First Immune-Modulating Drug Trial Targets Neuroinflammation in Prodromal Parkinson’s Disease

Researchers have published the full protocol for the first randomised, double-blind, placebo-controlled trial of an immune-modulating drug in isolated REM-sleep behaviour disorder (iRBD), a sleep condition widely regarded as an early warning sign of Parkinson’s disease and related synuclein disorders. The trial will test whether twelve weeks of oral treatment with PXS-4728A, a small molecule that dampens inflammatory activity in the brain, can measurably reduce neuroinflammation as detected by positron emission tomography (PET) imaging. The study, conducted at sites in Australia and the United Kingdom, has now completed recruitment and follow-up, and the protocol paper describes in detail how the trial was designed, powered and analysed.

iRBD is a parasomnia in which people act out their dreams, vocalising or making complex movements during REM sleep because the normal muscle paralysis of that sleep stage is lost. It is defined by international sleep medicine criteria as repeated episodes of dream enactment, polysomnographic evidence of REM sleep without atonia, and no other disturbance explaining the disorder. The condition affects roughly one percent of people over the age of sixty, but its significance extends far beyond disturbed sleep: individuals with iRBD face a conversion risk to a synucleinopathy of about six percent per year, and over fifteen years, eighty to ninety percent will convert to Parkinson’s disease, dementia with Lewy bodies or, less commonly, multiple system atrophy.

Because iRBD sits squarely in the prodromal phase, before a clinical diagnosis of neurodegeneration can be made, it represents what the investigators call a window of opportunity for disease modification. Many people with iRBD already show subtle features of impending disease, including impaired smell, reduced colour vision, autonomic dysfunction, mood and cognitive changes, and mild motor symptoms, which can predict earlier transition. Currently, however, iRBD is managed only symptomatically, with sleep environment modification to prevent injury and medications such as melatonin, clonazepam and pramipexole. No curative or disease-slowing treatment exists.

The biological rationale for the new trial rests on decades of evidence linking misfolded alpha-synuclein protein to brain inflammation. Activated microglia, the brain’s resident immune cells, were first demonstrated in postmortem tissue from people with Parkinson’s disease in 1988. Later work showed that alpha-synuclein inclusions activate microglia, triggering an inflammatory cascade involving local increases in tumour necrosis factor alpha and reactive oxygen species. Postmortem studies have since replicated evidence of elevated inflammatory signalling molecules in the brains and ventricular cerebrospinal fluid of patients with Parkinson’s disease, and animal studies have demonstrated that reactive microglia can themselves promote the propagation of alpha-synuclein, creating a bidirectional pathological loop.

In vivo evidence comes from PET imaging of the translocator protein, or TSPO, which is overexpressed by activated microglia and astrocytes. Earlier case-control work in iRBD showed increased binding of the radioligand [11C]-PK11195 in the substantia nigra, paired with reduced dopaminergic function in the putamen. A follow-up report found that iRBD subjects with elevated baseline TSPO binding showed a greater reduction in nigrostriatal function on repeat dopaminergic PET scanning three years later, linking neuroinflammation to subsequent neurodegeneration. Notably, although immune-modulating therapies have been trialled in established Parkinson’s disease without showing definitive large-trial benefit, no trial of such a treatment had previously been reported in prodromal disease.

PXS-4728A is an oral, irreversible inhibitor of two enzymes: semicarbazide-sensitive amine oxidase, which produces reactive oxygen species in blood vessels and recruits white blood cells, and monoamine oxidase B, which generates reactive oxygen species in mitochondria of cells including microglia and neurons and also breaks down dopamine in the brain. Dual inhibition of these enzymes could, the investigators argue, offer benefit in central inflammatory disorders with early dopaminergic involvement. The drug was previously well tolerated in Phase 1 and 2 trials targeting diabetic retinopathy and non-alcoholic steatohepatitis, and an analogous molecule reduced microglial activation and provided dopaminergic neuroprotection in mouse models of neuroinflammation.

