Azathioprine in Early Parkinson’s Disease: Trial Fails Primary Endpoint but Reveals Sex-Specific Immune Signals

The Neuroinflammation Hypothesis in Parkinson’s Disease

For decades, the management of Parkinson’s disease (PD) has focused primarily on dopaminergic replacement therapy. While highly effective for symptom control, these treatments do not alter the underlying neurodegenerative process. Recent advances in immunobiology have shifted the focus toward the role of the immune system in PD pathogenesis. Evidence suggests that both the innate and adaptive immune systems are involved in the progression of PD, with T-cell infiltration and microglial activation contributing to the loss of dopaminergic neurons.

Azathioprine, a broadly acting peripheral immunosuppressant commonly used in autoimmune conditions and organ transplantation, was hypothesized to potentially slow this progression by modulating the systemic immune response. The AZA-PD trial, a phase 2, randomized, double-blind, placebo-controlled study, sought to test this hypothesis in patients with early-stage Parkinson’s disease.

Study Design and Methodology

The AZA-PD trial was conducted at the Parkinson’s Disease Research Clinic in Cambridge, UK. The study enrolled 66 participants aged 50–80 years who were within three years of their PD diagnosis, ensuring a cohort in the early stages of disease where neuroprotective interventions might be most effective. Participants were randomized in a 1:1 ratio to receive either oral azathioprine (2 mg/kg daily) or a matching placebo for 12 months.

The primary outcome measure was the change from baseline in the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MSD-UPDRS) gait-axial score in the ‘off-state’ at 12 months. This specific endpoint was chosen to reflect axial motor symptoms that are often less responsive to levodopa and are significant drivers of disability. Secondary endpoints included total MDS-UPDRS scores, safety profiles, and exploratory analyses of peripheral and central immune biomarkers.

Key Findings and Statistical Analysis

Between May 2021 and July 2022, 78 participants were screened, and 66 were included in the intention-to-treat (ITT) analysis (32 in the azathioprine group and 34 in the placebo group). The study population was predominantly male (65%), reflecting the known sex distribution of PD.

Primary Endpoint Results

At the 12-month mark, the study failed to meet its primary endpoint. The mean change in the MDS-UPDRS gait-axial score was 0.54 points (SD 2.43) in the azathioprine group compared to 0.13 points (SD 2.09) in the placebo group. The resulting effect size was 0.438 (95% CI -0.694 to 1.57), with a p-value of 0.78, indicating no statistically significant difference between the two arms.

Safety and Tolerability

Azathioprine was generally well-tolerated. Adverse events (AEs) were frequent in both groups, with 159 reported in the azathioprine arm and 156 in the placebo arm. The most common AEs were infections (61% in azathioprine vs. 76% in placebo) and gastrointestinal disorders (58% vs. 50%). Notably, serious adverse events (SAEs) were more frequent in the azathioprine group (24%) compared to the placebo group (12%). Despite this, the investigators concluded that the drug’s safety profile was manageable within the context of early PD.

Exploratory Insights: Biomarkers and Sex Differences

While the primary clinical endpoint was negative, exploratory analyses provided intriguing signals that may guide future research.

Immune Modulation

Analysis of peripheral and central immune biomarkers suggested that azathioprine did successfully engage its target. Changes in leukocyte subsets and inflammatory markers in the cerebrospinal fluid indicated that the drug modulated immune activity both systemically and within the central nervous system. This confirms that azathioprine can cross the blood-brain barrier or at least influence the neuro-inflammatory environment through peripheral modulation.

The Female Signal

One of the most provocative findings of the AZA-PD trial was the suggestion of sex-specific treatment effects. Exploratory motor symptom analysis indicated that female participants receiving azathioprine showed a trend toward greater clinical benefit compared to their male counterparts. This observation aligns with emerging literature suggesting that the immune system’s role in PD may differ between sexes, potentially influenced by hormonal factors or baseline differences in immune reactivity.

Expert Commentary and Clinical Interpretation

In the context of Parkinson’s disease research, the AZA-PD trial represents a significant effort to translate the ‘immune hypothesis’ into clinical practice. However, the failure to reach the primary endpoint highlights several challenges in neuroprotective trial design.

Endpoint Selection

The use of the gait-axial score as a primary endpoint in a 12-month study of early PD may have been overly ambitious. In very early disease, axial symptoms often progress slowly, which may lead to a floor effect or insufficient sensitivity to detect a therapeutic signal over a relatively short follow-up period. Future trials might benefit from composite scores or digital biomarkers that capture more subtle changes in motor function.

Patient Heterogeneity

PD is increasingly recognized as a heterogeneous syndrome rather than a single disease entity. The varying degrees of neuroinflammation among patients may mean that a ‘one-size-fits-all’ immunosuppression strategy is ineffective. The sex-specific findings in this trial underscore the need for stratified approaches in future studies.

Summary and Future Directions

The AZA-PD trial provides a definitive answer regarding the broad use of azathioprine for the unselected early PD population: it does not appear to provide a significant short-term benefit for gait-axial symptoms. Nevertheless, the trial was successful as a proof-of-concept for target engagement.

The signals observed in female patients and the successful modulation of immune biomarkers warrant further investigation. The next generation of trials in this space should perhaps focus on specific ‘immune-active’ phenotypes of PD or explore whether earlier intervention or longer follow-up periods might reveal a neuroprotective effect. For now, azathioprine remains an experimental approach in PD, but the trial has paved the way for more refined, personalized immunomodulatory strategies in the quest to slow Parkinson’s progression.

Funding and Registration

This study was funded by the Cambridge Centre for Parkinson-Plus, Cure Parkinson’s, and the National Institute for Health Research (NIHR) Biomedical Research Centre. It is registered with ISRCTN (14616801) and EudraCT (2018-003089-14).

References

1. Greenland JC, Dresser K, Cutting E, et al. Azathioprine for the treatment of early Parkinson’s disease (AZA-PD): a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial. Lancet Neurol. 2026;25(1):39-49. doi:10.1016/S1474-4422(25)00386-2 IF: 45.5 Q1 B1.2. Tan EK, Chao YX, West A, et al. Parkinson disease and the immune system — associations, mechanisms and therapeutics. Nat Rev Neurol. 2020;16(6):303-318.
3. Williams-Gray CH, Wijeyekoon R, Scott KM, et al. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord. 2016;31(7):995-1003.