Chronic activation of microglia/astrocytes drives central inflammation, neurodegeneration, and demyelination leading to gray matter (GM) and white matter (WM) damage in MS. Activated microglia/astrocytes form clusters detectable by targeting an 18-kilodalton translocator protein (TSPO) using [F18]-PBR06-PET. Preclinical evidence suggests siponimod can shift microglia/astrocytes to a pro-repair phenotype and promote re-myelination. Clinical evidence from the EXPAND study demonstrated favourable siponimod effects on GM atrophy (neurodegeneration) and magnetization transfer ratio (myelin content), in line with pre-clinical findings.

To assess the effect of siponimod, compared to ocrelizumab, on reactive microglia/astrocytes using positron emission tomography (PET) and magnetic resonance imaging (MRI) in patients with active secondary progressive multiple sclerosis (aSPMS).

An open-label, single-blinded (MRI analysis), observational, comparative, prospective, 36-month, adaptive study will be conducted in aSPMS patients (aged 18–60 years with evidence of clinical and/or MRI disease activity [Lublin 2014 Criteria] and EDSS of 3.0 to 6.5). Following enrollment of each SPMS patient starting siponimod treatment, a matching (ratio 1:1) of SPMS patient starting ocrelizumab treatment will be enrolled. PET, MRI, serum biomarker, and clinical and cognitive assessments will be conducted at 0, 6, 12, 24 and 36 months.

The study plans to enroll 60 patients with aSPMS who are treatment-naïve to siponimod/ocrelizumab. The primary endpoint is change from baseline in PET-activation of PBR06 in lesional/non-lesional normal appearing (NA) WM, NAGM, and peri-plaque area of chronic lesions. Secondary endpoints include change in PET-activation of PBR06 in these areas between siponimod and ocrelizumab groups, and cumulative number of ultra-small superparamagnetic particle iron oxide-positive lesions on MRI between two treatment arms. First and second interim analyses are planned after 50% and 100% of ongoing patients have reached month 12. The first-patient-first-visit is scheduled in October 2021.

This is the first and largest PET/MRI imaging/bio-signature study in MS evaluating siponimod’s effect on microglia/astrocyte activation compared with ocrelizumab.