Variations in the LRRK2 gene are one of the strongest known genetic contributors to Parkinson’s. These variations cause overactivity in the LRRK2 protein pathway that ultimately 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 with the goal 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, Biogen and Denali Therapeutics reported results for one of the field’s leading LRRK2 clinical trial efforts, called the LUMA trial. 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 motor symptoms in more than 600 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. It also tested the drug’s safety and tolerability. The trial largely included Parkinson’s patients without known genetic mutations, though a small number of individuals with LRRK2-mutations were also included.
Trial participants who took that drug for at least 48 weeks experienced Parkinson’s symptom worsening at a similar rate to those who received 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.
To learn more about the results and their implications, we spoke with Andrew Siderowf, MD, MS, the Hurtig-Stern Professor of Neurology and the Chief of the Movement Disorders Division in the Penn Perelman School of Medicine Department of Neurology. Dr. Siderowf was a site investigator for the LUMA trial and is the current Chair of the Parkinson Study Group, where he is developing innovative clinical trials including those targeting LRRK2.
The Michael J. Fox Foundation (MJFF): How do results like this help move the field forward?
Andrew Siderowf (AS): LUMA was designed to test the safety and efficacy of BIIB122.
The safety findings were notable and encouraging. It was a long study and, at least at the dose tested, there were no safety concerns. These results raise confidence that safety won’t be a barrier to testing similar LRRK2 drugs in the future. That’s very important.
While the efficacy findings were disappointing, they provide an opportunity to better understand variables that can impact the testing of LRRK2 and other precision-targeted drugs for PD.
LUMA tested the drug in a mixed group that included some people with the LRRK2 mutations that are linked to Parkinson’s but mostly people who have Parkinson’s but don’t have these mutations. This broader population could have affected the results. The ongoing BEACON trial could provide more clarity about targeting LRRK2. It’s a smaller and shorter-duration trial that is testing the same drug [BIIB122] but only in people with LRRK2 mutations.
LUMA’s main endpoint assessed whether the drug changed Parkinson’s motor symptom progression. Since Parkinson’s symptoms often change slowly and unpredictably, it might be that different measures are needed to capture the drug’s impact on disease progression. LUMA exploratory biomarker assessments indicated that the drug had some effect on reducing LRRK2 activity. BEACON is likely to give some more clarity around this issue. Since its endpoints are entirely based on biomarkers, it will give us the chance to learn more about how well the drug engages with its target. That kind of precision tracking will be important for learning about the drug’s impact.
We're looking forward to being able to dissect more of the trial’s granular data when it is released. The data can help us learn more about the impact of targeting LRRK2 in PD, and these learnings can in turn help us adjust how we go about targeting LRRK2.
MJFF: What's next for this and other drugs that target LRRK2?
AS: This is just the first LRRK2 therapy to have an efficacy read out. We still have a lot of reasons to hope that LRRK2 is a promising avenue for treating Parkinson’s.
There are many promising LRRK2 compounds in early development and clinical testing, including ones that have different mechanisms of action for targeting LRRK2. And there is an active research community that is working to improve development of drugs that target LRRK2. Collaborative efforts like the LRRK2 Investigative Therapeutics Exchange [LITE] especially hold potential for advancing therapeutic research at an accelerated pace, including by supporting research on drug potency and target engagement that helps in selecting and de-risking the pathway forward for drugs with highest potential for success.
MJFF: What lessons have we learned from this trial?
AS: LUMA was an ambitious trial and a major achievement. It took dedication from people throughout the Parkinson’s field, and it wouldn’t have been possible without the participation of volunteers living with Parkinson’s disease who took part in trial.
Lessons from the trial are certain to hold scientific value for helping advance the field toward precision medicine. What we learn can move LRRK2 drug development forward more strategically and increase the chances of success in the future for drugs able to slow the progression of the disease.
The results don’t change the fact that LRRK2 continues to be one of the most promising targets for treating Parkinson’s.
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.
The LITE program benefits from collaboration with Aligning Science Across Parkinson’s (ASAP) initiative-supported programs including the Parkinson’s Precision Medicine Initiative (PPMI), Collaborative Research Network (CRN) and the Global Parkinson’s Genetics Program (GP2).
In point of collaboration, ASAP, in partnership with MJFF, are supporting scientists around the world to work together to answer some of the most pressing questions in Parkinson’s research, including the mechanisms behind different manifestations of Parkinson’s disease with the goal of moving toward precision medicine tailored to specific patient subtypes.
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.