Denali Therapeutics’ reports that its investigational compound for Parkinson’s disease, DNL201, was found to be safe and well-tolerated by healthy individuals in a Phase 1 clinical trial. The company is planning to advance the compound into a Phase 1b study in patients, a press release states.
DNL201 is an inhibitor of leucine-rich repeat kinase 2 (LRRK2). Mutations in the LRRK2 gene are the most frequent genetic cause of Parkinson’s and are usually associated with problems in the working of lysosomes, a structure within cells that breaks down molecules and provides the cell with the simpler nutrients it requires.
Lysosomal dysfunction contributes to the formation of Lewy body protein aggregates, and consequently, neurodegeneration. LRRK2 is known to regulate the formation and function of lysosomes, which are impaired in Parkinson’s disease and may eventually be restored by inhibiting LRRK2 activity, both in patients with a genetic LRRK2 mutation as well as in those with sporadic Parkinson’s disease.
The randomized, double-blind, placebo-controlled Phase 1 study investigated the safety, pharmacokinetic and pharmacodynamic of DNL201 in more than 100 healthy individuals. Pharmacokinetics refers to a drug’s absorption, bioavailability, distribution, metabolism, and excretion in the body; pharmacodynamics refers to the relationship between a medicine’s concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects.
Participants took single or multiple ascending doses of DNL201 or placebo, the company reports, adding that all were generally well-tolerated, with no serious side effects.
Treatment was also well-tolerated at elevated doses that achieved high levels of cerebrospinal fluid (CSF) exposure. LRRK2 inhibition was effective, as measured by two blood biomarkers and effects on lysosomal function — the main mechanism affected by LRRK2 mutations.
“We conclude from this clinical trial that DNL201 was able to achieve the targeted levels of LKKR inhibition at doses that were safe and well-tolerated,” Carole Ho, MD and chief medical officer of Denali Therapeutics, said in the release.
“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,” Ho added.
Preclinical studies demonstrated DNL201’s capacity to stop an average 90 percent of LRKK2 activity at its highest concentration and 50 percent when the compound’s levels dropped to a lower concentration, showing its potential as a Parkinson’s therapy. The release did not specify what dose levels were used, and a trial document was not available on clinicaltrials.gov website.
Details of the Phase 1 study will be presented at a future medical conference, Denali said.
“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, PhD and chief executive officer of Denali. “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.”
Denali is developing a second inhibitor of LRRK2, called DNL151, that is now testing in a dose-escalation Phase 1 study in healthy volunteers in the Netherlands.