A hallmark sign of Parkinson’s disease (PD) is the accumulation of misfolded alpha-synuclein proteins in the brain. The proteins are the earliest known sign of PD, and research indicates that as they clump in the brain, they become toxic and lead to dopamine degeneration. So alpha-synuclein is a priority biologic target in the Parkinson’s therapeutic pipeline. A diverse range of alpha-synuclein-directed therapies are currently under investigation. 

This week, pharmaceutical companies reported results from two Phase II clinical trials of two respective experimental drugs designed to slow the progression of PD by targeting alpha-synuclein.  

• The UCB–Novartis ORCHESTRA trial of minzasolmin (UCB0599) found the drug had no effect on Parkinson’s, and the companies do not plan to continue testing.  

• The Roche PADOVA trial of prasinezumab did not meet its primary endpoint, but results suggested possible benefits, and the company plans to continue evaluating the data to determine next steps. 

The PD community has been watching these trials closely, along with several others testing additional approaches to alpha-synuclein, and any trial not meeting its outcomes can feel like a setback. To learn more about these results and their implications, we spoke with Kenneth Marek, MD, president and senior scientist at the Institute for Neurodegenerative Disorders, and Catherine Kopil, PhD, head of clinical research at The Michael J. Fox Foundation for Parkinson’s Research (MJFF). 

MJFF: Some media outlets are reporting that two Parkinson’s trials have “failed,” but is this really the takeaway? 

Kenneth Marek (KM): No, this is too simplistic a takeaway. 

It is fair to say that the ORCHESTRA Phase II study was not successful. The study tested an oral small-molecule drug (i.e., a pill) designed to prevent alpha-synuclein from clumping in the brain. After 18 months, the drug was found to be safe, and it appeared to travel to the brain as it was supposed to, but it definitively did not show an effect on PD based on results of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UPDRS is an assessment tool that evaluates motor and nonmotor symptoms, including things like daily living activities, movement function and mental state.  

Results from the PADOVA Phase II study were far less clear, and potentially encouraging, though more research is needed. 

PADOVA tested a different type of drug, a monoclonal antibody, designed to prevent the spread of toxic alpha-synuclein. Though PADOVA did not meet its primary objective, it did show signs of providing benefit to study participants on multiple tests that were part of the study. After 18 months, it appeared to have some impact on slowing the progression of Parkinson’s motor symptoms based on the MDS-UPDRS. And it also showed positive effects on some other trial goals, in addition to being safe and well-tolerated. Notably, another Roche Phase II trial of this same drug, the longer four-year PASADENA trial, reported stronger evidence recently that suggests prasinezumab does help slow the progression of PD symptoms over time.  

MJFF: What do these results mean for alpha-synuclein as a PD drug target? 

KM: All our best information indicates that alpha-synuclein plays a key role in the biology of Parkinson’s disease and should continue to be a focus for therapeutic development. Many readers will recall the beta-amyloid protein, which is similarly fundamental in Alzheimer’s disease. In the Alzheimer’s field, initial efforts to target beta-amyloid were not successful. But Alzheimer’s researchers learned from these efforts and continued to move forward, and today there are approved drugs that reduce beta-amyloid clumps and help slow the progression of the disease.  

Similarly, with alpha-synuclein, it may take a number of different studies to evolve the science before we have a clear sense of how a drug focused on alpha-synuclein can have a meaningful impact on PD. These first trials, even if their outcomes are not exactly what we’d hoped, provide critical learnings to build on in the near-term future. 

Catherine Kopil (CK): We continue to watch and be hopeful about a number of alpha-synuclein-targeted therapies that are being studied for Parkinson’s disease. The whole purpose of trials is to test the science until we learn what works. Because the trials that are reporting out are so well-designed and well-executed, they offer important lessons that now can be applied in the ongoing development of drugs targeting alpha-synuclein and help future trials be more successful. Drug development is incremental, and these early steps are essential to building knowledge and important to moving the field forward so that there is opportunity for a cure. 

MJFF: What will happen to other drugs in development that target alpha-synuclein? 

