LIGHTHOUSE Phase 3 Study of LRRK2 Inhibitor BIIB122 Initiated in Parkinson’s Disease

Assay for the large-scale Phase 3 LIGHTHOUSE study (NCT05418673) evaluating the safety and efficacy of BIIB122 (Biogen/Denali Therapeutics), an investigational agent for patients with Parkinson’s disease (PD) with a mutation pathogen confirmed in the LRRK2 gene, started.1

BIIB122, a small molecule inhibitor of LRRK2 discovered and initially developed by Denali, will be evaluated in a cohort of 400 people with genetically mutated PD. In the multicenter, double-blind study, individuals will be randomly assigned to either 225 mg tablets of BIIB122, orally once daily, for up to 180 weeks, or a matching placebo. Primary outcomes include Parts II and III of the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which assesses daily life experiences and motor signs of Parkinson disease.

“The changes in LRRK2 gene include the most common mutations found in Parkinson’s disease, indicating that LRRK2 inhibition may be a promising therapeutic approach to the disease,” said Samantha B. Haeberlein, PhD, head of neurodegeneration development at Biogen, in a statement.1 “The LIGHTHOUSE study will specifically recruit individuals with a pathogenic mutation in LRRK2, allowing us to test the genetic hypothesis and the lysosomal pathway involved. The LIGHTHOUSE study is the largest study ever undertaken in people with Parkinson’s disease caused by a LRKK2 mutation.”

The study involves patients between the ages of 30 and 80 who have a clinical diagnosis of PD that meets the clinical diagnostic criteria for MDS within 5 years of the screening visit. Additionally, these patients had modified Hoehn and Yahn scale stages between 1 and 2.5 at screening, and a combined score of less than 40 in MDS-UPDRS Parts II and III at that time. People with a clinically significant neurological disorder other than PD or those with signs of atypical parkinsonism were excluded from the study.

Mutations in the LRRK2 represent one of the most common genetic causes of PD, explaining about 4% to 5% of familial PD cases and 1% to 2% of sporadic PD cases. In some ethnic groups, particularly those of Ashkenazi Jewish or North American Berber Arab descent, this frequency rises to between 30% and 40% of familial and sporadic cases, respectively.2 It has also been reported that dysfunction of LRRK2 can influence alpha-synuclein accumulation and its pathology to alter cellular functions and signaling pathways through activation of alpha-synuclein kinase LRRK2. Accumulation of α-synuclein is one of the main stimulators of microglial activation, which is thought to contribute to neuroinflammation and neuronal death in PD.3

“Together with Biogen, we are excited to pursue the potential of LRRK2 inhibition as an effective treatment for Parkinson’s disease,” Carole Ho, MD, chief medical officer of Denali Therapeutics, said in a statement.1 “The launch of the LIGHTHOUSE phase 3 study marks an important step in the development program of BIIB122. Alongside the recent launch of the LUMA phase 2b study in early-stage Parkinson’s disease, we hope to have the opportunity to bring a new therapeutic option to people living with Parkinson’s disease. »

Biogen and Denali’s other study, the Phase 2b LUMA trial (NCT05348785), initiated in June 2022, will also evaluate BIIB122 in a large cohort of patients with LRRK2– PD associated with an early stage. Similar to LIGHTHOUSE, this double-blind, placebo-controlled study includes 640 participants who will be randomly assigned to oral BIIB122 225 mg or placebo once daily for a minimum of 48 weeks and a maximum of 144 weeks. In addition to using MDS-UPDRS Parts II and III, investigators will also assess treatment-related adverse events (AEs) and serious AEs, as well as time to confirmed worsening in the Activities of Daily Living Scale from Schwab and England.4

REFERENCES
1. Biogen and Denali Therapeutics announce the initiation of the LIGHTHOUSE Phase 3 study in Parkinson’s disease associated with LRRK2 pathogenic mutations. October 3, 2022. Accessed October 11, 2022. https://www.globenewswire.com/news-release/2022/10/03/2526798/0/en/Biogen-and-Denali-Therapeutics-Announce-Initiation-of- the-Phase-3-LIGHTHOUSE-Study-in-Parkinson-s-Disease-Associated-with-LRRK2-Pathogenic-Mutations.html
2. Bardien S, Marsberg A, Keyser R, et al. LRRK2 G2019S mutation: frequency and haplotype data in South African patients with Parkinson’s disease. J Neural Transm (Vienna). 2010;117(7):847-853. doi: 10.1007/s00702-010-0423-6.
3. Rui Q, Ni H, Li D, Gao R, Chen G. The role of LRRK2 in neurodegeneration in Parkinson’s disease. Curr Neuropharmacol. 2018;16(9):1348-1357. doi:10.2174/1570159X16666180222165418
4. Denali Therapeutics and Biogen announce the initiation of a phase 2b study of the LRRK2 inhibitor in Parkinson’s disease. Press release. May 31, 2022. Accessed October 11, 2022. https://www.globenewswire.com/news-release/2022/05/31/2453199/0/en/Denali-Therapeutics-and-Biogen-Announce-Initiation-of- Phase-2b-Study-of-LRRK2-Inhibitor-in-Parkinson-s-Disease.html

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