LRRK2 Drug Trial Shares Promising Results, Company to Begin Second Study

by  Maggie McGuire Kuhl,
December 21, 2017


Yesterday Denali Therapeutics announced positive results from its first-in-human LRRK2 inhibitor clinical trial. The experimental treatment is safe, and it lowers LRRK2 protein activity in humans' body cells. This is a meaningful milestone in the clinical development of a drug with potential to slow or stop Parkinson's progression (something no currently available treatment can do).

Denali also shared it is testing a second compound in a separate Phase I trial in control volunteers. Following completion of both trials, one of the two compounds will move into studies in people with Parkinson's carrying a LRRK2 mutation.

Read more below on this project and its treatment potential from our earlier report on Denali's initial public offering.

In a press release, the company announced its first trial showed greater than 90 percent inhibition of LRRK2 activity at peak drug levels. This is a critical early step in testing a drug -- does it do what you want it to do in the cell? Denali used two tests to measure inhibition, including one based on a finding from a Michael J. Fox Foundation-organized consortium linking LRRK2 to another protein.

"Mutations in LRRK2 are a major risk factor for Parkinson's disease. Targeting this degenogene represents a promising approach to develop disease-modifying medicines," said Ryan Watts, PhD, Denali CEO.

Read more on the findings and next steps.


December 8, 2017 -- San Francisco-based Denali Therapeutics has raised nearly $250 million in its initial public offering, marking the largest biotech IPO of the year. In announcing terms of the IPO -- a major milestone in the life cycle of any company as it first offers stock options publicly, garnering capital for growth and expansion -- Denali shared it is testing a LRRK2 inhibitor drug in a small trial of control volunteers.

Mutations in the LRRK2 gene are a cause of Parkinson's disease (accounting for one to two percent of all cases, but behind up to 40 percent in some populations) and are associated with higher activity of the LRRK2 protein. Scientists, therefore, are developing inhibitor drugs to offset that over-activation and protect cells. The Michael J. Fox Foundation has a robust roadmap strategy around LRRK2: funding many studies to understand more about the protein's connection to Parkinson's and how we may target it to slow or stop disease.

While we have not directly funded Denali, our investments have been critical to helping the company achieve its current promising LRRK2 program. Denali has used MJFF-supported research tools in its experiments, and an August 2016 Forbes article reported CEO Ryan Watts cited a unique MJFF-led consortium as influential in his decision to license and develop LRRK2 inhibitor compounds. The LRRK2 Safety Initiative tested compounds from Genentech, Merck and Pfizer for safety, finding lung tissue changes were reversible and not associated with functional problems.

"This is a textbook example of what we exist to do: persevere to overcome issues that would otherwise set PD drug development back by years," MJFF CEO Todd Sherer, PhD, told Forbes. "We're thrilled on behalf of everyone living with the disease that a highly-promising target continues to move forward."

Therapies like this -- targeting dysfunction associated with a genetic mutation -- are examples of precision medicine, prescribing treatments based on one's biology rather than clinical diagnosis. Earlier this year another Parkinson's trial began enrolling people with a mutation in the GBA1 gene, also associated with the disease.

A common question is if such therapies will work for people without those specific mutations. While we do not yet know, our Foundation is funding research to draw lines between implicated proteins and pathways, which may lead to wider use of treatments.

As its first human study continues, Denali gained approval to begin a trial of a different LRRK2 inhibitor compound in the Netherlands and also is developing therapies against Alzheimer's disease and amyotrophic lateral sclerosis (ALS). We will share more news on the company's Parkinson's trials as it is available.

TAGS: Research News, LRRK2

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