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Similar to the recently commenced phase 2b LUMA study, BIIB122, an investigational small molecule inhibitor of LRRK2, will be evaluated in a cohort of 400 individuals with genetically mutated Parkinson disease.
Samantha B. Haeberlein, PhD
Dosing 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 disease (PD) with a confirmed pathogenic mutation in the LRRK2 gene, has commenced.1
BIIB122, a small molecule inhibitor of LRRK2 discovered and initially developed by Denali, will be assessed in a cohort of 400 individuals with genetically mutated PD. In the multicenter, double-blind study, individuals will be randomly assigned to either 225-mg BIIB122 tablets, orally once daily, for up to 180 weeks, or matching placebo. The primary outcome measures include the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts II and III, which evaluates experiences of daily living and motor signs of PD, respectively.
"Mutations in the LRRK2 gene comprise the most frequent mutations found in Parkinson’s disease, indicating that LRRK2 inhibition may be a promising therapeutic approach to the disease," Samantha B. Haeberlein, PhD, head of Neurodegeneration Development, Biogen, said in a statement.1 "The LIGHTHOUSE study will specifically recruit individuals with a pathogenic mutation in LRRK2, enabling us to test the genetic hypothesis and implicated lysosomal pathway. The LIGHTHOUSE study is the largest study ever undertaken in individuals with Parkinson’s disease caused by a LRKK2 mutation."
The study features patients aged 30 to 80 years who have a clinical diagnosis of PD that met the MDS clinical diagnostic criteria within 5 years of the screening visit. Additionally, these patients have modified Hoehn and Yahn scale stages between 1 to 2.5 at screening, and a combined score of less than 40 in MDS-UPDRS Parts II and III at that time. Individuals with a clinically significant neurological disorder other than PD or those with evidence of atypical parkinsonism were excluded from the study.
Mutations in the LRRK2 gene represent 1 of the most common genetic causes of PD, explaining an estimated 4% to 5% of familial and 1% to 2% of sporadic PD cases. In some ethnic groups, in particular those of Ashkenazi Jewish or North American Arab Berber decent, this frequency rises to between 30% and 40% of familial and sporadic cases, respectively.2 It has also been reported that dysfunction of LRRK2 may influence the accumulation of alpha-synuclein and its pathology to alter cellular functions and signal pathways by the kinase activation of LRRK2. The accumulation of α-synuclein is among the main stimulants of microglial activation, which is believed to contribute to neuroinflammation and neuronal death in PD.3
The NDA for the Supernus therapy, supported by data from the phase 3 TOLEDO study in patients with Parkinson disease, will require additional information and 6 months of further review. No additional efficacy or safety studies are required.
"In collaboration with Biogen, we are excited to be pursuing the potential of LRRK2 inhibition as an effective treatment for Parkinson’s disease,” Carole Ho, MD, chief medical officer, Denali Therapeutics, said in a statement.1 "The initiation of the phase 3 LIGHTHOUSE study marks an important milestone in the BIIB122 development program. Together with the recent initiation of the phase 2b LUMA study in early-stage Parkinson’s disease, we hope to have the opportunity to bring a novel therapeutic option to people living with Parkinson’s disease."
Biogen and Denali’s other study, the phase 2b LUMA trial (NCT05348785), commenced in June 2022, will also evaluate BIIB122 in a large cohort of patients with LRRK2-associated, early-stage PD. Similar to LIGHTHOUSE, that double-blind, placebo-controlled study includes 640 participants who will be randomly assigned to 225 mg of oral BIIB122 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-emergent adverse events (AEs) and serious AEs, as well as time to confirmed worsening in Schwab and England Activities of Daily Living Scale.4
