and nausea. There was one case of Legionella pneumonia; there was no dose-dependent effect on pulmonary function.
For details on DNL201 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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