Cladribine Tablets: Collaborative Study to Evaluate the Impact on Central Nervous System Biomarkers in Multiple Sclerosis (CLOCK-MS) – Current Baseline Characteristics

Background: Increasing evidence suggests that in relapsing multiple sclerosis (RMS), early signs of neuronal degeneration are dependent on inflammatory activity in the central nervous system (CNS). Previous investigations on the effect of MS disease modifying treatments on cerebrospinal fluid (CSF) immune biomarkers reflect different features of MS immunopathogenesis. Cladribine tablets, approved for RMS, are proposed to function as an immune reconstitution therapy with potential to exert effects within the CNS. Questions remain regarding the effect of cladribine tablets on CSF biomarkers relevant to RMS.

Objectives: To provide initial assessment of mechanisms of action of cladribine tablets in RMS by assessing blood and CSF levels of immune cells and soluble immunological and neuronal injury markers.

Methods: CLOCK-MS is an open-label, randomized, multicenter, collaborative Phase IV biomarker research study. Approximately 50 subjects aged 18–65 years (yrs) with RMS initiating treatment with cladribine tablets per the United States Prescribing Information will participate. Patients will undergo CSF analysis at baseline and be randomized 1:2:2:1 for a second CSF analysis at 5 weeks, 10 weeks, 1 yr, or 2 yrs. Blood samples before and after (either 5 weeks, 10 weeks, 1 yr, or 2 yrs) treatment will be examined along with features on magnetic resonance imaging. Humoral vaccine responses will be captured in a subset of participants.

Results: To date, 22 subjects have been enrolled (11 male, 11 female). At study entry, mean ± standard deviation (SD) age was 42.6 ± 11.9 yrs and mean time interval since diagnosis was 8.5 ± 8.5 yrs. The median score on the Expanded Disability Status Scale was 3.3 (quartiles: 1.5–4.0). 18.2% of subjects were randomized to the Week 5 timepoint, 27.3% to Week 10, 36.4% to Yr 1, and 18.2% to Yr 2. Lymphocytes were detected in the CSF prior to treatment (mean ± SD; 17.9 ± 24.3 CD19+ cells/mL, 501.6 ± 634.9 CD3+ cells/mL). Pre- and post-immunization titers to Influenza or SARS-CoV-2 vaccines have been obtained from 8 subjects to date; all available data will be presented.

Conclusions: Recruitment for CLOCK-MS is ongoing and subject characteristics are consistent with real-world use of cladribine tablets. The results of CLOCK-MS are expected to provide insights into the impact of cladribine tablets on pathological B and T cell subsets, and inflammatory and neurodegeneration biomarkers in blood and CSF.