Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. The inflammation is driven significantly by autoreactive lymphocytes, which recruit cells of the innate immune system such as macrophages that contribute to subsequent tissue damage, ultimately resulting in demyelination and axonal damage that are characteristic in MS lesions. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic chlorinated deoxyadenosine analog that is biologically active in selected cell types and provides targeted and sustained reduction of circulating T and B lymphocytes implicated in the pathogenesis of MS. The biologic activity of cladribine depends on the preferential accumulation of cladribine phosphates in cell types with a high intracellular ratio of deoxycytidine kinase to 5′-nucleotidases. Cladribine-phosphates interfere with DNA synthesis and repair through incorporation into DNA and through inhibition of enzymes involved in DNA metabolism, including DNA polymerase and ribonucleotide reductase. This in turn leads to DNA strand breaks and ultimately cell death. This review explores the mechanism of action of cladribine further, in the context of recent clinical data, after completion of the phase III, 96-week, placebo-controlled CLARITY study. In this study, cladribine tablets demonstrated significant efficacy on clinical and neuroimaging outcomes in relapsing-remitting MS.
*Thomas Jefferson University, Philadelphia, PA; †Merck Serono S.A. - Geneva; and ‡Department of Neurology, Geneva University Hospital, Geneva, Switzerland.
Address correspondence and reprint requests to Robert Weissert, MD, PhD, Department of Neurology Geneva University Hospital Micheli-du-Crest 24 1211 Geneva 14 Switzerland; E-mail: email@example.com
Thomas Leist has received honoraria from EMD Serono, Teva Neuroscience, Biogen-Idec, Pfizer, and Bayer and has received research support and has participated in clinical trials sponsored by the following: Bayer, Sanofi-Aventis, EMD Serono, Teva Neuroscience, Biogen-Idec, Daichi, Ono, and Acorda. Robert Weissert was an employee of Merck Serono S.A. - Geneva, Switzerland at the time of submission.
Editorial assistance and medical writing support was provided by ACUMED and Caudex Medical. This work was funded by Merck Serono S.A. - Geneva, Geneva, Switzerland, an affiliation of Merck KGaA, Darmstadt, Germany.