Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results
ABSTRACT In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7-36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15-24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88-89%) or new T2 lesions (70-78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20-0.21, and 68-73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3-5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.
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ABSTRACT: Classical multiple sclerosis (MS) treatments using first-line injectable drugs, although widely applied, remain a major concern in terms of therapeutic adherence and efficacy. New oral drugs recently approved for MS treatment represent significant advances in therapy. The oral route of administration clearly promotes patient satisfaction and increases therapeutic compliance. However, these drugs may also have safety and tolerability issues, and a thorough analysis of the risks and benefits is required. Three oral drugs have been approved by regulatory agencies for MS treatment: fingolimod, teriflunomide, and dimethyl fumarate. This article reviews the mechanisms of action, safety, and efficacy of these drugs and two other drugs that have yielded positive results in phase III trials: cladribine and laquinimod.Journal of Clinical Neurology 01/2015; 11(1):9-19. DOI:10.3988/jcn.2015.11.1.9 · 1.81 Impact Factor
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ABSTRACT: The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic head group and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors towards bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3-receptors, efficacy at <1mg/kg oral doses and developability properties suitable for progression into preclinical development.Journal of Medicinal Chemistry 11/2014; 57(24). DOI:10.1021/jm5010336 · 5.48 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a chronic auto-immune disease. Most therapeutic strategies for treatment of this disease direct immune modulation and control of inflammatory processes. First-line therapeutic agents showed moderate efficacy and frequent side-effects with moderate efficacy in trials. Their parental administration and limited long-term adherence restrict their efficacy compared with second-line therapies. Fingolimod as a second-line therapeutic agent has been shown to reduce annualized relapse rate, risk of disability progression and inflammatory activity of relapsing MS. Safety and efficacy FTY720: Safety and efficacy issues are the main metrics for judgment of drug efficacy. In this article, we focus on cardiovascular effects of FTY720 treatment. Effect of FTY720 on rate and rhythm, impact of FTY720 on endothelial cells, its atheroprotective effects, its effects on cardiac transplantation outcomes, vascular complications of FTY720, effects of FTY720 on endocrine functions and interaction of FTY720 with cardioactive agents are explained in this review article.Iranian Journal of Neurology 07/2014; 13(3):119-26.