Denali’s DNL201 Safely Engages Target Enzyme: Multiple Studies

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by Steve Bryson, PhD |

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Denali Therapeutics‘ DNL201, an investigational therapy for Parkinson’s disease, was well tolerated in healthy volunteers and patients, and showed evidence of engaging its target protein, according to multiple preclinical and clinical studies.

LRRK2, a protein associated with Parkinson’s, is also the target of BIIB122 (formerly DNL151), which is being tested by Denali in collaboration with Biogen in a Phase 2b clinical trial called LUMA (NCT05348785).

The trial, underway at four sites in the U.S., is recruiting participants, ages 30 to 80, with early-stage Parkinson’s disease.

Although DNL201 and BIIB122 both met the requirements for further clinical assessment, the researchers noted that BIIB122 was selected because its pharmacological properties provided additional dosing flexibility.

Study details, “Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease,” were published in Science Translational Medicine.

Mutations in the enzyme LRRK2 are the most common genetic risk factor for Parkinson’s disease. These mutations increased LRRK2 activity, which is thought to impair lysosomes, structures within cells that break down and recycle molecules, and may contribute to developing Parkinson’s.

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Thus, inhibiting LRRK2 is a potentially disease-modifying therapeutic approach to slow the disease’s progression. DNL201 is an investigational small molecule that can access the brain and spinal cord and inhibit the protein.

Scientists at Denali, with researchers at various sites in the U.S. and Canada, have reported the details of preclinical animal studies and two Phase 1 clinical trials with healthy volunteers and Parkinson’s patients that evaluated DNL201.

In various cell-based tests, DNL201 suppressed LRRK2 activity depending on the dose, including cells isolated from patients who carry the most common disease-causing LRRK2 mutation called G2019S. Experiments in mouse and human cells showed DNL201 restored lysosome structure and function, which were abnormal due to the LRRK2 mutation.

DNL201 inhibited LRRK2 in a dose-dependent manner in both kidney and brain tissue isolated from rats one hour after treatment. Similar results were observed in macaque monkeys.

A chronic toxicity study in macaques lasting nine months — a duration to detect late-occurring toxicities — showed DNL201 was tolerated up to the highest dose tested. No DNL201-related mortality or effects on vital signs were observed. Further exams indicated DNL201 is not expected to affect human lung function at therapeutic doses, and there were related effects on kidney function.

Using cells from people that carry the G2019S mutation, with or without Parkinson’s, patients with sporadic disease, and healthy individuals, the research team established a 50% minimum reduction in LRRK2 activity by DNL201 was sufficient to show effectiveness in human clinical trials.

The team next evaluated the safety, tolerability, and pharmacological properties of DNL201 in two clinical trials: a Phase 1 dosing study (NCT04551534) with 122 healthy adult volunteers and a Phase 1b study (NCT03710707) in 28 Parkinson’s patients with and without LRRK2 mutations.

In the Phase 1 study, 63 were randomly assigned to single ascending doses (SAD) of DNL201 ranging from 10 to 225 mg, or a placebo, for 10 days. In the multiple ascending dose (MAD) group, 59 volunteers were randomly assigned doses ranging from 40 mg once daily to 100 mg twice daily or a placebo for 10 days.

In those who received multiple doses of DNL201, there was a dose-dependent reduction in LRRK2 activity and the treatment showed potent inhibition measured by whole-blood LRRK2, with 75 to 82% median reduction in activity at 80 and 100 mg twice daily. The treatment also reduced urinary BMP, a marker for lysosomal function, at those same doses, “consistent with modulation of lysosomal pathways,” the researchers wrote.

The LRRK2 and lysosomal pathway engagement were also examined in the Phase 1b study in patients with mild to moderate Parkinson’s who received standard-of-care therapy. Here, patients were assigned 30 or 50 mg DNL201, three times daily, or a placebo, for 28 days.

Likewise, there was a dose-dependent reduction of LRRK2 activity in whole blood, with a median drop of more than 85% at the higher dose and more than 55% at the lower dose. There was also a decrease in urinary BMP at the 50 mg dose, suggesting the “reversal of the lysosomal pathway defects that are present in G2019S mutation carriers who show elevated urinary BMP concentrations,” the researchers said.

The pharmacological profiles and the levels of LRRK2 inhibition were similar among the healthy volunteers and patients, overall.

DNL201 was generally well tolerated in the Phase 1 healthy volunteer study, at doses of 150 mg or more once daily and 100 or more mg twice daily. No serious side effects were reported. The most common treatment-emergent adverse event (TEAE) was headache (40%), dizziness (13%), and nausea (13%).

In the Phase 1b study, DNL201 was generally well tolerated in patients at both the twice-daily doses. Most TEAEs were mild or moderate, with a higher incidence of moderate TEAEs in the higher dose group. The most common TEAE was headache (33%). For both doses, the TEAEs were generally manageable and reversible.

DNL201 was not associated with changes in lung or kidney function or blood test results across the Phase 1 and 1b studies.

“Our nonclinical and human clinical data in healthy volunteers and in patients with [Parkinson’s disease] have demonstrated the safety and tolerability of DNL201 at doses with substantial LRRK2 target and lysosomal pathway engagement,” the researchers wrote. “DNL201 provides proof of mechanism in humans and demonstrates characteristics of a viable therapeutic.”