Variations in the LRRK2 gene are one of the strongest known genetic contributors to Parkinson’s disease (PD). These variations cause overactivity in the LRRK2 protein pathway that increases neuroinflammation, damages dopamine neurons and leads to PD. Scientists think lowering that activity could protect cells and slow Parkinson’s progression.
Several PD therapies in clinical trials aim to reduce LRRK2 activity in hopes of slowing disease progression, which is something that no currently approved medications can yet do. There is hope that these treatments could meaningfully help people with inherited LRRK2 variations and potentially many other people who develop Parkinson’s that involves the same biological pathway.
Recently, researchers reported clinical trials results for one of the field’s leading LRRK2 clinical trial efforts, called the LUMA trial. Led by Denali Therapeutics in collaboration with Biogen Inc., the Phase II trial tested whether the experimental therapy, a LRRK2-inhibitor called BIIB122 (also known as DNL151), could slow worsening of Parkinson’s symptoms in people with early-stage disease.
The trial assessed whether BIIB122 extended the “time to confirmed worsening” of Parkinson’s symptoms in 648 people with early-stage Parkinson’s as assessed by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts II and III, which measure patient-reported and clinician-assessed motor symptoms. It also tested the drug’s safety and tolerability. The trial included people both with and without PD-linked LRRK2-mutations.
This week, Biogen and Denali reported that trial participants who took that drug for at least 48 weeks did not experience a slower time to worsening of symptoms than those receiving the placebo. The drug did show signs of reducing LRRK2 activity, and it was generally well-tolerated with an acceptable safety profile. Based on the results, Denali plans to continue testing the drug only in people with LRRK2-related PD (and not the general Parkinson’s population) through its independent Phase II BEACON study.
Given the broader LRRK2 research pipeline and longstanding investment in this therapeutic approach, the results are particularly important. The PD community has been watching the trial closely, along with several others testing additional approaches to LRRK2, and any trial not meeting its outcomes can feel like a setback.
Stay tuned to MJFF’s channels for additional insights and expert Q&A with leading researchers on ongoing LRRK2 therapeutic development.
MJFF’s Role in the LRRK2 Therapeutic Pipeline
Over the past two decades, MJFF has helped transform LRRK2 from a genetic discovery into a validated, druggable target, including enabling multiple LRRK2 inhibitors in clinical trials, guiding fieldwide adoption of biomarkers for target engagement, and establishing a model for collaborative therapeutic development in Parkinson’s. MJFF is committed to continuing to work to de-risk therapeutic development. MJFF’s LRRK2 Investigative Therapeutics Exchange (LITE) is a large-scale global collaboration of academic researchers, industry experts and clinicians who are working to fast-track a diverse portfolio of LRRK2 therapeutic approaches, standardized biomarker assays and target engagement strategies that may inform future LRRK2-directed therapy development.
A related project focusing on LRRK2 signaling pathways is part of the Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network (CRN), creating a point of collaboration across initiatives. The LITE program also benefits from collaboration with other ASAP initiative-supported programs including the Parkinson’s Precision Markers Initiatives (PPMI) and the Global Parkinson’s Genetics Program (GP2).
Through PPMI, MJFF also supports precision recruitment for genetic stratification and patient identification. An MJFF-led LRRK2 Platform Trial is being planned to target a LRRK2-enriched population and offer greater potential to test a range of LRRK2-directed therapies in parallel, potentially speeding answers.
At the heart of these efforts are tens of thousands of study volunteers and researchers around the world. The Michael J. Fox Foundation remains committed to funding and facilitating collaborative research in all these areas to ensure drug developers have the best tools to measure the effects of their drugs and bring them to market faster.