The first on the stage: cladribine
53 slide(s) – 00:20:56– English –2010-09-28
Background: Cladribine is a purine analogue that is resistant to breakdown by adenosine deaminase. Cladribine is phosphorylated inside cells to the active compound 2-chloro-2'-deoxy-B-D-adenosine triphosphate (2-CdATP), which is preferentially activated in T and B lymphocytes, causing sustained reductions in peripheral T and B cell populations whilst sparing other immune cells and haematological components. A parenteral formulation of cladribine has been tested in phase II/III proof-of-concept studies forMS.An oral short-course formulation of cladribine tablets,with acceptable bioavailability, has been tested in a pivotal 96-week phase III trial in patients with relapsing-remitting multiple sclerosis.
Methods: 1326 patients were randomized 1:1:1 to receive cladribine tablets 3.5 or 5.25mg/kg cumulative dose or matching placebo, given in short courses (once daily for 4-5 days per 28-day period) in 2 or 4 courses for the first 48 weeks, then in 2 short courses commencing atWeeks 48 and 52.The primary endpoint was the qualifying relapse rate at 96 weeks.
Results: Cladribine 3.5 and 5.25mg/kg resulted in significantly lower annualized relapse rates than placebo (0.14 and 0.15 versus 0.33, respectively; relative reduction 57.6% and 54.5%, both p<0.001), higher relapse-free rates (79.7% and 78.9% versus 60.9%, respectively; both p<0.001) and lower risk of sustained 3-month disability progression (31% and 33% reductions versus placebo; (hazard ratio [95% confidence interval]: 0.69 [0.49, 0.96], p=0.026; and 0.67 [0.48, 0.93], p=0.018, respectively). Clinical efficacy outcomeswere accompanied by significant reductions in brain lesion activity on magnetic resonance imaging. Overall frequencies of adverse events were comparable in all three treatment groups, with some exceptions related to cladribine's mechanism of action.
Conclusions: Cladribine treatment significantly reduced relapse rates, risk of disability progression, and radiologic measures of disease activity. These results were accompanied by good safety and tolerability. Oral short-course treatment with cladribine tabletswill provide an important newoption in relapsing multiple sclerosis therapy.