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Ludwig Kappos - One of the best experts on this subject based on the ideXlab platform.

  • randomized trial of vaccination in Fingolimod treated patients with multiple sclerosis
    Neurology, 2015
    Co-Authors: Ludwig Kappos, Guillermo Izquierdo, Matthias Mehling, Krzysztof Selmaj, Rafael Arroyo, Valentina Curovicperisic, Astrid Keil, M Bijarnia, Arun Singh, Philipp Von Rosenstiel
    Abstract:

    Objective: To evaluate immune responses in Fingolimod-treated patients with multiple sclerosis (MS) against influenza vaccine (to test for responses against anticipated novel antigens in seronegative patients) and recall (tetanus toxoid [TT] booster dose) antigens. Methods: This was a blinded, randomized, multicenter, placebo-controlled study. Patients aged 18 to 55 years with relapsing MS were randomized (2:1) to Fingolimod 0.5 mg or placebo for 12 weeks. At week 6, patients received seasonal influenza vaccine (containing antigens of California, Perth, and Brisbane virus strains) and TT booster dose. Antibody titers against influenza and TT were estimated at baseline (prevaccination) and 3 and 6 weeks postvaccination. The primary efficacy variable was responder rate (proportion of patients showing seroconversion or significant increase [≥4-fold] in antibody titers against at least one influenza virus strain) at 3 weeks postvaccination and vs placebo. Results: Of 138 randomized patients (Fingolimod 95, placebo 43), 136 completed the study (2 discontinued in Fingolimod group). The responder rates (odds ratio; 95% confidence interval) for influenza vaccine (Fingolimod vs placebo) were 54% vs 85% (0.21; 0.08–0.54) at 3 weeks and 43% vs 75% (0.25; 0.11–0.57) at 6 weeks postvaccination. For TT, responder rates were 40% vs 61% (0.43; 0.20–0.92) at 3 weeks and 38% vs 49% (0.62; 0.29–1.33) at 6 weeks postvaccination. Adverse events were reported in 86.3% and 79.1% of patients receiving Fingolimod and placebo, respectively. Conclusion: Most Fingolimod-treated patients with MS were able to mount immune responses against novel and recall antigens and the majority met regulatory criteria indicating seroprotection. However, response rates were reduced compared with placebo-treated patients. This should be kept in mind when vaccinating patients on Fingolimod. Classification of evidence: This study provides Class I evidence that in some patients with MS receiving immunizations, concurrent Fingolimod treatment in comparison to placebo decreases vaccination-induced immune responses.

  • first dose effects of Fingolimod pooled safety data from three phase 3 studies
    Multiple sclerosis and related disorders, 2014
    Co-Authors: John P Dimarco, Jeffrey A. Cohen, Anthony T. Reder, Paul Oconnor, Lixin Zhangauberson, Dejun Tang, William Collins, Ludwig Kappos
    Abstract:

    Abstract Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose Fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data ( n =3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4–5h after the first dose, with a maximum reduction of 8 (Fingolimod 0.5mg) and 11 beats per minute (Fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (Fingolimod 0.5mg) and 2.1% (Fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, Fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block Fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, Fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention.

  • Fingolimod in relapsing multiple sclerosis an integrated analysis of safety findings
    Multiple sclerosis and related disorders, 2014
    Co-Authors: Ludwig Kappos, Jeffrey A. Cohen, Shannon Ritter, Philipp Von Rosenstiel, Lixin Zhangauberson, William Collins, Ana De Vera, Gordon Francis
    Abstract:

    Abstract Background Fingolimod 0.5mg once daily is the first approved oral therapy for relapsing multiple sclerosis (MS). Objective To report integrated long-term safety data from phase 2/3 Fingolimod studies. Methods Descriptive safety data are reported from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, double-blind study comparing Fingolimod 0.5mg and 1.25mg with placebo, and an All Studies group (patients who received Fingolimod 0.5mg ( n =1640) or 1.25–0.5mg ( n =1776) in phase 2/3 studies and associated extensions). Relevant post-marketing experience, up to December 2011, is included. Results The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with Fingolimod and placebo in FREEDOMS. In the All Studies group, Fingolimod 0.5mg was associated with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular block on treatment initiation, minor blood pressure increases, frequent (9%) but generally asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections (including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to AEs were similar with Fingolimod 0.5mg and placebo. Conclusion The safety profile of Fingolimod has been well characterized in this large combined trial population. Although infrequent SAEs can occur, there is no increased risk of infections, malignancies or serious cardiovascular events versus placebo.

