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Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients. We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients—those aged 18–55 years with relapsing-remitting multiple sclerosis—to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134. Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34–0·48) in patients given placebo and 0·21 (0·17–0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40–0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was −0·86 (SD 1·22) for fingolimod 0·5 mg versus −1·28 (1·50) for placebo (treatment difference −0·41, 95% CI −0·62 to −0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61–1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]). Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis. Novartis Pharma AG.

In this 24-month, randomized trial involving patients with relapsing–remitting multiple sclerosis, oral fingolimod reduced the rates of relapse and disability progression, as compared with placebo. Adverse events reported in patients treated with fingolimod included bradycardia, atrioventricular conduction block, macular edema, elevations in liver-enzyme levels, and mild hypertension. In patients with relapsing–remitting multiple sclerosis, oral fingolimod reduced the rates of relapse and disability progression, as compared with placebo. Adverse events included bradycardia, atrioventricular conduction block, macular edema, elevations in liver-enzyme levels, and mild hypertension. Fingolimod (FTY720) is an oral sphingosine-1-phosphate–receptor modulator 1 that is currently being evaluated for the treatment of multiple sclerosis. There is evidence that fingolimod acts by preventing lymphocyte egress from lymph nodes. 2 , 3 This leads to a reduced infiltration of potentially autoaggressive lymphocytes into the central nervous system. 4 , 5 Preclinical findings also suggest that fingolimod may promote neuroprotective and reparative processes within the central nervous system through modulation of sphingosine-1-phosphate receptors expressed on neural cells. 6 – 12 A 6-month, phase 2, placebo-controlled study 13 and its open-label extension study 14 showed sustained suppression, for up to 5 years, of both relapse and inflammatory activity . . .

Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. −1, respectively ( P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery. Significance In patients with acute ischemic stroke (AIS), the abrupt and massive influx of lymphocytes from the periphery to the ischemic region orchestrates focal inflammatory responses, catalyzes tissue death, and worsens clinical outcomes. In this early phase clinical study, we reduced lymphocyte migration to the brain during the first 72 h of AIS via oral administration of three doses of fingolimod. This administration led to a significant reduction of secondary lesion enlargement, microvascular permeability, and better clinical outcomes during the acute phase and 3-mo follow-up visit. This study will provoke new investigations on the efficacy of modulation of brain inflammation in AIS.

In this 12-month trial involving patients with relapsing–remitting multiple sclerosis, oral fingolimod was more effective than intramuscular interferon beta-1a in reducing relapse rates. Adverse events associated with fingolimod included herpesvirus infections (two fatal infections), atrioventricular block, macular edema, skin cancer, and liver-enzyme elevation. In patients with relapsing–remitting multiple sclerosis, oral fingolimod was more effective than intramuscular interferon beta-1a in reducing relapse rates. Adverse events included herpesvirus infections (two fatal infections), atrioventricular block, macular edema, skin cancer, and liver-enzyme elevation. Oral fingolimod (FTY720) is a sphingosine-1-phosphate–receptor modulator. After phosphorylation, fingolimod acts as a functional antagonist of the sphingosine-1-phosphate type 1 receptor, inducing receptor internalization and rendering T and B cells insensitive to a signal necessary for egress from secondary lymphoid tissues. 1 , 2 The resulting redistribution to lymph nodes reduces recirculation of autoaggressive lymphocytes to the central nervous system. 3 – 5 Also, fingolimod is lipophilic, readily crosses the blood–brain barrier, and is phosphorylated within the central nervous system. 6 Through interaction with sphingosine-1-phosphate receptors on neural cells, fingolimod may have neuroprotective or reparative effects. 6 – 9 Fingolimod effectively treats experimental autoimmune encephalomyelitis, an animal . . .

Fingolimod 0·5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics. We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0·5 mg or 1·25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978. Treatment with fingolimod 0·5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0·76 (95% CI 0·54–1·09; p=0·13) in patients aged over 40 years to 0·29 (0·16–0·52; p<0·0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0·5 mg versus placebo ranged from 0·85 (95% CI 0·53–1·36; p=0·50) in patients with a T2 lesion volume of 3300 mm3 or less to 0·32 (0·14–0·73; p=0·0066) in patients with an EDSS over 3·5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0·5 mg versus placebo was 0·38 (95% CI 0·21–0·68, p=0·0011), and for treatment-naive patients with rapidly evolving severe disease it was 0·33 (0·18–0·62, p=0·0006). Hazard ratios for confirmed disability progression over 24 months were 0·68 (0·29–1·62; p=0·39) and 0·73 (0·25–2·07; p=0·55), respectively, in these groups. Patients with relapsing-remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0·5 mg fingolimod. Novartis.

