Positive Clinical Results announced for LRRK2 in Parkinson’s Disease


  • Healthy volunteer study of DNL201 met all objectives in phase 1 clinical study, including CSF exposure levels and LRRK2 inhibition, as well as pathway engagement, at doses that were safe and well tolerated
  • DNL201 will advance to Phase 1b in Parkinson’s disease patients with and without a genetic LRRK2 mutation

Denali Therapeutics announced positive results from its Phase 1 clinical study with DNL201, a small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2).

In a randomized, double blind, placebo-controlled, oral dose study in healthy subjects, DNL201 achieved its safety, pharmacokinetic, and pharmacodynamic objectives. DNL201 was generally well tolerated with no serious adverse events at doses that achieved high levels of cerebrospinal fluid (CSF) exposure, robust target engagement as measured by two blood-based biomarkers of LRRK2 activity, and effects on biomarkers of lysosomal function.

Mutations in the LRRK2 gene are the most frequent genetic cause of Parkinson’s disease and a major driver of lysosomal dysfunction, which contribute to the formation of Lewy body protein aggregates and neurodegeneration. LRRK2 regulates lysosomal genesis and function, which is impaired in Parkinson’s disease and may be restored by LRRK2 inhibition, thereby potentially positively modifying disease progression in patients with a genetic LRRK2 mutation as well as in patients with sporadic Parkinson’s disease.

In the study of DNL201, more than 100 healthy subjects, including healthy elderly subjects, received either single or multiple ascending doses or placebo. Based on the clinical data from this study, Denali intends to advance DNL201 into a Phase 1b clinical study in Parkinson’s disease patients with and without a genetic LRRK2 mutation by year-end 2018. Detailed clinical data from the Phase 1 study with DNL201 will be presented at a future medical conference.

“We conclude from this clinical trial that DNL201 was able to achieve the targeted level of LRRK2 inhibition at doses that were safe and well tolerated. We are pleased that the trial was a success in all these key measures. The trial data give us confidence to proceed with further clinical testing in Parkinson’s patients and provide a solid basis for selection of the optimal dose for future clinical trials in patients,” said Carole Ho, M.D., Chief Medical Officer.

“We are leading the way in testing LRRK2 inhibitors in humans with the goal of bringing a disease modifying therapeutic to patients suffering from Parkinson’s disease,” said Ryan Watts, Ph.D., CEO. “We are also encouraged to see mounting evidence supporting a role of LRRK2 inhibition in the broader sporadic Parkinson’s disease population, in addition to Parkinson’s disease genetically associated with a LRRK2 mutation.”

A Phase 1 dose escalation study with DNL151, a second small molecule inhibitor of LRRK2, is ongoing in the Netherlands.


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News Source: Denali Therapeutics website

Image Source: https://parkinsonsnewstoday.com/2017/02/06/side-effects-limit-long-term-treatment-with-apomorphine-infusions-in-parkinsons/