  • safety and efficacy of Fingolimod in patients with relapsing remitting multiple sclerosis freedoms ii a double blind randomised placebo controlled phase 3 trial
    Lancet Neurology, 2014
    Co-Authors: Peter A Calabresi, Ludwig Kappos, Anthony T. Reder, E W Radue, Douglas S Goodin, Douglas Jeffery, K Rammohan, Timothy Vollmer, Mark A Agius, Tracy Stites
    Abstract:

    Summary Background 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. Methods 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. Findings 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 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 [ 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%]). Interpretation 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. Funding Novartis Pharma AG.

  • pregnancy outcomes in the clinical development program of Fingolimod in multiple sclerosis
    Neurology, 2014
    Co-Authors: Goeril Karlsson, Ludwig Kappos, Jeffrey A. Cohen, Gordon Francis, Gideon Koren, Peter Heining, Xiaoli Zhang, William Collins
    Abstract:

    Objective: To report outcomes of pregnancies that occurred during the Fingolimod clinical development program. Methods: Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as Fingolimod treatment at the time of conception or in the 6 weeks before conception. Results: As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in Fingolimod treatment arms. Of 66 pregnancies with in utero exposure to Fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (patient lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia and 1 with acrania. Elective abortions were performed for 1 case each of tetralogy of Fallot, spontaneous intrauterine death, and failure of fetal development. There were 5 cases (7.6%; 95% confidence interval 3%–17%) of abnormal fetal development in the 66 pregnancies that had in utero exposure to Fingolimod. In all 5 cases, fetal exposure to the drug took place in the first trimester of pregnancy. Conclusions: The number of patients becoming pregnant during Fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of Fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during Fingolimod therapy and for 2 months after discontinuation.

Jeffrey A. Cohen - One of the best experts on this subject based on the ideXlab platform.

  • long term up to 4 5 years treatment with Fingolimod in multiple sclerosis results from the extension of the randomised transforms study
    Journal of Neurology Neurosurgery and Psychiatry, 2016
    Co-Authors: Jeffrey A. Cohen, Giancarlo Comi, Frederik Barkhof, Hanspeter Hartung, Xavier Montalban, Jean Pelletier, Tracy Stites, Bhupendra O Khatri, Shannon Ritter, Philipp Von Rosenstiel
    Abstract:

    OBJECTIVE: The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of Fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. METHODS: Patients randomised to Fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-Fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to Fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-Fingolimod 0.5 mg and pooled IFN-switch groups. RESULTS: Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-Fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to Fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to Fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. CONCLUSIONS: These results support a continued effect of long-term Fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to Fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834.

  • Experience with Fingolimod in clinical practice
    International Journal of Neuroscience, 2014
    Co-Authors: Carrie M. Hersh, Claire Hara-cleaver, Richard A. Rudick, Jeffrey A. Cohen, Robert A. Bermel, Daniel Ontaneda
    Abstract:

    Aim: To report experience with Fingolimod in clinical practice. Design/Methods: Patients in an academic medical center who were prescribed Fingolimod from October 2010 to August 2011 were identified through the electronic medical record and followed for 12 months after Fingolimod initiation. Adverse effects (AEs), clinical measures, MRI data, and quality of life measures were assessed. Results: Three hundred seventeen patients started Fingolimod. Eleven patients were treatment naive (3.5%) and 76 (24.0%) had remote disease modifying therapy (DMT) use prior to Fingolimod. One hundred fifty-one (47.6%) switched because of patient preference and 79 (24.9%) switched because of breakthrough disease. About 11.6% transitioned from natalizumab. Follow-up data were available for 306 patients (96.5%) with mean follow-up time 332 days. Fingolimod was discontinued in 76 of 306 patients (24.8%) at mean 248 days after Fingolimod start. Discontinuation most often was due to AEs (n = 40) or breakthrough disease (n = 22)....

