Therapeutics

DNL151

Overview

Name: DNL151
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

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).

Findings

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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References

Therapeutics Citations

  1. DNL201

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. company presentation
  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.