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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 . . .

In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFNβ)-1a in patients with relapsing–remitting multiple sclerosis (RRMS). This study analyzed fingolimod efficacy compared with IFNβ-1a in patient subgroups from TRANSFORMS. Patients were randomized to receive fingolimod or weekly IM IFNβ-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy. Fingolimod 0.5 mg reduced ARR over 12 months by 32–59 % relative to IFNβ-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd-enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFNβ-1a in most (95 %) subgroups. In patients with high disease activity despite IFNβ treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFNβ-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these patients. In conclusion, consistently better efficacy was observed for fingolimod compared with IFNβ-1a across different subgroups of patients with RRMS.

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 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: Health-related quality of life (HRQoL) worsens with multiple sclerosis (MS) relapses and disease progression. Common symptoms including depression and fatigue may contribute to poor HRQoL. Objectives: To report exploratory analyses assessing the impact of fingolimod (FTY720) on HRQoL and depression in a phase II study of relapsing MS. Methods: The Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and Beck Depression Inventory second edition (BDI-II) scores were assessed during a 6-month, placebo-controlled study and optional extension. Results: HAQUAMS total score improved with fingolimod and worsened with placebo. Mean score change from baseline to month 6 was −0.02 with fingolimod 1.25 mg (p < 0.05 versus placebo), −0.01 with fingolimod 5.0 mg and + 0.12 with placebo. Categorical data supported a clinically important effect of fingolimod on HRQoL. Fingolimod 1.25 mg was also beneficial over placebo in the fatigue/thinking HAQUAMS sub-domain (p < 0.05 versus placebo). Change in mean BDI-II scores from baseline to month 6 and the proportion of patients with BDI-II scores indicative of clinical depression favored fingolimod 1.25 mg over placebo (p < 0.05 for both). At month 4, mean BDI-II and HAQUAMS total scores appeared to be maintained in fingolimod-treated patients. Conclusion: Fingolimod 1.25 mg may improve HRQoL and depression at 6 onths compared with placebo in patients with relapsing MS.

Fingolimod is a once-daily orally administered disease-modifying therapy (DMT) indicated for treatment of relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical relapses and delay accumulation of physical disability. In the randomized, double-blind, phase 3 TRANSFORMS trial, 0.5 mg/d oral fingolimod substantially reduced relapse frequency when compared with IM interferon-β1a (IFN-β1a) at 12-months. In a 12-month, double-blind, extension phase of the TRANSFORMS study, patients assigned to receive fingolimod continued to receive the same dosage, whereas patients who originally received IM IFN-β1a were randomized to receive either 0.5 or 1.25 mg/d fingolimod. To investigate the cost-effectiveness of initiating fingolimod therapy early versus after 1 year of IFN-β1a therapy using TRANSFORMS study extension data. A Microsoft Excel-based model was used to calculate the cost per relapse avoided for 2 years with continuous treatment with fingolimod compared with first-year treatment with IM IFN-β1a and second-year treatment with fingolimod. One-way sensitivity analyses were conducted on key input variables to assess their effect on cost per relapse avoided. The 2-year relapse rate in the early fingolimod arm was 0.23, and in the delayed fingolimod arm was 0.53. The cost per relapse avoided was $83,125 in the early fingolimod arm versus $103,624 in the delayed fingolimod arm. Results of the sensitivity analyses showed an effect of drug acquisition cost and number of relapses in patients who received no treatment. Continuous treatment with fingolimod for 2 years resulted in a lower cost per relapse avoided compared with treatment with IM IFN-β1a for the first year and then switching to fingolimod therapy. Thus, delaying fingolimod therapy does not seem to be cost effective.