KM: As we’re seeing with the differing results of these two trials, the results of any one trial should not be taken as a signal to abandon therapies targeting alpha-synuclein. There is still a very strong rationale for treating PD with drugs that target alpha-synuclein. A lot more testing still is needed, and luckily that testing already is well underway, with around 15 drugs in the pipeline that seek to target the production, spread or clearance of PD-related alpha-synuclein clumps in the nervous system. The field will continue to rapidly test other alpha-synuclein drugs as well as many other strategies for treating PD.  

CK: MJFF funded earlier development of the drug in the ORCHESTRA trial [minzasolmin] and, both trials were enabled in party by data from our Parkinson’s Progression Markers Initiative. This is MJFF’s landmark study that follows thousands of people with and without Parkinson’s over time to learn more about how the disease starts and progresses. We continue to partner with the research community to keep advancing strategies in this area. As we learn more and develop better tools for drug development, these studies will have more informed designs and increasing chances for success. 

MJFF: How do these results relate to the alpha-synuclein seed amplification assay (SAA), the biomarker that detects misfolded alpha-synuclein in spinal fluid of people with Parkinson’s? 

KM: Readers will likely recall that the alpha-synuclein seed amplification assay, the first biological test capable of detecting these misfolded proteins in living people, became available in 2023. The ORCHESTRA and PADOVA trials were launched before the tool existed. So we do not know for sure that the people enrolled in the trials had the misfolded alpha-synuclein pathology that the drugs targeted. But we can assume based on the way that the participants were recruited that about 90 percent would test positive on SAA.  

Trials launched since the SAA became available can benefit by using the SAA to identify people most likely to respond to alpha-synuclein treatments. And for trials that started prior, the SAA still can be used to better understand the results —trial sponsors can apply it even after a trial ends to learn which participants were positive or negative for alpha-synclein, as long as spinal fluid samples were collected and banked.  

Something the results really highlight is the critical unmet need for a so-called “quantitative” biomarker. To understand a quantitative test, just think of today’s cholesterol tests, which we all undergo at routine check-ups. These tests reveal not just when bad cholesterol is present as a “yes or no” but tell your doctor how much bad cholesterol there is; higher levels indicate further progression of heart disease. Similarly, a quantitative biomarker for PD could help show if a drug to prevent alpha-synuclein clumps, or minimize alpha-synuclein spread, actually does what it is designed to do. Not having tests like this is one of the big challenges for trials today, but we are hopeful that we will have them soon.  

CK: Having effective research tools like the alpha-synuclein SAA is so important for being able to understand Parkinson’s and assess drugs designed to treat it. We expect that as biomarkers for PD improve, they will in turn help drive innovation and make clinical trials more effective. It’s worth noting that one of the main drivers in the development of these tools is our Parkinson’s Progression Markers Initiative, which funnels a wealth of insights, practical tools and data directly into Parkinson’s drug development. 

MJFF: Beyond just alpha-synuclein, what is the outlook today for PD therapeutic development? 

KM: Drug trials in PD continue to build on each other in ways that advance the field. It is important and hopeful that so many drug trials for PD are happening. Multiple innovative studies are testing therapies targeting alpha-synuclein as well as a variety of other promising targets. We feel that we are on a path now that can and will lead us to effective, next-generation drugs.  

CK: We continue to see so much momentum. There is growing energy among researchers and robust industry interest and investment in Parkinson’s. And the Foundation is well-positioned to accelerate much-needed work to find better and faster ways to assess the experimental drugs exploiting our growing understanding of Parkinson’s biology.  

MJFF’s Clinical Research Team is executing a comprehensive effort to partner with key players, including regulators, the Critical Path Institute, industry researchers, clinicians and patient advocates to develop a wide array of clinical trial-enabling tools. Together, we are making important progress to identify and validate urgently needed measurements of drug effects in clinical trials. These include clinical outcome assessments, digital measures, and biomarkers, and they work together to streamline and accelerate how we assess the benefits and risks of new therapies. MJFF is 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. All of this is possible because of the people who volunteer for studies, and we are learning every day from the gift of their contributions to science.