The trial design is deliberately tailored to an early-phase question of biological activity rather than definitive efficacy. Forty participants aged fifty to eighty with polysomnography-confirmed iRBD and at least one prodromal feature, such as mild parkinsonism, impaired olfaction or impaired colour vision, were randomised three to one to receive fifteen milligrams of PXS-4728A or matched placebo once daily for twelve weeks, followed by a twelve-week washout. The primary outcome is the within-arm change in TSPO PET binding across nigrostriatal and cortical regions in the treatment group from baseline to week twelve, alongside drug safety and tolerability. Between-arm differences versus placebo are treated as exploratory, because with only ten placebo participants the study is not powered to test them.

This design choice carries an important caveat that the authors state plainly: a reduction in TSPO binding within the treatment arm alone does not measure treatment effect relative to placebo. It could reflect measurement variability, regression towards the mean, or time-related change. A significant within-arm reduction will instead be interpreted as evidence of biological activity, justifying a larger placebo-controlled trial, with the exploratory between-group comparison, reported with ninety-five percent confidence intervals, helping to contextualise the result. The sample size calculation, based on variability estimates from longitudinal PET data in Parkinson’s disease, gives the study over ninety-five percent power to detect a forty percent decrease and over eighty percent power to detect a thirty percent decrease in binding potential within the treatment arm.

The imaging methodology is technically detailed. Each participant receives 500 megabecquerels of [11C]-PK11195 with sixty minutes of emission acquisition, scanned on the same scanner with identical protocols at both timepoints so that within-participant change is unaffected by between-site scanner differences. Binding potential is quantified using a simplified reference tissue model with a supervised cluster analysis pseudo-reference approach, necessary because TSPO is expressed throughout the brain and no true reference region exists. The first-generation tracer was chosen deliberately: despite its lower signal-to-noise ratio, it is unaffected by the TSPO gene polymorphism that complicates second-generation ligands, and a substantial body of reference data already exists. Participants must also show a robust striato-cortical signal on a screening PET scan, an enrichment criterion that improves measurability but restricts how far the findings generalise to all people with iRBD.

Beyond the primary imaging endpoint, the trial collects an unusually rich set of exploratory measures: clinical scales covering motor and non-motor prodromal symptoms, blood and cerebrospinal fluid biomarkers including inflammatory cytokines, alpha-synuclein seed amplification assays and neurofilament light, and digital biomarkers from a validated smartphone motor assessment, actigraphy and an online cognitive battery. The trial enrolled participants from longitudinally phenotyped, polysomnography-confirmed iRBD cohorts at Macquarie University in Sydney and the University of Oxford, supporting diagnostic certainty. Funded through the Parkinson’s UK Virtual Biotech programme in partnership with the Parkinson’s Foundation and sponsored by Syntara Limited, the study completed on 17 June 2026. Its published protocol may serve as a template for future disease-modifying trials in prodromal synuclein disease, a field where intervening before irreversible neurodegeneration takes hold remains the central unmet challenge.

Subject of Research: A phase IIa trial protocol testing the immune-modulating drug PXS-4728A on PET-measured microglial activation in isolated REM-sleep behaviour disorder, a prodromal stage of Parkinson's disease.

Article Title: The protocol for a phase 2A, multi centre, double-blind, randomized, placebo-controlled, parallel-group study to assess the effect of 12 weeks treatment with oral PXS-4728A on microglia activation, as measured by positron emission tomography, in participants with isolated rapid eye movement sleep behaviour disorder

Article References: Groenewald, K., Klein, J. C., Fryer, T. D., Smith, G., Dzamko, N., Chua, M., Scott, A. M., Baskar, J., Hamprecht, D., Everett, J., Leadbetter, J., Hu, M. T., & Lewis, S. J. G. (2026). The protocol for a phase 2A, multi centre, double-blind, randomized, placebo-controlled, parallel-group study to assess the effect of 12 weeks treatment with oral PXS-4728A on microglia activation, as measured by positron emission tomography, in participants with isolated rapid eye movement sleep behaviour disorder. Frontiers in Neurology, 17, Article 1951452. https://doi.org/10.3389/fneur.2026.1951452

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1951452

Keywords: isolated REM-sleep behaviour disorder, Parkinson's disease, neuroinflammation, microglia, PXS-4728A, TSPO PET, prodromal synucleinopathy, clinical trial protocol, alpha-synuclein, [11C]-PK11195, monoamine oxidase B, disease modification