Objective: In multiple system atrophy (MSA) patients to: 1) evaluate ¹⁸F-PBR06 positron emission tomography (PET) for longitudinal assessment of 18-kilodalton-translocator protein (TSPO) binding; 2) assess relationship of PET with clinical parameters and automated 3D volumetric segmentation of defined brain regions; and 3) determine pharmacodynamic effects of verdiperstat, an orally administered myeloperoxidase inhibitor.

Background: Neuroinflammation and focal cerebral volume loss are hallmarks of MSA and track with clinical subtype and can be measured in vivo with ¹⁸F-PBR06, a second-generation TSPO radioligand for assessment of cerebral microglial activation¹, and 3D-MRI volumetric segmentation². Verdiperstat is being developed as a treatment for neurodegenerative diseases; a Phase 3 trial in MSA is ongoing (NCT03952806).

Method: 20 patients with clinically probable MSA-P or MSA-C are planned to be enrolled in this study, which has observational and treatment phases (NCT04616456). Observational: patients undergo clinical (Unified MSA Rating Scale [UMSARS] and Brief Ataxia Rating Scale [BARS]), PET and MRI assessments at entry and 6-9 months. Biospecimens (blood, stool, skin biopsy and CSF) are collected. Treatment: patients are treated with verdiperstat 600-mg twice daily for 6-months and clinical, PET, MRI and biospecimens are subsequently obtained. Standardized Uptake Value Ratios (SUVRs) are normalized to global brain SUV for the 60-90 minute PET frames. FreeSurfer is used for automatic volumetric segmentation of high-resolution isotropic T1 MRI images.

Results: Four female probable MSA-C patients (UMSARS Part I: 7-26; Part II:12.5-21; BARS: 9.5-15.5) were enrolled in the observational phase. Putaminal SUVRs were significantly elevated in MSA patients vs. controls (p<0.01). One subject (‘MSA-03’) experienced significant clinical decline over the observation period. Blinded assessment of volumetric MRI and ¹⁸F-PBR06 singled out progression in these imaging parameters. A linear decrease in volume of multiple deep gray structures, pons, and cerebellum was noted over time.

Conclusion: This is the first study to evaluate the role of ¹⁸F-PBR06 PET in MSA and will provide data on the pharmacodynamic effects of verdiperstat in MSA, complementing the ongoing Phase 3 trial.

References: [1] Fujimura et al. J Nucl Med 2009 Jul;50(7):1047-53 [2] Scherfler, C, et al. Neurology. 2016 Mar29;86(13):1242-9

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