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Remyelinating Effects Seen With Cladribine in Relapsing Multiple Sclerosis
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The 2-year study highlighted the potential of cladribine to promote remyelination in highly active relapsing-remitting MS, particularly when early disease control is achieved.
Giordani Rodrigues dos Passos
Data from a small-scale, open-label study of patients with highly active relapsing-remitting multiple sclerosis (RRMS) revealed that nearly one-fifth of all lesions remyelinated over a 2-year period with cladribine (Mavenclad; EMD Serono), an FDA-approved disease-modifying therapy. Using a q-Space myelin map, the results showed that the effects on remyelination were influenced by the rapid control of disease activity.1
Presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held September 18-20 in Copenhagen, Denmark, the study featured 10 patients with RRMS who were prospectively examined for myelin content changes in lesions over a 2-year treatment period with cladribine. The cohort of participants was characterized as young and early in their disease course, indicated by a median age of 24.1 years and a disease duration of 13.8 months.
Led by Giordani Rodrigues dos Passos, a researcher at the Pontifical Catholic University of Rio Grande do Sol, in Brazil, participants had 2 relapses in the previous year and an average Expanded Disability Status Scale (EDSS) score of 2.5, and a median of 77 brain lesions at baseline. Over the 2-year period, treatment with oral cladribine resulted in remyelination in 19.2% of the 812 MS lesions, with effects seen mostly within the first year. Overall, there was an inverse correlation between the proportions of remyelinating and demyelinating lesions in the q-Space myelin map (r = –0.729; P = .017).
Remyelination relies on the repair of damaged myelin sheaths, involving microglia cells, oligodendrocyte precursor cells, and mature oligodendrocytes. This process drives the pathophysiology of autoimmune disease of the central nervous system (CNS), MS, leading to nerve cell damage and progressive neurodegeneration. Traditionally, stimulating the reconstruction of damaged myelin sheaths is one of the goals in terms of delaying the progression of MS symptoms and preventing neuronal damage.2
In the study, achievement of No Evidence of Disease Activity (NEDA)-3 status from the start of cladribine treatment resulted in greater odds of remyelination. Specifically, 27.1% of lesions remyelinated in patients who achieved NEDA-3 vs 12.0% of lesions in others who did not (P <.001). A generalized linear mixed model, including subject- and lesion-specific factors, identified NEDA-3 as the only clinical variable predictive of remyelination (P = .007) while lesion location, contrast enhancement and myelin content at baseline were also significant (P <.020). Notably, higher frequencies of regulatory T cells at months 3, 6, and 12 emerged as positive predictors of remyelination (P <.010).1
Cladribine, approved in 2019 for the treatment of adults with relapsing forms of MS, is a synthetic deoxyadenosine (purine) analog classified as an anti-metabolite and anti-pyrimidine agent. Within cells, high cladribine concentrations increase the expression of deoxycytidine kinase (DCK), leading to lymphocyte apoptosis. The phosphorylated form of cladribine disrupts intracellular processes, inhibiting DNA synthesis/repair, ribonucleotide enzymes, and alternating endonuclease activity—low intracellular levels of cladribine increase phosphatase 5’-nucleotidase, which inactivates phosphorylated (active) cladribine.
Earlier this year, at the 2024 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, post-hoc data from the phase 4 MAGNIFY-MS trial (NCT03364036) showed that treatment with cladribine resulted in increased rates of NEDA or progression (NEPAD), suggesting a substantial direct impact on CNS. MAGNIFY-MS was a study that assessed the sustained efficacy of cladribine tablets at 3.5 mg/kg cumulative dose over a 2-year period, NEDA and no evidence of progression or active disease, otherwise considered NEPAD, were calculated for 270 patients.3
In year 1 (Y1), NEDA-3 rate was 32.8% (95% CI, 26.9%-39.4%; n = 229) and NEPAD rate was 32.1% (95% CI, 26.3%-38.6%; n = 229). During year 2 (Y2), NEDA-3 rate was 64.1% (95% CI, 57.2%-70.4%; n = 207) and NEPAD rate was 60.2% (95% CI, 53.3%-66.7%; n = 207). Of note, treatment-naive participants had the highest rates of NEDA-3 (69.1%) and NEPAD (67.85%) at the end of Year 2. Oligoclonal bands (OCBs) were reduced or eliminated at least once at post-BL visits (M12, M24) in 13 of 17 (76.5%) participants. Complete OCBs disappearance was seen in 11.8% (2/17) from BL to M12 and was maintained for one participant (5.9%) to M24.
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