Denali, Biogen Partner to Move DNL151 Into Late-stage Parkinson’s Trials

Denali Therapeutics announced a partnership with Biogen to jointly develop and advance DNL151, an investigational small molecule treatment for Parkinson’s disease, to late-stage clinical testing following results from ongoing Phase 1/1b trials.

The partnership also includes Biogen and Denali working to co-develop and, upon approval, jointly market this and other small molecule treatments coming from the research program that led to DNL151, among other points.

Plans call for patient enrollment to begin next year in two last-stage clinical trials of DNL151, the company announced in a separate press release.

“Our collaboration partner Biogen is a respected leader in neurodegenerative diseases and brings deep scientific and development expertise in Parkinson’s disease which will allow us to accelerate our development plan and we believe increase the likelihood of ultimate success,” said Carole Ho, MD, Denali’s chief medical officer.

Although Parkinson’s does not have a clear genetic cause, evidence supports an association between the disease and mutations in the gene that codes for the protein leucine-rich repeat kinase 2 (LRRK2), also known as dardarin. In fact, mutations in the LRRK2 gene are one of the most common genetic abnormalities associated with Parkinson’s.

LRRK2 regulates the activity of cellular components called lysosomes, which are responsible for breaking down of material taken up from outside a cell and for damaged cell parts. They act as a cell’s “digestive” system.

Lysosomal function is often impaired in the neurons (nerve cells) of Parkinson’s patients, and this can contribute to neurodegeneration.

To address this underlying pathology of Parkinson’s, Denali worked to identify small molecules that could inhibit LRRK2 activity, and protect against problems in lysosomal function in the brain.

Researchers identified two compounds, DNL151 and DNL201, each with the ability to act as a neuronal LRR2K inhibitor. By selectively suppressing LRRK2, DNL151 aims to restore lysosomal function, which may slow Parkinson’s progression in all patients.

Denali has launched parallel Phase 1/1b clinical trials investigating the safety, tolerability, pharmacokinetics (essentially how the body affects a medicine) and pharmacodynamics (the interactions between the body and a compound) of DNL151 (Phase 1b, NCT04056689) and DNL201 (NCT03710707) in both healthy volunteers and Parkinson’s patients.

Results of both these ongoing studies found DNL151 and DNL201 met the requirements for further development, Denali announced. However, it selected DNL151 due to pharmacokinetic properties allowing for greater dosing regimen flexibility.

In the 28-day DNL151 trial, a total of 25 patients have been given one of three escalating doses, or a placebo, the company stated in its release. A goal is to determine an optimal dose for future trials.

This Phase 1b study is still enrolling up to 35 adults with mild-to-moderate Parkinson’s at sites in the U.S. and Europe. Under Phase 1, 162 healthy volunteers were also given doses, and researchers found DNL151 to have an acceptable safety and tolerability profile in these participants. Both these trial phases have been expanded to include more people, Denali said.

Results to date in DNL151 also show a target engagement of over 50%, and up to a 50% reduction of the lysosomal marker BMP (22:6-bis-monoacylglycero-phosphate) in urine samples, with this drop dependent on the DNL151 dose given. These data indicated that the study’s pharmacological goals were being met.

“Safety and biomarker data from studies of our two LRRK2 molecules in Parkinson’s patients support moving DNL151 into late stage clinical studies with the aim of addressing the devastating clinical decline and pathology of disease in Parkinson’s patients,” Ho said.

One of the two late-stage trials planned for 2021 is expected to be in patients with sporadic (of unknown cause) Parkinson’s disease, and the other in patients with a mutation causing excessive LRRK2 activity.

The collaboration with Biogen will also allow Denali to expand its LRRK2 inhibitor development program, with the goal of developing treatments for other neurodegenerative diseases.