Objective: To characterize the pharmacokinetics (PK), pharmacodynamics, safety, and exposure-response (E-R) relationships of BIIB122/DNL151 to inform on clinical dose selection.

Background: Increased LRRK2 kinase activity has been linked to lysosomal dysfunction and Parkinson’s disease (PD) pathogenesis. Inhibition of LRRK2 kinase is a promising approach to treat PD with a LRRK2 mutation and sporadic PD. BIIB122/DNL151 is a potent, selective, CNS-penetrant LRRK2 kinase inhibitor under investigation for treatment of PD.

Method: PK, pharmacodynamics, and safety of oral, once-daily dosing of BIIB122/DNL151 were evaluated in Phase 1 and Phase 1b double-blind, placebo-controlled, single- and multiple-ascending dose studies in healthy volunteers (HVs) and PD participants, respectively. E-R relationships were characterized using inhibitory I_max models. PK endpoints included BIIB122/DNL151 plasma concentrations. Pharmacodynamic biomarker endpoints included peripheral LRRK2 inhibition (reduction in pS935 LRRK2 in whole blood and reduction in pRab10 in PBMCs), central LRRK2 inhibition (reduction in total LRRK2 in CSF), and modulation of downstream lysosomal function (reduction in di‑22:6‑bis(monoacylglycerol)phosphate [BMP] in urine). Safety assessments included vital signs, ECGs, laboratory tests, pulmonary function testing (PFT), and adverse event reporting.

Results: HVs (n=186) and PD participants (n=36) were randomized. LRRK2 inhibition in the periphery and in the CNS was concentration-dependent. Reduction of urine BMP corresponded to ~80-90% of LRRK2 inhibition based on average concentrations. Similar E-R relationships were observed in HVs and PD participants. BIIB122 was generally well tolerated with no serious adverse events. No PFT values met the threshold (20% reduction from baseline) for discontinuation.

Conclusion: E-R analysis indicated BIIB122/DNL151 potently inhibited peripheral and central LRRK2 activity. Higher average concentrations associated with ~80-90% LRRK2 inhibition were required to impact downstream lysosomal pathways. These concentrations were achieved at doses that were generally well tolerated in HVs and PD participants. PK, pharmacodynamic and safety data from these studies informed dose selection for the ongoing LUMA and LIGHTHOUSE studies.

References: [1] Jennings D, Wetering de Rooij Jvd, Vissers MFJM, Heuberger JAAC, Groeneveld GJ, Maciuca R, Kay A, Borin M, Wong B, Daryani V, Huntwork-Rodriguez S, Cruz-Herranz A, Chin P, Ho C TM. LRRK2 Inhibition by BIIB122 / DNL151: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Ph 1 Healthy Volunteer and Ph 1B Parkinson’s Disease Trials. In: MDS Virtual Congress 2021. International Parkinson and Movement Disorder Society; 2021.
[2] A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL151 in Healthy Volunteers. https://clinicaltrials.gov/ct2/show/NCT04557800.
[3] Study to Evaluate DNL151 in Subjects With Parkinson’s Disease. https://clinicaltrials.gov/ct2/show/NCT04056689.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-inhibition-by-biib122-dnl151-demonstrates-robust-target-and-lysosomal-engagement-pharmacokinetics-pharmacodynamics-and-safety-in-phase-1-and-phase-1b-studies-in-healthy-and-parkinsons/