Cladribine to Treat Relapsing Forms of Multiple Sclerosis

Abstract

Cladribine is a purine nucleoside analogue that selectively depletes peripheral lymphocytes without a major impact on cells of the innate immune system. An oral formulation of cladribine has been developed to be given as short courses over two annual cycles. Oral cladribine results in the peripheral depletion of lymphocytes that is gradual, occurring over several weeks, and is not associated with a cell lysis syndrome, has a greater impact on B cells than T cells, and is followed by gradual reconstitution of the peripheral lymphocyte counts over several months. Oral cladribine is effective in relapsing forms of multiple sclerosis. As a selective immune reconstitution therapy (SIRT), cladribine acts as a short-term immunosuppressant, relative to other maintenance immunosuppressive therapies that result in long-term immunosuppression. The main safety signal that has emerge relates primarily to herpes zoster infection, which was more common in patients with higher grades of lymphopenia, in particular grade 3 and 4 lymphopenia. Data from the oral cladribine extension trial and safety register, and reanalysis of the pivotal phase III trial has indicated that oral cladribine is unlikely to be associated with an increased short- to intermediate-term risk of malignancy.

Keywords: Multiple sclerosis; Oral cladribine; Selective immune reconstitution therapy.

Conflict of interest statement

Professor Giovannoni has received consulting fees for participating on advisory boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from AbbVie, Almirall, Atara Bio, Bayer Schering Healthcare, Biogen, Five Prime Therapeutics, Genzyme-Sanofi, Merck-Serono, Merck, Novartis, Synthon, Teva, UCB Pharma, and Vertex Pharmaceuticals; lecture fees from AbbVie, Bayer Schering Healthcare, Biogen, Merck Serono, and Vertex Pharmaceuticals; and grant support from Bayer Schering Healthcare, Biogen, GW Pharmaceuticals, Ironwood Pharmaceuticals, Merck Serono, Merz, Novartis, and Teva.

Figures

Fig. 1

The accumulation of active cladribine (2-CdATP) is dependent on the ratio of deoxycytidine kinase (DCK), which creates it, to 5’-nucleotidase (5’-NTases), which break it down [13]. This ratio varies between different cell types. Data from mRNA profiling studies in the public domain (BioGPS Database) [14] show that levels of DCK and the ratio of DCK:5’-NTases are high in T cells (CD4+, CD8+), B cells, and dendritic cells compared with non-hematological cell types, including liver, heart, skin, brain, lung, kidney, ovarian, testicular, and germ cells. This results in selective accumulation of CdATP in lymphocytes, allowing cladribine to preferentially target these cells [15].

Fig. 2

Effects of treatment with cladribine (Clad) tablets or placebo (PBO) on (A) annualized relapse rates and (B) proportions of patients who remained relapse free [45] CP = Cladribine-Placebo; CC = Cladribine-Cladribine; PC = Placebo-Caldribine

Fig. 3

Effects of treatment with cladribine tablets or placebo on median lymphocyte counts in CLARITY and CLARITY Extension [43]