Upcoming Clinical Trial Will Test Immunosuppressant in Slowing Parkinson’s

An upcoming clinical trial, known as the AZA-PD study, will test whether limiting the activity of the immune system through the use of an immunosuppressant can slow the progression of Parkinson’s disease.

The Phase 2 trial (ISRCTN14616801) — officially Azathioprine immunosuppression and disease modification in Parkinson’s disease — is a proof of concept study expected to enroll 60 patients with an elevated risk of disease progression. The participants will be randomly divided into two groups, with one set given a placebo and the other treated with an “old drug” called azathioprine.

Azathioprine is an immunosuppressant, or a medication that limits the inflammatory activity of the immune system. The medication itself has a long history; for many years, it has been used to prevent rejection after transplants and to treat certain kinds of arthritis.

According to Caroline Williams-Gray, PhD — a clinician scientist at the University of Cambridge, in the U.K., who is leading the AZA-PD study — targeting the immune system “would represent an entirely new strategy for treating Parkinson’s disease.”

Williams-Gray spoke in a video released by The Cure Parkinson’s Trust.

Although Parkinson’s is usually thought of as a neurological condition, the disease disrupts multiple bodily systems, including the immune system. According to Williams-Gray, the evidence that the immune system contributes to Parkinson’s progression is quite strong at this point. Experiments in animal models of the disease support such a role of the immune system, and there has even been evidence in human studies.

“For example, genetic studies have provided some really strong evidence supporting this idea that the immune system is really critical in Parkinson’s,” said Williams-Gray, explaining that mutations in some immune-associated genes have been linked with Parkinson’s risk. Studies of human immune cells and epidemiological research also have supported the role of the immune system in Parkinson’s.

“Our theory is that, in Parkinson’s, cell death in the brain and the release of toxic proteins from these cells leads to activation of the immune system, and this immune activation then drives further cell damage and death in a sort of vicious cycle,” Williams-Gray said.

“If we can suppress the immune response and break that vicious cycle, we can slow down cell death, and we can slow down disease progression in patients,” she added.

Williams-Gray stressed that all currently available Parkinson’s treatments are symptomatic — that is, they can ease its symptoms, but they don’t actually slow the course of the disease.

The upcoming trial will evaluate participants given azathioprine or a placebo over the course of a year. Participants also will be followed for an additional six months. The study’s main goal is to determine the effect of the immunosuppressant treatment on Parkinson’s progression.

Laboratory markers, such as levels of proteins in the blood and brain imaging, also will be assessed. In particular, the researchers will measure markers of immune activity, to better understand the connection between the immune system and Parkinson’s.

Even if the results from this trial are positive, however, Williams-Gray stressed that azathioprine won’t necessarily become a standard treatment for Parkinson’s. Instead, she said, this trial will serve as a “proof-of-concept” to support further clinical studies into the potential effectiveness of azathioprine or other immunosuppressants as a Parkinson’s treatment.

“Is it a good idea to suppress the peripheral immune system; does that have beneficial effects in Parkinson’s?” she said. “If we find evidence that that’s the case, then it will mean that we can look at immunosuppressants as a class of drugs more carefully, and then we can think about which immunosuppressant drug might be the very best one to take forward in a larger trial.”

Azathioprine was chosen for this study largely because it is an immunosuppressant that has been in use for a long time — so a lot is already known about it.

“The fact that it’s an old drug is actually quite helpful to us, because it means we know exactly how to use it,” Williams-Gray said.

In addition to having well-established dosing regimens, the side effects of azathioprine are known, so clinicians can monitor for them, she added.

The study is expected to begin enrolling in March 2021. It is recruiting participants from a single site in Cambridge, in England, who will be identified from the PD Research clinic database at the John van Geest Centre for Brain Repair. These individuals have undergone detailed clinical examination and have available information on demographics, other underlying conditions, and current medications.

Only people in the early stages of Parkinson’s disease — within three years of diagnosis — who are at high risk of rapid disease progression will be included. Williams-Gray said that including only people who are likely to experience rapid Parkinson’s progression will give the small trial optimum odds for detecting statistically significant treatment effects. 

For safety reasons, the trial is not enrolling people who are already on immunosuppressants or have other immune conditions.

Results from the trial originally had been expected early in 2023, but that timeframe may be pushed back due to COVID-19. The researchers noted that recruitment has not yet commenced due to safety concerns regarding the pandemic. The current aim is to start recruiting in March 2021, with the last patient visit expected by November 2023. However, those dates may change depending on the pandemic.