Clinical Trial for Parkinson’s Disease Provides New Avenues for Research

The brains of many people with Parkinson’s disease include aggregations of a misfolded protein called alpha-synuclein. These aggregations accumulate in neurons and are believed to spread from nerve cell to nerve cell (neurons) as part of the progression of Parkinson’s disease.

While many current treatments for Parkinson’s disease treat the symptoms, such as tremor, muscle stiffness and difficulty with movement, researchers had recently developed a new monoclonal antibody called cinpanemab that was meant to bind to the abnormal alpha-synuclein so they could be cleared by the immune system — thus treating what is thought to be a major contributor to the root cause of the disease.

In pre-clinical research, the drug was able to bind to alpha-synuclein aggregates, reduce the spread of the proteins and slow the progression of disease.

“Alpha-synuclein is believed to be very important player in Parkinson’s disease, and in recent years, a number of approaches have been proposed to try to either eliminate or de-aggregate it,” says Lang, a senior scientist in the Krembil Research Institute at University Health Network’s Toronto Western Hospital. “This candidate is one of the first attempts to reduce alpha-synuclein, specifically the extracellular forms of the protein that may be spreading from cell to cell.”

Researchers including Lang conducted a phase 2 clinical trial of the drug, recruiting more than 350 people diagnosed with early Parkinson’s disease from centres in Canada, the United States and Europe. The patients were randomized into groups that received either a placebo or one of three different doses of cinpanemab. After one year, the patients in the placebo group also received the drug.

At the beginning of the trial and after one year, the researchers assessed and scored the patients’ motor and non-motor symptoms and performed brain imaging to visualize disease progression.

While the trial had originally been expected to continue for about two years, the researchers stopped it early when they found at 72 weeks that there were no differences between the placebo and treatment groups in either the scores of motor and non-motor function or in the brain images.

One possible explanation for the results is that the therapy was started too late — that the disease mechanisms are already well underway by the time it is diagnosed, even if the clinical diagnosis is considered “early.” The study authors note that, if this is the case, treatments using this approach might be more effective if they are started even earlier, at the onset of very first symptoms.

“The analogy is that we may be closing the barn door after the horse has already bolted. What we diagnose as early Parkinson’s is early clinical Parkinson’s, maybe not early pathological Parkinson’s,” says Lang, who is also a professor in the department of medicine and Institute of Medical Science at U of T’s Temerty Faculty of Medicine. “The cell-to-cell transmission may already be well-established in the brain and it may be too late to reverse, particularly using the mechanism of action of the various drugs that have been tried.”

Although the trial results did not demonstrate that cinpanemab is effective, Lang says negative results still provide critical information about Parkinson’s disease and potential treatment avenues. In fact, the trial’s research team will publish more data collected as part of the trial’s outcomes.

“A lot of subsequent studies are designed based on the results in the negative trial, such as how many people you need to enroll and for how long,” says Lang. “And you can also learn a lot from the ancillary studies, like the results of the brain imaging or biologic markers. We always learn from negative trials, with every bit of information that comes from it.”

He argues that negative results don’t necessarily mean that researchers should abandon a particular approach but simply that more research is needed to address questions such as those related to the timing of starting medication and methods of monitoring outcomes. In the future, developing disease modifying therapies for neurodegenerative diseases such as Parkinson’s may require combination therapies or cocktails in the same way that cancer therapy is commonly approached.

“I think it simply argues that we need more well-designed trials, and we need to interpret data carefully,” he says. “The field moves forward, sometimes slowly, sometimes taking one step forward and two steps back. But that’s the nature of clinical research.”