Category: Parkinson’s Disease: Clinical Trials
Objective: To evaluate safety, tolerability, and target engagement of DNL201, a LRRK2 inhibitor, in Parkinson’s disease (PD) patients.
Background: Mutations in LRRK2 impact both familial and non-familial PD and are among the most common genetic causes and risks PD. Inhibition of LRRK2 kinase activity and consequent improvement in lysosomal function is a promising new approach to treating both familial PD with a LRRK2 kinase activating mutation and sporadic PD. DNL201 is a potent, selective, CNS-penetrant LRRK2 kinase inhibitor under investigation for treatment of PD.
Method: This multi-center, double-blind, placebo-controlled Phase 1B trial evaluated safety, tolerability and biomarker responses of DNL201 in PD (LRRK2 mutation carriers and non-carriers). Subjects received low dose DNL201 (LD), high dose DNL201 (HD), or placebo (PBO) for 28 days. Assessments included vital signs, ECG, laboratory tests, pulmonary function testing, and adverse events. Both plasma and CSF pharmacokinetic measures were evaluated. Biomarkers included whole blood LRRK2pS935. Exploratory endpoints included biomarkers of lysosomal function, and clinical and imaging endpoints.
Results: Twenty-eight PD subjects were randomized and treated with HD (n=12), LD (n=9) or PBO (n=7). DNL201 was generally well tolerated with the most common treatment related adverse events (TEAEs) across both dose groups of headache and nausea. The majority of LD subjects experienced no or mild TEAES and the majority of HD subjects experienced mild to moderate TEAEs. At the LD, one SAE occurred and was considered unrelated to study drug. At the HD, there was one severe AE headache that led to dose reduction and one study withdrawal (headache and nausea). All TEAEs were manageable and reversible. At the dose levels studied, 50-75% inhibition of pS935 was achieved across the dosing period at steady state. Additional data on lysosomal biomarkers will be presented.
Conclusion: LRRK2 inhibition with two doses of DNL201 demonstrated substantial target and downstream pathway engagement, including effects on lysosomal biomarkers, at doses that were generally well tolerated. This first ever trial of LRRK2 inhibitors in PD patients with and without LRRK2 mutations supports further investigation of LRRK2 inhibition for the treatment of Parkinson’s disease.
To cite this abstract in AMA style:
D. Jennings, P. LeWitt, D. Kern, I. Goodman, A. Siderowf, O. Omidvar, A. Ellenbogen, J. Aldred, R. Macuica, S. Huntwork-Rodriguez, C. Ho, M. Troyer. Safety, Tolerability, and Pharmacodynamic Profile of DNL201 at dose levels demonstrating LRRK2 inhibition in Parkinson’s Disease Patients with and without LRRK2 mutations [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/safety-tolerability-and-pharmacodynamic-profile-of-dnl201-at-dose-levels-demonstrating-lrrk2-inhibition-in-parkinsons-disease-patients-with-and-without-lrrk2-mutations/. Accessed September 7, 2024.« Back to MDS Virtual Congress 2020
MDS Abstracts - https://www.mdsabstracts.org/abstract/safety-tolerability-and-pharmacodynamic-profile-of-dnl201-at-dose-levels-demonstrating-lrrk2-inhibition-in-parkinsons-disease-patients-with-and-without-lrrk2-mutations/