Longitudinal 18F-PBR06 (TSPO) and Volumetric MR Imaging as Pharmacodynamic Endpoints for MSA – Ongoing Investigator-Sponsored Trial of Verdiperstat

Principal Investigator: Dr. Vikram Khurana

Authors: Tarun Singhal, Ariana T. Pitaro, Jisoo Kim, Andrew S. Willett, Kristie A. Jones, Merlyne Mesidor, John H. Ficke, Steven Cicero, Kelsey O’Connor, Irfan A. Qureshi, Geoffrey S. Young and Vikram Khurana
Lay Abstract

Multiple system atrophy (MSA) is a degenerative brain disease that progressively compromises a patient’s movement and “autonomic” functions (control of bladder, bowels, breathing, and blood pressure). The disease is related to Parkinson’s disease: the same protein that accumulates in Parkinson’s brain cells also accumulates in MSA. However, MSA typically follows a more aggressive course. Currently, only symptom management is possible for this devastating disease as there is not a single drug that slows down progression.

To design adequate clinical trials, we need biomarkers that can aid early diagnosis and track clinical progression. Here, we tested the utility of imaging modalities that measure neuroinflammation (PET scanning) and structural changes in the brain (MRI scanning) in correlating with clinical assessment of disease progression and responding to treatment with a clinical trial drug, verdiperstat, that blocks inflammation in the brain.

Our preliminary findings suggest that brain imaging tracks well with findings from clinical examination, and there is a suggestion that imaging outperforms clinical assessment in tracking disease progression. Before treatment, our recruited patients showed brain loss in regions associated with movement, as expected. After treatment, preliminary PET data suggest that a few brain regions associated with movement show decreased inflammation.

Scientific Abstract

Neuroinflammation and focal cerebral volume loss are hallmarks of a rare and devastating movement disorder, multiple system atrophy (MSA). Our drug-based clinical trial (NCT04616456) explores how brain imaging can measure cortical changes associated with disease progression, and whether verdiperstat, an orally administered myeloperoxidase inhibitor, slows this progression. Data from 18F-PBR06 PET, a second-generation PET-translocator protein (TSPO) radioligand, aids longitudinal assessment of disease progression, and informs clinical findings and quantitative “volumetrics” from fully automated segmentation of brain MRIs.

Twenty-one patients with clinically probable MSA have entered the trial. Both the 6-9 month observation phase and the 6 month treatment phase with verdiperstat involve clinical assessment (Unified MSA Rating Scale [UMSARS] and Brief Ataxia Rating Scale [BARS]), imaging analysis, and biospecimen collection. Preliminary data from four patients show pontine and putaminal MRI volume loss and concomitant increase in 18F-PBR06 signal correlated well with clinical deterioration, as measured by UMSARS. For the two patients who completed treatment, the 18F-PBR06 signal clearly reduced within the pons and striatum. Some regions continued to exhibit increased signal despite verdiperstat.

Tracking structural brain alterations with 3D-volumetric MRI, or neuroinflammation with 18F-PBR06 PET-TSPO imaging correlate with (and may outperform) clinical scales as MSA progresses over ≥6 months.

Clinical Implications
In understanding the relationship between clinical examination findings and brain imaging, we can better understand the progressive nature of multiple system atrophy (MSA), and the therapeutic potential of verdiperstat in altering the trajectory of the disease.

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