Phase 2b Study of Parkinson Disease LRRK Inhibitor BIIB122 Initiated

Carole Ho, MD

Dosing for the global phase 2b LUMA study (NCT05348785), which will evaluate the efficacy and safety of BIIB122 (also known as DNL151), an investigational LRRK inhibitor for patients with Parkinson disease (PD), has officially commenced, according to an announcement from Biogen and Denali Therapeutics.¹

The double-blind, placebo-controlled study includes 640 participants between the ages of 30 and 80 years with early-stage PD 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. To understand whether BIIB122 slows the worsening of symptoms, researchers will evaluate patients on Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) parts II and III.

"Initiation of the LUMA study marks an important milestone in the development of BIIB122 as a potentially first-in-class oral LRRK2 therapy for Parkinson disease," Carole Ho, MD, chief medical officer, Denali, said in a statement.¹ "We look forward to continuing our collaboration with Biogen and the Parkinson’s community in our unified goal to develop BIIB122 as a potential treatment option for people and families living with Parkinson disease."

Discovered and developed by Denali, BIIB122 is a selective, central nervous system-penetrant small molecule inhibitor of LRRK2 that is hypothesized to improve dysfunction. To date, the investigational drug has not had its efficacy and safety established. As part of the clinical program, another trial, a phase 3 study called LIGHTHOUSE, will evaluate BIIB122’s effectiveness in nearly 400 patients with LRRK2-mutated PD.

In addition to MDS-UPDRS, other outcomes investigators will key in on include treatment-emergent adverse events (AEs) and serious AEs, and time to confirmed worsening in Schwab and England Activities of Daily Living Scale (SEADL). The SEADL scale reflects the speed, ease, and independence with which an individual performs daily activities or personal chores with 100% indicating total independence, falling to 0%, which indicates a state of complete dependence.

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"Inhibition of LRRK2 is a novel approach designed to target an underlying biological pathway implicated in Parkinson disease,” Samantha B. Haeberlein, PhD, senior vice president, head of Neurodegeneration Development, Biogen, said in a statement.¹ "Together, Biogen and Denali have designed a rigorous development program to evaluate BIIB122 in patients with and without LRRK2 mutations. With the LUMA study underway and the LIGHTHOUSE study planned to initiate this year, we have the opportunity to advance BIIB122 for the treatment of Parkinson disease, a progressive neurodegenerative disease with a high unmet need."

Mutations in the LRRK2 gene represent one 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 cases.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 one of the main stimulants of microglial activation, which is believed to contribute to neuroinflammation and neuronal death in PD.³

REFERENCES
1. Denali Therapeutics and Biogen announce initiation of phase 2b study of LRRK2 inhibitor in Parkinson disease. News release. May 31, 2022. Accessed June 23, 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

2. Bardien S, Marsberg A, Keyser R, et al. LRRK2 G2019S mutation: frequency and haplotype data in South African Parkinson disease patients. 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 of Parkinson disease. Curr Neuropharmacol. 2018;16(9):1348-1357. doi:10.2174/1570159X16666180222165418