Oral BIIB122/DNL151 Safely Lowers LRRK2 Activity in Phase 1 Trials

Treatment with investigational oral therapy BIIB122/DNL151 safely lowered the activity of disease biomarkers that reflect LRRK2 activity, a protein whose mutations are associated with Parkinson’s disease, according to results from two Phase 1 clinical studies.

Plans are being put in place to advance the therapy into late-stage clinical testing in Parkinson’s patients later this year.

Trial results were presented at the International Association of Parkinsonism and Related Disorders Virtual Congress held May 1–4.

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. Mutations in the LRRK2 gene are one of the most common genetic abnormalities seen in Parkinson’s patients.

LRRK2 regulates the activity of cellular structures called lysosomes, which act as a cell’s “digestive” system and are responsible for breaking down excess material and damaged cell parts. Lysosomal function is often impaired in the neurons (nerve cells) of Parkinson’s patients, which can contribute to neurodegeneration.

Patients both with and without mutations in the LRRK2 gene show increased levels of active LRRK2 protein (called pS935 LRRK2) and of its substrate Rab10. As such, levels of these two forms of active (phosphorylated) proteins can be used as biomarkers to measure the efficacy of a given therapy.

BIIB122/DNL151, developed in a collaboration between Denali Therapeutics and Biogen, is a small molecule that blocks LRRK2 activity specifically in the nervous system, which the companies believe could restore lysosomal function and potentially slow Parkinson’s progression. 

“This rigorous Phase 1/1b dataset exemplifies Denali’s approach of using biomarkers to guide drug development for neurodegenerative diseases and supports our plans with Biogen to advance BIIB122/DNL151 into late-stage clinical development for the potential treatment of Parkinson’s disease,” Carole Ho, MD, chief medical officer at Denali, said in a press release. 

The Phase 1 trial (NCT04557800) evaluated BIIB122/DNL151’s safety, tolerability, pharmacokinetics (the drug’s effects on the body), and pharmacodynamics (the drug’s movement in, through, and out of the body) in 184 healthy volunteers. 

Participants were randomly assigned to either BIIB122/DNL151 (145 participants) or a placebo (39 participants) in a single or once-daily oral dose, ranging from 15 mg to 300 mg for up a maximum of 28 days or twice-daily doses of up to 400 mg for a maximum of 14 days.

The Phase 1b trial (NCT04056689) evaluated these same parameters in 36 Parkinson’s patients, who were randomly assigned to either BIIB122/DNL151 (26 participants) or placebo (10 participants) in once-daily doses of up to 300 mg for 28 days.

A dose-dependent reduction of at least 50% in active LRRK2 was observed in the blood of healthy volunteers at doses higher than 70 mg, the release reported, and in Parkinson’s patients at all dose levels: 80 mg, 130 mg, and 300 mg once daily. A reduction of at least 80% in the levels of active LRRK2 were also observed at doses of 225 mg or higher in both studies. 

A dose-dependent reduction in the levels of phosphorylated Rab10 was observed in healthy volunteers, and that of at least 50% at all dose levels in Parkinson’s patients.

These observed reductions were of the magnitude required to normalize elevated Rab10 activity observed in these patients, Denali stated in its release.

In both healthy volunteers and Parkinson’s patients, a dose-dependent reduction was also seen in the levels of urine lysosomal lipid 22:6-bis[monoacylglycerol] phosphate (BMP), a biomarker of lysosome function. 

The treatment was well-tolerated with no serious adverse events reported in either trial. Most reported side effects were mild to moderate, and a total of four people — two healthy volunteers and two Parkinson’s patients — discontinued treatment due to adverse events (nausea and headache in the volunteers; hypotension or low blood pressure in the patients). Symptoms resolved once the treatment’s use was stopped.

“LRRK2 is a novel and promising target for the development of new, potentially disease-modifying therapies that have not yet been available as treatment options for people living with Parkinson’s disease,” said Alfred W. Sandrock Jr., MD, PhD, executive vice president of research and development at Biogen. “Denali’s Phase 1 and Phase 1b data support BIIB122/DNL151 as a potential first-in-class oral therapy that may slow the progression of Parkinson’s disease.”

Planned late-stage clinical studies of BIIB122/DNL151 intend to enroll Parkinson’s patients both with and without LRRK2 mutations.