Advancing Development of LRRK2-Targeted Therapeutics for Parkinson's Disease: Conference Proceedings and Roadmap for Research

With this study, we synthesize insights from a roundtable event held in June 2025 that brought together a diverse group of stakeholders, including academic researchers, clinicians, pharmaceutical industry leaders, and patient-advocacy organizations. The primary goal of the roundtable was to identify strategies that could advance the clinical development of therapeutics targeting the leucine-rich repeat kinase 2 (LRRK2) protein in individuals with Parkinson's disease (PD) given the importance of this protein for PD pathogenesis.

As discussed in the roundtable, PD is a progressive neurodegenerative condition that affects millions of individuals worldwide. A sizable proportion (almost 10 percent) of PD cases have been linked to genetic variants, including pathogenic variants in the LRRK2 gene, which make up between 1 and 2 percent of all PD cases (Simpson et al., 2022). The clinical development of novel therapeutics that target the LRRK2 pathway is particularly compelling because pathogenic variants in the LRRK2 gene are associated with both familial and idiopathic PD and drive the disease through enhanced kinase activity, thus providing a strong ration ale for therapeutic intervention (Alessi and Sammler, 2018). Individuals with PD that is associated with such pathogenic LRRK2 variants as LRRK2 p.G2019S or LRRK2 p.1441C/G/H remain a population of high interest for LRRK2-targeted therapies, although the rarity of these variants poses a significant challenge for recruitment. Additional research is critically needed to identify the broader role of LRRK2 pathobiology in the risk and progression of idiopathic PD (i.e., cases without pathogenic LRRK2 variants). This was the motivation for the LRRK2 Investigative Therapeutics Exchange (LITE) initiative, which The Michael J. Fox Foundation for Parkinson's Research (MJFF) began funding in 2025. The LITE initiative focuses on developing critical infrastructure and precompetitive partnerships to advance research on new therapeutic approaches to target LRRK2, support active LRRK2 therapeutic programs, and promote the development of LRRK2 pathway-relevant clinical biomarkers (The Michael J. Fox Foundation for Parkinson's Research, undated).

The LRRK2 pathway offers therapeutic promise for several key reasons. First, data suggest that 50-percent LRRK2 inhibition is not associated with negative health consequences (Whiffin et al., 2020). Second, there have been important advances in understanding the LRRK2 biology that could facilitate the development of LRRK2-targeted therapies, including the identification of Rab proteins as cognate substrates (Steger et al., 2016), which has enabled the development of target-engagement biomarkers in cerebrospinal fluid (CSF) and neutrophils (e.g., phosphorylated Rab [pRab]10 levels). Third, genome-wide association studies have identified several protein coding variants in the lrrk2 locus of unknown clinical significance that associate with pathogenic LRRK2 kinase activation (Kalogeropulou et al., 2022) and PD risk (Nalls et al., 2019), suggesting that these additional variants could be used to inform patient-enrichment strategies in clinical trials of LRRK2-targeted therapeutics. Fourth, there are promising candidate biomarkers of the endolysosomal pathway (Mabrouk et al., 2020), which have the potential to serve as pharmacodynamic indicators of pathway modulation.

Despite advances in LRRK2 therapeutic development, the field faces critical strategic decisions regarding how to approach clinical trial design for LRRK2 therapies. For example, there is an ongoing debate about what constitutes the most appropriate population in which to assess therapeutic effects of LRRK2-targeting agents. One option is to conduct the therapeutic study only with participants with LRRK2-PD, in which the mechanistic rationale is strongest, even though the feasibility of such a study would be limited by these variants' rarity (as mentioned, they account for about 1 to 2 percent of PD cases) (Simpson et al., 2022). Alternatively, the study population could be broadened to include the subset of individuals within the idiopathic PD group who do not carry a LRRK2 pathogenic variant but exhibit the LRRK2 pathway dysfunction observed in LRRK2-PD (hereafter referred to as LRRK2-like). A third strategy could be to include anyone with idiopathic PD without employing strategies for enriching the sample with LRRK2-PD or LRRK2 pathway dysfunction to enhance the feasibility of recruitment, although this would present a substantial risk of missing a biological effect of treatment. An enrichment approach is ideal, but significant additional research is required to establish more-robust biomarkers of LRRK2 pathobiology. These and other trial design approaches have distinct advantages and disadvantages that must be carefully considered to ensure that LRRK2 therapeutic trials yield data that are interpretable and informative for future development efforts.

