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      Emerging oral treatments in multiple sclerosis – clinical utility of cladribine tablets

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          Abstract

          Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that represents one of the first causes of neurological disability in young adults. Although the pathogenesis of MS is still unclear, an autoimmune mechanism has been demonstrated. According to this evidence in the last 15 years different treatments acting on the immune system have been developed. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Moreover the clinical efficacy of these disease-modifying drugs is suboptimal. Thus, there is an important need for the development of new therapeutic strategies. Several oral therapies (fingolimod, fumaric acid, teriflunomide, laquinimod) are in development; Among these cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers sustained regulation of the immune system through a preferential lymphocyte depleting action. Cladribine has a well-characterized and well-known safety profile, derived from more than 15 years of use of the parenteral formulation both in the oncology field and in MS. This paper reviews the new oral emerging treatments and presents the available data about the use of cladribine in MS and the future perspective of its clinical use.

          Most cited references38

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          A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

          Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis. In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point). A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension. As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.) Copyright 2010 Massachusetts Medical Society
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            Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

            Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.) 2010 Massachusetts Medical Society
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              Variations in patients' adherence to medical recommendations: a quantitative review of 50 years of research.

              The literature on patient adherence to treatment includes hundreds of empirical studies. A comprehensive examination of the findings requires the organization and quantification that is possible with meta-analysis. The goals of this research are retrieval, compilation, and averaging of adherence rates in all published empirical studies from 1948 to 1998; assessment of variation according to sample characteristics, time period of publication, measurement method, disease, and regimen; and examination of the effects on adherence of patient demographic characteristics. We calculated a meta-analysis of 569 studies reporting adherence to medical treatment prescribed by a nonpsychiatrist physician, and 164 studies providing correlations between adherence and patients' age, gender, education, and income/socioeconomic status; group comparison and multiple regression analysis of moderators. The average nonadherence rate is 24.8%. Controlling for intercorrelations among moderator variables, adherence is significantly higher in more recent and smaller studies and in those involving medication regimens and adult samples. The use of physical tests and self-report have respectively significant and borderline negative effects on the level of adherence, and disease severity and use of the medical record have no significant effects. Adherence is highest in HIV disease, arthritis, gastrointestinal disorders, and cancer, and lowest in pulmonary disease, diabetes, and sleep. Demographic effects on adherence are small and moderated by sample, regimen, and measurement variables. This review offers insights into the literature on patient adherence, providing direction for future research. A focus on reliability and validity of adherence measurement and systematic study of substantive and methodologic moderators are recommended for future research on patient adherence.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2010
                2010
                7 September 2010
                : 6
                : 391-399
                Affiliations
                [1 ]Department of Neurosciences, S Camillo Forlanini Hospital, Rome, Italy;
                [2 ]Department of Neurological Sciences, University of Rome “La Sapienza”, Italy
                Author notes
                Correspondence: C Gasperini, Dipartimento Testa Collo, Azienda Ospedaliera S Camillo-Forlanini, Circonvallazione Gianicolense, 87, 00152 Rome, Italy, Tel +39 6 58704272, Fax +39 6 58704650, Email c.gasperini@ 123456libero.it
                Article
                tcrm-6-391
                2940747
                20856685
                01c1d956-faad-4072-a3c7-0ca1bd2643ad
                © 2010 Gasperini et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                : 28 August 2010
                Categories
                Review

                Medicine
                treatment adherence,cladribine,multiple sclerosis,disease modifying drugs,oral therapy
                Medicine
                treatment adherence, cladribine, multiple sclerosis, disease modifying drugs, oral therapy

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