Results of the CLARITY Study of Cladribine for the Treatment of MS

Disease-modifying drugs currently available for the treatment of multiple sclerosis (MS), including various formulations of interferon beta (IFNβ ), glatiramer acetate, natalizumab, and mitoxantrone, require parenteral administration. Patients may consider parenteral administration less convenient, and infections at the injection site are not uncommon, according to authors of a recent review of treatments of MS. Patient adherence to therapeutic regimen is essential for the long-term efficacy of any medication; development of medications with less burdensome administration methods, such as oral agents, may be able to improve overall adherence in patients with MS. The review, published in Clinical Neuropharmacology [2011;34(1):28-35], explored the mechanism of action of cladribine, a synthetic chlorinated deoxyadenosine analog activated by intracellular phosphorylation in specific cell types, provides targeted and sustained reduction in 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 (DCK) to 5′-nucleotidases (5′-NT). 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 leads, in turn, to breaks in DNA strands and then to cell death. The CLARITY (Cladribine Tablets Treating Multiple Sclerosis Orally) trial, a phase 3, 96-week, double-blind, placebo-controlled, multicenter study, evaluated treatment with cladribine in patients with relapsing-remitting multiple sclerosis (RRMS). Compared with placebo, cladribine tablets administered using a short-course annual dosing regimen (cumulative dose of 3.5-5.25 mg/kg for 96 weeks) demonstrated significant efficacy. In the CLARITY trial, 433 patients with RRMS were randomized to receive cladribine at a dose of 3.5 mg/kg, 456 to receive cladribine at a dose of 5.25 mg/kg, and 437 to receive placebo. The annualized relapse rates among the 3 groups were 0.14 (95% confidence interval [CI], 0.12-0.17; P<.001), 0.15 (95% CI, 0.12-0.17; P<.001), and 0.33 (95% CI, 0.29-0.38), respectively. The relative reduction in the annualized rate for cladribine compared with placebo was 57.6% for the 3.5-mg/kg group and 54.5% for the 5.25-mg/kg group. The relapse rate was 79.7% for the 3.5-mg/kg group and 78.9% for the 5.25-mg/kg group, compared with 60.9% for the placebo group. The time to sustained change in Expanded Disability Status Scale score was 13.6 months for the 3.5- and 5.25-mg/kg groups compared with 10.8 for the placebo group. There were relative reductions in magnetic resonance imaging (MRI) active lesions/patient/scan of 85.7% in the 3.5-mg/kg group and 87.9% in the 5.25-mg/kg group, compared with the placebo group. The authors noted that at the time of writing the review, a phase 2 clinical trial was assessing the safety and efficacy of cladribine tablets as add-on therapy to IFNβ in MS. They added that another ongoing phase 3 trial is evaluating the efficacy of cladribine tablets to delay conversion to definite MS in patients with clinically isolated syndrome. In conclusion, the reviewers summarized by saying, “Cladribine tablets showed significant clinical benefits and reductions in MRI activity compared with placebo in the phase 3 CLARITY study in RRMS. The sustained and targeted effects of cladribine, resulting from its preferential accumulation in lymphocytes due to their high ratio of DCK to 5′-NTs, are reflected in the short-course annual dosing regimen and in the efficacy observed in clinical trials to date. Ongoing research aims to further elucidate the cellular and physiologic effects of cladribine and how these translate to clinical benefits in MS.”