Objective: Describe Luma and Lighthouse, two studies that investigate efficacy and safety of BIIB122, a LRRK2 inhibitor.

Background: Increased LRRK2 kinase activity has been linked to lysosomal dysfunction and Parkinson’s disease (PD) pathogenesis. Inhibition of LRRK2 kinase activity is a promising new approach to treat PD with and without a LRRK2 mutation. BIIB122 is a potent, selective, CNS-penetrant LRRK2 kinase inhibitor under investigation for treatment of PD.

Method: Two multi-center, randomized, double-blind, placebo-controlled trials will investigate the efficacy and safety of BIIB122 in early-stage PD patients.  
 
The Luma study will enroll PD patients who do not carry a LRRK2 pathogenic variant (n~640 patients) diagnosis within 2 years, Hoehn and Yahr 1-2, untreated with symptomatic PD medications or stably treated with MAOB inhibitor or levodopa monotherapy.  Luma participants will be randomized (1:1) to BIIB122 225 mg or placebo administered orally daily for a 48-week minimum to 144-week maximum treatment period.
The Lighthouse study will enroll patients carrying a LRRK2 pathogenic variant (n~400 patients) diagnosis within 5 years, Hoehn and Yahr 1-2.5, untreated or stably treated with symptomatic PD medications. Lighthouse participants will be randomized (1:1) to BIIB122 at doses of 225 mg or placebo administered orally daily for a 96-week minimum to 180-week maximum treatment period. 
Primary outcome measure will be a time to event endpoint using the Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) for both studies. Secondary outcomes will include safety, Schwab and England Activities of Daily Living Scale, and MDS-UPDRS. Pharmacokinetics of BIIB122 will be examined through plasma levels. Pharmacodynamics will be characterized by phosphorylated serine 935 in whole blood for target inhibition, BMP in urine for downstream lysosomal pathway modulation, and total LRRK2 and lysosomal markers in cerebrospinal fluid for central target and lysosomal pathway engagement.

Results: Early studies on BIIB122 support its continued development through Luma and Lighthouse.

Conclusion: Luma and Lighthouse are the first studies of LRRK2 inhibition in PD patients with efficacy endpoints that measure clinical progression of PD and biomarkers that measure the expected biologic impact of LRRK2 inhibition.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-inhibition-by-biib122-trial-designs-for-two-efficacy-and-safety-studies-in-parkinsons-disease-patients-with-and-without-lrrk2-mutations-lighthouse-and-luma/