The full results of the AZA-PD study, a phase 2 clinical trial of the immunosuppressive drug azathioprine, have now been published. Although the study did not meet its primary outcome, it does lay the groundwork for future clinical trials of anti-inflammatory drugs, including the ongoing trial of dapansutrile.
The full results of the AZA-PD study have now been published in the scientific journal The Lancet Neurology and are publicly available.
What was AZA-PD?
Over-activity of the immune system in the brain, referred to as neuroinflammation, is a known driver of Parkinson’s. Therefore, researchers have been interested in whether anti-inflammatory drugs could treat and slow Parkinson’s progression.
Starting in 2020, Dr Caroline Williams-Gray at the University of Cambridge led a phase 2 clinical trial of azathioprine (AZA-PD) – an immunosuppressive drug currently used to treat autoimmune conditions, such as rheumatoid arthritis. This trial involved 66 people with Parkinson’s taking azathioprine or a placebo (dummy drug) for 12 months. The researchers aimed to evaluate whether azathioprine can “correct” the Parkinson’s immune profile and slow progression of the condition by suppressing immune activity in the brain and body. They also compared the immune profiles of all participants in the trial to get a better idea of how this differs in people with Parkinson’s.
What were the results?
Although some participants did report improvements, the researchers did not find a clinically significant difference between the motor symptoms of people taking azathioprine and those taking the placebo. This means that the trial, unfortunately, did not meet its primary endpoint. Additionally, any positive effects seen during the trial did not persist after stopping the treatment, indicating that azathioprine did not have a lasting effect on Parkinson’s progression.
The team did, however, identify several sub-populations who may have responded better to azathioprine. For example, they saw greater beneficial effects in women. This finding is of particular interest as women are often under-represented in Parkinson’s research, and autoimmune conditions are also more common in women. Researchers also found that participants with faster-progressing Parkinson’s showed signs of improved memory and thinking. Although these outcomes are interesting, this was a small, proof-of-concept trial, meaning they will need to be validated in larger, more robust clinical trials.
Cure Parkinson’s funded a sub-study of the trial, which aimed to better understand azathioprine’s mechanism of action, or what the drug interacts with in the body to achieve the desired effect. Using blood and cerebrospinal fluid (the fluids surrounding the brain and spinal cord) samples, as well as brain imaging, researchers found that azathioprine suppressed immune activity in the central nervous system (brain and spinal cord) and appeared to slow the spread of inflammation in the brain.
Why is this study important?
Although the trial did not meet its primary outcome, it does lay important groundwork for further investigations of anti-inflammatory drugs. This is the first trial to show that broadly suppressing the immune system could improve Parkinson’s symptoms for some individuals. Additionally, AZA-PD demonstrated that immunosuppressive medications can be a safe treatment for people with Parkinson’s. The researchers found that the risk of infection was not higher in the participants taking azathioprine, and the treatment was well tolerated.
These outcomes are important for future clinical trials of drugs targeting inflammation, including the ongoing phase 2 trial of dapansutrile. This trial, called DAPA-PD, is being funded by Cure Parkinson’s and again led by Dr Caroline Williams-Gray. Dapansutrile provides a more targeted approach than azathioprine, with the drug lowering the activity of a specific pro-inflammatory protein that is commonly found in the brain’s immune cells.
The scientific justification for testing dapansutrile in Parkinson’s
The Cure Parkinson’s Research Team have put together a document summarising the science behind dapansutrile, intended for all audiences. This document can be downloaded below.
We are pleased to announce that DAPA-PD is now underway, and we look forward to seeing how the trial progresses.
