Innovative Trial Employs Novel PET Imaging to Track Cladribine’s Effect on Microglial Activation

A newly introduced study aims to determine the effect of Cladribine (Mavenclad; EMD Serono) tablets (CladT) on microglial activation using [F-18]PBR06-PET, a novel positron emission tomography (PET) ligand, in people with multiple sclerosis (PwMS) experiencing disease worsening in the absence of relapse or MRI activity during treatment with anti-CD20 therapies. Investigators suggest the use of CladT in PwMS may be partly because of a decrease in microglial activation, while [F-18]PBR06 could serve as an ideal marker for microglial activity in MS.

Methods of the CLAD-MAPET Trial

Senior author Tarun Singhal, MD, MBBS, associate professor of neurology at the Bringham and Women’s Hospital in Boston, Massachusetts, and colleagues oversee the trial, which includes a total of 5 adult PwMS with advanced disease who will be followed up for 14 months following CladT initiation after switching from anti-CD20 therapies.

The primary outcome of the single center, single arm, open-label, longitudinal trial is cortical, lesional, perilesional, and normal-appearing white matter uptake of [F-18]PBR06-PET at 14 months after initiating CladT against baseline. Secondary outcomes include changes in [F-18]PBR06-PET uptake from baseline to 3 months and 6 months after CladT initiation; and longitudinal correlations between [F-18]PBR06-PET uptake and peripheral blood markers, clinical, and cognition outcomes from baseline over 14 months. Furthermore, safety will be monitored throughout the study.

Recently presented at the 2026 American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 5-7, in San Diego, California, CLAD-MAPET also evaluates the relationship between the changes in microglial activation and changes in clinical disability measures, neuropsychological evaluation, and peripheral blood markers.

Preclinical Results

At the meeting, investigators presented preliminary clinical data for one patient who was previously treated with ocrelizumab and had experienced cognition deficits, fatigue, and balance issues before switching to CladT. This patient completed baseline and 3 months PET scan post CladT. At baseline, the PET scan indicated microglia activation across brain regions.

Three months after initiating CladT, the uptake of [F-18]PBR06-PET was reduced by 21.5%, 12.3%, and 16.9% in the cortex, thalamus, and cerebellum, respectively, suggesting a decrease in microglial activation. Numerical improvements were also seen on the timed 25-foot walk (T25FW) and 9-hole peg test (9HPT) outcomes at 3 month vs baseline. Additional clinical and PET outcomes for this patient and for those completing 3m of follow up after initiating CladT will be presented at the meeting.

Previous Cladribine Studies: MAGNIFY-MS

A previous follow-up extension of the pivotal MAGNIFY-MS (NCT03364036) study confirmed the long-term efficacy of cladribine tablets among patients with relapsing MS over a 4-year treatment period.¹

Among 219 patients who enrolled in the extension study (women, 64.8%; mean age, 40.4 years; treatment-naïve, 40.6%; MRI lesions [baseline period]: T1 Gd+, 50.2%; active T2, 42.9%), the Kaplan-Meier estimated no evidence of disease activity (NEDA-3) rate was 78.6% (95% CI, 72.5-83.5) at 3 years and 79.2% (95% CI, 72.3-84.6) at 4 years.

Additionally, the estimated NEDA-3 rate for years 3 and 4 combined was 54.2% (95% CI, 47.3-60.7; crude event rates for individual components, free from relapse, 80.8%; 6-month confirmed disability progression [6MCDP], 84.5%; MRI activity, 53.0%).

Initially presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 18-20, in Copenhagen, Denmark, the study included patients who received at least 1 dose of cladribine tablets in MAGNIFY-MS and had MRI data available from 18 or 24 months of the parent study. Additionally, patients were required to have 24-month data on the Expanded Disability Status Scale (EDSS) and relapse activity.

Click here for more 2026 ACTRIMS Forum coverage.

REFERENCES
1. Cicero S, Horan N, Zurawski J, et al. The Effects of Cladribine Tablets on Microglial Activity in Patients with Advanced Multiple Sclerosis, Using a Novel PET Ligand [F-18]PBR06: The CLAD-MAPET Study Design and Preliminary Data. Actrims Forums.
2. De Stefano N, Vermersch P, Wiendl H, et al. Long-term effectiveness of cladribine tablets over 4 years in relapsing multiple sclerosis: Results from the MAGNIFY-MS Extension study. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract P349.