Phase 2 Trial of Azathioprine Fails to Meet Primary Endpoint in Early Parkinson's Disease
Key Insights
The AZA-PD phase 2 trial found that azathioprine did not significantly slow motor symptom progression in early Parkinson's disease (search) compared to placebo over 12 months.
Despite missing its primary endpoint, the study demonstrated that immunosuppressive therapy was safe and well-tolerated in Parkinson's patients, with no increased infection risk.
Exploratory analyses revealed potential benefits in specific subgroups, including women and patients with faster-progressing disease, suggesting personalized immune interventions may hold promise.
The first randomized controlled trial testing broad immunosuppression in early Parkinson's disease (search) has failed to meet its primary endpoint, though researchers say the findings provide crucial groundwork for future anti-inflammatory approaches to treating the neurodegenerative condition.
The AZA-PD study, led by Dr. Caroline Williams-Gray at the University of Cambridge, evaluated whether azathioprine—an immunosuppressive drug currently used for autoimmune conditions like rheumatoid arthritis (search)—could slow Parkinson's progression by dampening harmful immune responses in the brain.
Trial Design and Results
The randomized, double-blind, placebo-controlled phase 2 trial enrolled 66 participants aged 50-80 years who were within three years of Parkinson's diagnosis. Between May 2021 and July 2022, patients received either daily oral azathioprine at 2 mg per kg or placebo for 12 months.
At the 12-month endpoint, the mean change in the MDS-UPDRS gait axial score was 0.54 points with azathioprine compared to 0.13 points with placebo, yielding an effect size of 0.438 with a 95% confidence interval from -0.694 to 1.57 and a p-value of 0.78. The difference was not clinically significant, meaning the trial did not meet its primary endpoint.
Additionally, any positive effects observed during the trial did not persist after stopping treatment, indicating that azathioprine did not have a lasting effect on Parkinson's progression.
Safety Profile and Tolerability
Despite the lack of efficacy, the trial demonstrated that immunosuppressive medications can be safely administered to Parkinson's patients. A total of 159 adverse events occurred in the azathioprine group compared to 156 in the placebo group. Serious adverse events were reported in eight participants receiving azathioprine and four receiving placebo.
Importantly, researchers found that the risk of infection was not higher in participants taking azathioprine, and the treatment was well tolerated overall. Infections and gastrointestinal disorders were the most common events in both groups.
Subgroup Analyses Reveal Potential
While the overall trial was negative, exploratory analyses identified several subpopulations who may have responded better to azathioprine. The researchers observed greater beneficial effects in women, a finding of particular interest given that women are often under-represented in Parkinson's research and autoimmune conditions are more common in women.
Participants with faster-progressing Parkinson's also showed signs of improved memory and thinking abilities. However, researchers caution that this was a small, proof-of-concept trial, and these outcomes will need validation in larger, more robust clinical trials.
Mechanistic Insights
A Cure Parkinson's (search)-funded sub-study aimed to better understand azathioprine's mechanism of action using blood and cerebrospinal fluid samples along with brain imaging. Researchers found that azathioprine suppressed immune activity in the central nervous system and appeared to slow the spread of inflammation in the brain, confirming the drug's intended biological effects.
Implications for Future Research
Although azathioprine did not meet its primary outcome, the trial establishes important precedent for anti-inflammatory drug development in Parkinson's disease (search). This represents the first trial to show that broadly suppressing the immune system could improve Parkinson's symptoms for some individuals.
The findings are particularly relevant for the ongoing phase 2 trial of dapansutrile (DAPA-PD), also led by Dr. Williams-Gray and funded by Cure Parkinson's (search). Dapansutrile provides a more targeted approach than azathioprine, specifically lowering the activity of a pro-inflammatory protein commonly found in the brain's immune cells.
The exploratory signals in immune biomarkers and possible sex-specific effects suggest that more targeted or personalized immune interventions may still hold potential for disease modification in Parkinson's disease (search). Future studies may refine patient selection and immune targets to better address the underlying neuroinflammation that drives disease progression.