Cladribine. Spirella Building, Letchworth, SG6 4ET reg charity no

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1 Cladribine Spirella Building, Letchworth, SG6 4ET reg charity no

2 Cladribine Date of issue: February 2009 Contents Section Page 1. Introduction 1 2. How cladribine works 2 3. Current research Side effects and contraindications 3 5. Further information 4 6. References 4 1. Introduction Cladribine (brand name Leustat) is currently an anti cancer agent that is administered by intravenous infusion in the treatment of leukaemia. An oral version of cladribine with a different dosing pattern is now being studied as a potential treatment for relapsing/remitting MS. Cladribine is not licensed for the treatment of multiple sclerosis but is currently in clinical trials. It is being studied against placebo for its effectiveness as a single drug therapy in relapsing/remitting MS. It is also being studied to assess its safety in combination with beta interferon (as an add-on therapy) compared with beta interferon alone in adults who continue to show signs of active disease whilst on beta interferon therapy. Results of a two year phase III study comparing two doses of cladribine and placebo indicated that cladribine significantly reduces relapse rates in people with relapsing/remitting MS 1. Based on these positive results, the manufacturers, Merck Serono, hope to submit the drug for licensing later this year. The National Institute for Health and Clinical Excellence (NICE) intends to appraise cladribine through its Single Technology Appraisal (STA) process and has already drawn up a draft scope for the appraisal 2. 1

3 2. How cladribine works The autoimmune attack that is seen in MS results in the destruction of myelin, the substance covering and protecting nerves in the central nervous system. As with other chemotherapy drugs used in the treatment of MS, cladribine is used to kill off certain immune cells (lymphocytes) that prompt the autoimmune destruction of myelin. By reducing the number of destructive immune cells in circulation, it is thought it may slow down or stop this autoimmune attack. 3. Current research - CLARITY: CLAdRIbine Tablets Treating MS OrallY This two-year phase III trial looked to evaluate the safety and efficacy of oral cladribine in people with relapsing/remitting MS. 1,326 people were randomized to one of three different treatment groups consisting of two different dose regimens or matching placebo tablets. Cladribine tablets were administered in two dosage arms. One arm consisted of two courses for the first and second year; the other arm consisted of four courses for the first year and two courses for the second year. Each course consisted of once daily administration for four to five consecutive days. The primary end-point of the CLARITY study was clinical relapse rate reduction. A 58% relative reduction in yearly relapse rate was seen in the low total dose treatment group and 55% in the high total dose treatment group. Secondary endpoints of the study were also met, including reduced lesion activity as measured by magnetic resonance imaging (MRI); proportion of participants relapse-free; and disability progression. - The CLARITY extension study The clinical development program for cladribine tablets includes a two year placebo controlled extension of the CLARITY study, designed to provide data on the long-term safety and efficacy of extended administration of cladribine tablets for up to four years. People in the placebo arm of the original CLARITY study will receive cladribine tablets while people in the two cladribine treatment groups will be randomised 2:1 to receive either cladribine or placebo. 2

4 There are two further studies of oral cladribine currently underway: - The ORACLE MS (ORAl CLadribine in Early MS) study. Recruitment is underway for this two-year Phase III placebo-controlled trial to evaluate the efficacy and safety of cladribine tablets as a single therapy in patients at risk of developing MS (patients who have experienced a first clinical event suggestive of MS). The single primary endpoint for the study is time to conversion to MS. - The ONWARD (Oral Cladribine Added ON To Rebif New Formulation in Patients With Active Relapsing Disease) study Recruitment is underway to this Phase II placebo-controlled trial which is designed to evaluate the safety and tolerability of cladribine as an add-on therapy to people with relapsing forms of MS, who continue to show signs of active disease while on established interferon-beta therapy. 4. Side effects and contraindications Lymphopenia - an abnormally low level of lymphocytes (white blood cells that fight off disease) occurred more frequently in the cladribine tablet treatment groups. With the exception of lymphopenia, headaches and nasopharyngitis (inflammation of the nasal passages and upper part of the throat) were the most frequently reported adverse events in the three treatment groups. More detailed information on the safety profile will follow when the results are presented at an upcoming scientific meeting. 3

5 5. Further information ClinalTrials.gov For further information about current and completed clinical trials of cladribine tablets visit ClinicalTrials.gov is a registry clinical trials conducted around the world. The site provides information about a trial's purpose, who may participate, and trial locations. This information should be used in conjunction with advice from health care professionals 6. References 1. Merk Serono. Merck Serono s oral investigational treatment cladribine tablets for multiple sclerosis significantly reduced relapse rate in two-year phase III pivotal trial [press release]. Geneva: Merck Serono; 2009 Jan National Institute for Health and Clinical Excellence (NICE). Draft scope for the proposed appraisal of cladribine for relapsing-remitting multiple sclerosis. Issue Date: December [cited 2009; January 26] Available from URL: edraftscope.pdf ^ Note - Drug trials Phase I studies primarily assess the safety of a drug or procedure. They usually involve a small number of healthy volunteers (10-100) all of whom are given the same treatment. Once a medical intervention has been proven safe, phase II trials test its effectiveness and whether it has the potential to be of benefit. These trials are larger, typically involving people with the condition for which the intervention has been developed - in this case MS. If the phase II study shows the treatment to be beneficial, phase III studies are conducted to gain a definitive understanding of the effectiveness, benefits and potential side effects in a large group of people (300-3,000) with the condition to be treated. Interventions have to successfully complete a phase III trial before they can be considered for a licence by regulatory authorities. 4

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