Key Points Multiple sclerosis (MS) is a chronic, autoimmune disorder of the central nervous system (CNS) that is characterized by inflammation leading to astrogliosis, demyelination and oligodendrocyte and neuronal loss. Current treatment strategies in MS involve management of symptoms and use of disease-modifying drugs, all of which must be injected. Oral fingolimod (FTY720/Gilenya; Novartis) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that, in relapsing–remitting MS, has demonstrated improved efficacy compared to placebo and one of the first-line interferon (IFN) products in terms of relapses and magnetic resonance imaging measures. Fingolimod has also shown an effect on disability and reduces brain atrophy compared to placebo and IFN-β on intent-to-treat analysis over the full duration of the studies. The therapeutic activity of the drug requires phosphorylation in vivo by sphingosine kinases to form the active moiety fingolimod phosphate. Fingolimod phosphate binds to lymphocytic S1P 1 receptors, causing internalization and degradation of the receptors. This reduces S1P–S1P 1 -dependent egress of lymphocytes from lymph nodes and reduces the recirculation of autoaggressive T cells via lymph and blood to the CNS. Fingolimod retains central but not effector memory T cells in lymph nodes; this leads to a preferential reduction of MS-pathogenic immune responses and spares large parts of protective immunity. Based on its lipophilic nature, fingolimod crosses the blood–brain barrier, where the drug may down-modulate S1P receptors on neural cells, particularly astrocytes, to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap-junctional communication of astrocytes with neurons and cells of the blood–brain barrier. Fingolimod may act through immune-based and central mechanisms to reduce inflammation and to support structural restoration of the CNS parenchyma. In September 2010, 0.5 mg fingolimod was approved by the US Food and Drug Administration as an oral first-line treatment for relapsing–remitting MS. In September 2010, fingolimod (FTY720/Gilenya; Novartis) became the first oral disease-modifying therapy to be approved by the US Food and Drug Administration for relapsing–remitting multiple sclerosis. Brinkmann and colleagues describe its discovery and development, and how elucidation of its effects on sphingosine 1-phosphate receptors has improved the understanding of the biology of these receptors. The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod — mediated by the modulation of sphingosine 1-phosphate (S1P) receptors — has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.

Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa . Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P. aeruginosa . Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P. aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection. Synopsis Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase. Sphingosine is present on the luminal side of trachea and bronchi epithelia in healthy individuals. Sphingosine level is reduced on trachea and bronchi epithelia in diseases such as cystic fibrosis or in mice lacking ceramide synthase 2. Acid ceramidase or sphingosine inhalation corrects sphingosine levels in cystic fibrosis and ceramide synthase 2‐deficient mice, prevents their infection with Pseudomonas aeruginosa and cures an existing Pseudomonas aeruginosa infection. Sphingosine kills a broad spectrum of pathogens at nanomolar to low micromolar concentrations including Pseudomomas aeruginosa , Acinetobacter baumannii , Haemophilus influenzae , Moraxella catarrhalis and Burkholderia cepacia . Graphical Abstract Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase.

Endothelial cells play significant roles in conditioning tissues after injury by the production and secretion of angiocrine factors. At least two distinct subsets of monocytes, CD45 ⁺CD11b ⁺Gr1 ⁺Ly6C ⁺ inflammatory and CD45 ⁺CD11b ⁺Gr1 ⁻Ly6C ⁻ anti-inflammatory monocytes, respond differentially to these angiocrine factors and promote pathogen/debris clearance and arteriogenesis/tissue regeneration, respectively. We demonstrate here that local sphingosine 1-phosphate receptor 3 (S1P ₃) agonism recruits anti-inflammatory monocytes to remodeling vessels. Poly(lactic-co-glycolic acid) thin films were used to deliver FTY720, an S1P ₁/₃ agonist, to inflamed and ischemic tissues, which resulted in a reduction in proinflammatory cytokine secretion and an increase in regenerative cytokine secretion. The altered balance of cytokine secretion results in preferential recruitment of anti-inflammatory monocytes from circulation. The chemotaxis of these cells, which express more S1P ₃ than inflammatory monocytes, toward SDF-1α was also enhanced with FTY720 treatment, but not in S1P ₃ knockout cells. FTY720 delivery enhanced arteriolar diameter expansion and increased length density of the local vasculature. This work establishes a role for S1P receptor signaling in the local conditioning of tissues by angiocrine factors that preferentially recruit regenerative monocytes that can enhance healing outcomes, tissue regeneration, and biomaterial implant functionality.