In this proof-of-concept study, fingolimod, an oral immunomodulating agent, reduced lesions detected on magnetic resonance imaging and the rate of clinical relapse among patients with relapsing multiple sclerosis. Adverse events associated with fingolimod included elevations in liver enzyme levels, a reduction in the heart rate, a decrease in forced expiratory flow, and one case of posterior reversible encephalopathy. Fingolimod, an oral immunomodulating agent, reduced lesions detected on magnetic resonance imaging and the rate of clinical relapse among patients with relapsing multiple sclerosis. Multiple sclerosis is the most common nontraumatic cause of neurologic disability in young adults. 1 , 2 It is generally believed to be an autoimmune condition in which autoreactive T cells attack myelin sheaths, 3 leading to demyelination and axonal damage. 4 Currently approved immunomodulating treatments for multiple sclerosis (interferon beta and glatiramer acetate) 5 – 8 reduce relapse rates by about 30%. 9 Both these drugs are administered either subcutaneously or intramuscularly, and interferons are associated with systemic reactions in more than 60% of patients, 10 with implications for adherence to treatment. 11 Fingolimod (FTY720, Novartis Pharma) is an oral sphingosine-1-phosphate receptor modulator. After rapid phosphorylation, fingolimod-P acts . . .

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.

Background: Fingolimod (FTY720) has previously shown clinical efficacy in phase II/III studies of predominantly Caucasian populations with multiple sclerosis (MS). Objectives: To report six-month efficacy and safety outcomes in Japanese patients with relapsing MS treated with fingolimod. Methods: In this double-blind, parallel-group, phase II study, 171 Japanese patients with relapsing MS were randomized to receive once-daily fingolimod 0.5 mg or 1.25 mg, or matching placebo for six months. The primary and secondary endpoints were the percentages of patients free from gadolinium (Gd)-enhanced lesions at months 3 and 6, and relapses over six months, respectively; safety outcomes were also assessed. Results: 147 patients completed the study. Higher proportions of patients were free from Gd-enhanced lesions at months 3 and 6 with fingolimod (0.5 mg: 70%, p = 0.004; 1.25 mg: 86%, p < 0.001) than with placebo (40%). Odds ratios for the proportions of relapse-free patients over six months favoured fingolimod versus placebo but were not significant. Adverse events related to fingolimod included transient bradycardia and atrioventricular block at treatment initiation, and elevated liver enzyme levels. Conclusions: This study demonstrated the clinical efficacy of fingolimod for the first time in Japanese patients with MS, consistent with the established effects of fingolimod in Caucasian patients.

In a phase 3 trial, patients with moderately to severely active ulcerative colitis were randomly assigned to receive placebo or ozanimod, a selective sphingosine-1-phosphate receptor modulator. Clinical remission was significantly greater with ozanimod during the induction and maintenance periods. The incidence of infection was higher with ozanimod than with placebo during maintenance.

A 37-year-old man with multiple sclerosis has recurrent disease activity despite several previous therapies. Treatment with fingolimod is recommended. Fingolimod blocks the egress of lymphocytes from lymph nodes, preventing them from reaching the central nervous system. Foreword This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations. Stage A 37-year-old man with multiple sclerosis was evaluated for consideration of oral immunotherapy. Six years earlier, he had reported acute monocular visual disturbance. The diagnosis of multiple sclerosis was subsequently confirmed by means of examination of cerebrospinal fluid, which revealed an increased IgG index and oligoclonal banding, and by abnormal results on magnetic resonance imaging (MRI). There was no family history of multiple sclerosis. Daily injections of glatiramer acetate were initiated at the time of diagnosis, but two consecutive annual brain MRI scans revealed substantial disease activity. He was then switched to interferon beta therapy, but this treatment was . . .