Objective: To evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of the LRRK2 inhibitor, DNL151 (BIIB122), in healthy volunteers (HVs) and Parkinson’s disease (PD) patients.

Background: Increased LRRK2 kinase activity is thought to impair lysosomal function and drive Parkinson’s disease (PD) pathogenesis. Inhibition of LRRK2 kinase activity is a promising new approach to treat PD with a LRRK2 mutation and sporadic PD. DNL151 is a potent, selective, CNS-penetrant LRRK2 kinase inhibitor under investigation for treatment of PD.

Method: Two studies are being conducted to evaluate DNL151. DNLI-C-0001 is a double-blind, placebo-controlled Phase 1 single- and multiple-ascending dose HV trial evaluating multiple doses up to 28 days. DNLI-C-0003 is a multi-center, double-blind, placebo-controlled, Phase 1b PD patient trial evaluating 3 dose levels over 28 days. Safety assessments for both studies include vital signs, ECGs, laboratory tests, pulmonary function testing, and adverse events (AEs). Biomarker outcomes include pS935-LRRK2 in whole-blood for target engagement; pT73-pRab10 in PBMCs for pathway engagement; and urine BMP, a measure of lysosomal function downstream of LRRK2.

Results: DNLI-C-0001 randomized 186 HVs and DNLI-C-0003 randomized 36 PD patients. DNL151 has been generally well tolerated in both studies. No serious adverse events have been reported; AEs were experienced in 85% of HVs to date and 73% of PD on active treatment, the majority were mild in severity. One HV subject discontinued early in DNLI-C-0001 due to moderate nausea, headache, impaired concentration and diarrhea. Two PD patients discontinued early in DNLI-C-0003 due to hypotension or orthostatic hypotension; both resolved without intervention. At well-tolerated doses in both HVs and PD patients, a median, time-averaged reduction up to ~85% in pS935-LRRK2 and pT73-Rab10 and a reduction in urine BMP, a lysosomal biomarker, were observed. Final data will be presented for both DNLI-C-0001 and DNLI-C-0003 trials.

Conclusion: DNL151 achieved target engagement and biomarker goals supporting the hypothesis that LRRK2 inhibition modulates and improves lysosomal function at doses that are generally well tolerated.  These early phase studies in healthy volunteers and PD patients support continued investigation of LRRK2 inhibition with DNL151 for the treatment of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-inhibition-by-biib122-dnl151-safety-tolerability-pharmacokinetics-and-pharmacodynamics-in-ph-1-healthy-volunteer-and-ph-1b-parkinsons-disease-trials/