Potential Parkinson’s Treatment, DNL201, Safe and Well-Tolerated in Phase 1 Study, Denali Says

Potential Parkinson’s Treatment, DNL201, Safe and Well-Tolerated in Phase 1 Study, Denali Says

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.

Interested in Parkinson’s Disease research? Sign up to our forums and join the conversation!

“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.

4 comments

    • Marlen R Guity Norales says:

      WHO AM I?
      I’m Marlen Guity. My friends call me Leona (Lioness) because I’ve always been an independent woman who knows how to put up a fight. I was born in 1979 the middle child among 7 siblings in upbeat La Ceiba, Honduras and became an athlete at a young age.
      Always a helping leader in my community, at 20 I got a scholarship to study in the United States; not being fluent in English, I tackled the challenge. When my school course ended I returned to Honduras, where a violent home environment waited for me and, having glimpsed the opportunity of a better life, I worked my way back to the US.
      I swore I would never live the same life of abuse my mother suffered and in Boston I married an old childhood sweetheart. But that bubble quickly burst leading to a second hell of domestic violence in my life.
      Bringing any children into that marriage was out of the question but still the blessing of a songave my life new purpose among my trials.
      Things took a definitive turn when my son spent a month at Boston Children’s Hospital due to a heart condition and I was painfully the only parent visiting. That was the last straw; after being repeatedly thrown out of my own home by my abusive spouse, I took my son and found refuge at a shelter.
      Once again I rebuilt my life from scratch, going back to school and finally achieving my lifelong dream of becoming a bodybuilding model. After 10 years of sacrifice, I finally got my green card.
      WHAT HAPPENED?
      And then 6 years ago something went wrong. Curling toes, a dragging leg and stiffness in my right side were the initial symptoms of a disease that went misdiagnosed until last year: Parkinson’s.
      Once healthy and always athletic, I lost my job, my social life and, at times, the slightest glimmer of hope. Ultimately undeterred, I have spent hours on end looking for treatment options and alternatives to natural medications with little results.
      As if to add to my challenge, my beloved son John was diagnosed with lymphatic cancer.
      After countless hours of struggle and the doctors’ swift involvement, chemotherapy gave way to that oasis of hope: remission.
      Upon closing that dreaded chapter, I got back on track with an increased drive to find a way to be there to watch my son grow up. At least the confirmation of my diagnosis gives a clear face to my rival.
      I know what I’m up against. 
      I am doing all I can but living on $600 a month
      I want to be able to get back to work. I want to move on with my life. I want to be able to help other patients struggling likel me.
      I’m alone but not for long.  help me.  I will do the fighting. Be at my corner in this next round for “Leona” (Lioness), as people like to call me.

Leave a Comment

Your email address will not be published. Required fields are marked *