Therapeutics

DNL201

Overview

Name: DNL201
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.

Background

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).

Findings

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.

Denali has a back-up LRRK2 inhibitor, DNL151, currently in a Phase 1b trial, and plans to select one compound by mid-2020 to advance to Phase 2 (press release).

For details on DNL201 trials, see clinicaltrials.gov.

Last Updated: 19 May 2020

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References

Therapeutics Citations

  1. DNL151

News Citations

  1. Does LRRK2 Sweep α-Synuclein from the Cell?

Paper Citations

  1. . Precision medicine in Parkinson's disease: emerging treatments for genetic Parkinson's disease. J Neurol. 2020 Mar;267(3):860-869. Epub 2020 Jan 23 PubMed.
  2. . LRRK2 activation in idiopathic Parkinson's disease. Sci Transl Med. 2018 Jul 25;10(451) PubMed.
  3. . Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease. Curr Opin Cell Biol. 2020 Apr;63:102-113. Epub 2020 Feb 7 PubMed.
  4. . Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner. Sci Transl Med. 2019 Sep 25;11(511) PubMed.
  5. . Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9289-94. Epub 2014 Jun 9 PubMed.
  6. . Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. J Biol Chem. 2015 Aug 7;290(32):19433-44. Epub 2015 Jun 15 PubMed.
  7. . Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med. 2015 Feb 4;7(273):273ra15. PubMed.
  8. . LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci Transl Med. 2020 Apr 22;12(540) PubMed.

External Citations

  1. press release
  2. press release
  3. press release
  4. press release
  5. clinicaltrials.gov

Further Reading

Papers

  1. . Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present). Expert Opin Ther Pat. 2020 Apr;30(4):275-286. Epub 2020 Feb 18 PubMed.
  2. . G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. J Neurosci. 2016 Jul 13;36(28):7415-27. PubMed.
  3. . Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission. CNS Neurosci Ther. 2017 Feb;23(2):162-173. Epub 2016 Dec 9 PubMed.