Motivation for the Workshop

MJFF hosted an in-person workshop, LRRK2-Targeted Therapeutics Roundtable: Advancing Clinical Development for Parkinson's Disease, in June 2025 to discuss opportunities for communication, coordination, and collaboration to advance LRRK2-targeted therapeutic development. The purpose of this multistakeholder workshop was to create a collaborative platform for researchers, clinicians, industry representatives, and funders to discuss various clinical trial strategies, including trade-offs and opportunities related to target populations, endpoints, treatment durations, and target labels. By fostering precompetitive dialogue on clinical development for LRRK2-targeted therapies, MJFF sought to ensure that sponsors design robust and informative clinical trials that can accelerate drug development and meaningfully advance efforts to deliver effective treatments to patients.

Specifically, the goals of the workshop were as follows:

• Objective 1: Develop a roadmap to derisk LRRK2-targeted therapies across clinical development phases. This could include stratification approaches and go/no-go decisions for (1) advancing research in idiopathic PD patients versus genetically and/or biomarker-enriched populations, (2) identifying appropriate measures for biologic proof-of-concept and clinical efficacy studies, and (3) optimizing recruitment strategies for the target population(s).
• Objective 2: Identify opportunities for precompetitive collaboration on biomarker signatures and disease progression modeling to inform clinical trials of LRRK2-targeted therapies. Additionally, explore field-enabling investments to enhance recruitment efficiency in key geographies for drug approval and commercialization.

Key Takeaways

One of the core themes that emerged from the roundtable was the necessity to implement precision-medicine approaches for developing therapies targeting leucine-rich repeat kinase 2 (LRRK2), thereby increasing the chances for success of testing and delivering meaningfully beneficial therapies. To enable this critical objective, collaboration among various stakeholders is required. Key topics of the roundtable included discussion of: (1) creating approaches to harmonize clinical and biological assessments of cohorts of manifest carriers of pathogenic variants in the lrrk2 gene (hereafter referred to as LRRK2-PD patients) and corresponding nonmanifesting carriers to characterize disease progression and associated biomarker changes in this subgroup; (2) developing and validating of an armamentarium of biomarkers, which would include biomarkers of central target engagement and/or pathway modulation, patient-enrichment and -stratification markers, and measures of progression of LRRK2-PD; (3) identifying a biomarker signature (or signatures) of pathogenic LRRK2 phenotypes among idiopathic Parkinson's disease (PD) cases (i.e., cases without LRRK2 pathogenic variants), or the so-called LRRK2-like group; (4) generating effective strategies for clinical trial designs to test LRRK2-targeted therapeutics, including conceptualizing and implementing platform trials; and (5) optimizing trial design for regulatory approval in key markets. Participants highlighted that the complexity of existing regulatory frameworks and the need for new evidence and consensus to inform regulatory agencies, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) represent a significant challenge, especially considering the low prevalence of pathogenic LRRK2 variants.

Key short-term actions mentioned during the roundtable include developing a comprehensive inventory of existing LRRK2 cohorts and their associated clinical and biologic data and biospecimens to find opportunities for data acquisition and harmonization. This will accelerate efforts to understand the role that LRRK2 pathobiology plays in the onset and progression of PD, and it might facilitate participant recruitment. The identification and validation of biomarkers that are relevant to LRRK2 pathway dysfunction are essential for both identifying eligible participants and assessing therapeutic efficacy. We also discuss what participants cited as the need to adopt specialized clinical trial sites dedicated to LRRK2-PD research. This would include incorporating standardized protocols for genetic counseling and recruitment, along with staff training to improve operational effectiveness, and could be modeled on effective approaches to trial design that have been used with other rare diseases.

Ultimately, the roundtable participants envisioned the realization of using precision-medicine approaches, in which treatment strategies are tailored to individual patients based on specific underlying biological characteristics rather than a one-size-fits-all methodology. Achieving this realization will require not only the successful validation of biomarkers and a better understanding of the link between LRRK2 variants (and LRRK2 biology) and PD but also a robust clinical trial infrastructure that is capable of implementing these innovative trial designs.