June 9, 2009 (Atlanta, Georgia) — Oral short-course treatment with cladribine, at 2 dosing levels, demonstrated efficacy compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS), according to results from the Cladribine Tablets Treating MS Orally (CLARITY) trial, and a 96-week extension trial is now planned.
"The 2-year extension of the CLARITY study will provide important information on the safety, tolerability, and benefit/risk profile of up to 4 years of cladribine use," Peter Rieckmann, MD, from the Multiple Sclerosis Program at the University of British Columbia, in Vancouver, and colleagues note.
The latest findings from the CLARITY trial were presented here at the Consortium of Multiple Sclerosis Centers (CMSC) 23rd Annual Meeting and previously at the American Academy of Neurology meeting held April 25–May 2, 2009, in Seattle, Washington. If approved, cladribine will represent the first oral treatment for RRMS.
The new phase 3b extension study will enroll patients who completed 96 weeks in the CLARITY study evaluating cladribine vs placebo and follow them for over 2 additional years. Patients previously treated with cladribine will be randomized in a ratio of 2:1 to 4- or 5-day courses per year in consecutive months of once-daily cladribine tablets or to placebo. Patients previously randomized to placebo in the first 96 weeks of the CLARITY study will receive a 5-day course for 2 consecutive months per year of once-daily cladribine tablets.
The primary end point will be safety, including assessment of hematologic and hepatic function.
The CLARITY study included patients diagnosed with RRMS with at least 1 relapse within the past 12 months and no more than 1 prior failed disease-modifying treatment given at least 3 months prior to study entry. Patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Rescue therapy with interferon beta-1a was allowed after week 24.
For the main analysis, 1326 patients were randomized equally to receive placebo or 1 of 2 doses of cladribine tablets: either 4 courses, for a total dose of 3.5 mg/kg, or 5 courses, for a total dose of 5.25 mg/kg, over the 96-week study period. For each course, patients received 1 to 2 tablets according to body weight for 4 or 5 consecutive days per month.
The annualized rate of relapse was reduced with cladribine compared with placebo; patients treated with the low-dose regimen of cladribine tablets experienced a 58% relative reduction in annualized relapse rates with respect to placebo (0.14 vs 0.33 for the placebo group; P < .001). Patients in the high-dose regimen group experienced a 55% relative reduction in annualized relapse rates compared with placebo (0.15 vs 0.33; P < .001).
The proportion of patients who remained relapse-free, a secondary end point, was significantly higher with cladribine than with placebo. Over the 2-year period of the study, 80% of the patients treated with the low-dose regimen of cladribine tablets and 79% of the patients treated with the high-dose regimen experienced no clinical relapse, compared with 61% of the patients from the placebo group (P < .001 for both dose regimens vs placebo).
A reduction of at least 70% in the mean number of active T1 gadolinium-enhancing lesions per subject per scan, the mean number of active T2 lesions per subject per scan, and the mean number of combined unique lesions per subject per scan was also observed with cladribine (reductions ranging from 73% to 88%, depending on magnetic resonance imaging [MRI] measure and dose group; P < 0.001 for all measures).
Overall, adverse-event rates were comparable between treatment groups, with the exception of lymphopenia, which occurred more frequently with cladribine, 26.7% with both treatment groups combined vs 1.8% with placebo. Other adverse events with cladribine included leukopenia (7.1%), decreased lymphocyte count (4.4%), and vertigo (4.2%).
"Our findings suggest that annual short-course treatment with cladribine tablets, given 8 to 20 days during the year, depending on the dosing regimen, was significantly effective across multiple important clinical and MRI efficacy measures," Bruno Musch, MD, head of global clinical development for neurology at EMD Serono, told Medscape Neurology.
Cladribine may be taken at short intermittent courses, and this will "hopefully address the unmet need for an oral therapy in MS to improve compliance, adherence, and convenience," he said. EMD Serono expects to file an indication for cladribine in relapsing-remitting MS with the Food and Drug Administration in mid-2009, he added.
Intermittent Therapy a "Plus"
"An oral therapy is certainly an advance, and 1 taken so few times a year is an added plus," said Dr. Mark S. Freedman, professor of neurology at the University of Ottawa, in Ontario, and director of the multiple sclerosis research clinic at Ottawa Hospital.
"There are always safety concerns when one considers a possibly longer-term treatment," he told Medscape Neurology, "but the study doesn't really indicate any major problems. It is unlikely that the few cancerous conditions that were noted are any more frequent than would be expected for an age-matched population.
"It is imperative that physicians carefully consider all the options for a patient," he said. "Ongoing studies with cladribine will help us to know if treatment beyond 2 years is necessary. Until such time, cladribine will probably find itself readily replacing natalizumab in the treatment algorithm for drug escalation in patients breaking through first-line therapies."
The study was sponsored by Merck Serono. Dr. Musch is an employee of EMD Serono. Dr. Freedman has served as an advisor to and speaker for and has received honoraria from EMD Pharmaceuticals/Merck Serono.
The Consortium of Multiple Sclerosis Centers (CMSC) 23rd Annual Meeting and 2nd joint meeting of the American Committee for Treatment and Research in MS (ACTRIMS): Abstracts P11, S130, and W32. Presented May 29, 2009.
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Cite this: Oral Short-Course Cladribine to Be Evaluated in Extension Trial in MS - Medscape - Jun 09, 2009.