  • first dose effects of Fingolimod pooled safety data from three phase 3 studies
    Multiple sclerosis and related disorders, 2014
    Co-Authors: John P Dimarco, Jeffrey A. Cohen, Anthony T. Reder, Paul Oconnor, Lixin Zhangauberson, Dejun Tang, William Collins, Ludwig Kappos
    Abstract:

    Abstract Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose Fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data ( n =3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4–5h after the first dose, with a maximum reduction of 8 (Fingolimod 0.5mg) and 11 beats per minute (Fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (Fingolimod 0.5mg) and 2.1% (Fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, Fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block Fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, Fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention.

  • Fingolimod in relapsing multiple sclerosis an integrated analysis of safety findings
    Multiple sclerosis and related disorders, 2014
    Co-Authors: Ludwig Kappos, Jeffrey A. Cohen, Shannon Ritter, Philipp Von Rosenstiel, Lixin Zhangauberson, William Collins, Ana De Vera, Gordon Francis
    Abstract:

    Abstract Background Fingolimod 0.5mg once daily is the first approved oral therapy for relapsing multiple sclerosis (MS). Objective To report integrated long-term safety data from phase 2/3 Fingolimod studies. Methods Descriptive safety data are reported from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, double-blind study comparing Fingolimod 0.5mg and 1.25mg with placebo, and an All Studies group (patients who received Fingolimod 0.5mg ( n =1640) or 1.25–0.5mg ( n =1776) in phase 2/3 studies and associated extensions). Relevant post-marketing experience, up to December 2011, is included. Results The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with Fingolimod and placebo in FREEDOMS. In the All Studies group, Fingolimod 0.5mg was associated with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular block on treatment initiation, minor blood pressure increases, frequent (9%) but generally asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections (including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to AEs were similar with Fingolimod 0.5mg and placebo. Conclusion The safety profile of Fingolimod has been well characterized in this large combined trial population. Although infrequent SAEs can occur, there is no increased risk of infections, malignancies or serious cardiovascular events versus placebo.

  • temporal profile of lymphocyte counts and relationship with infections with Fingolimod therapy
    Multiple Sclerosis Journal, 2014
    Co-Authors: Gordon Francis, Paul Oconnor, Dejun Tang, William Collins, L Kappos, F Mercier, Jeffrey A. Cohen
    Abstract:

    Background Reduction in peripheral blood lymphocytes is an expected pharmacodynamic outcome of Fingolimod therapy. Objective The objective of this article is to evaluate lymphocyte dynamics during and after Fingolimod therapy and assess the relationship between lymphocyte counts and infections. Methods Lymphocyte counts and their relationship with infections were evaluated in three multiple sclerosis (MS) populations: (Group A) FREEDOMS phase 3 core study group (n = 1272); (Group B) All Studies group (one phase 2 and two phase 3 studies, plus their extensions; n = 2315); and (Group C) Follow-up group (after Fingolimod discontinuation; n = 538). Results Administration of Fingolimod 0.5 mg led to reductions in lymphocyte counts to a steady-state of 24%-30% of baseline values within two weeks, which remained stable while on therapy. Following Fingolimod discontinuation, average counts exceeded the lower limit of normal range within six to eight weeks, and were 80% of baseline values by three months. In Group A, infection rates per patient-year were 1.4 with placebo and 1.0 in Fingolimod-treated patients who had the lowest lymphocyte counts ( Conclusions Fingolimod induces a rapid and reversible reduction in lymphocyte counts without an increase in infections relative to placebo. Because Fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient.

Hanspeter Hartung - One of the best experts on this subject based on the ideXlab platform.

  • long term up to 4 5 years treatment with Fingolimod in multiple sclerosis results from the extension of the randomised transforms study
    Journal of Neurology Neurosurgery and Psychiatry, 2016
    Co-Authors: Jeffrey A. Cohen, Giancarlo Comi, Frederik Barkhof, Hanspeter Hartung, Xavier Montalban, Jean Pelletier, Tracy Stites, Bhupendra O Khatri, Shannon Ritter, Philipp Von Rosenstiel
    Abstract:

    OBJECTIVE: The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of Fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. METHODS: Patients randomised to Fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-Fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to Fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-Fingolimod 0.5 mg and pooled IFN-switch groups. RESULTS: Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-Fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to Fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to Fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. CONCLUSIONS: These results support a continued effect of long-term Fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to Fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834.

  • oral Fingolimod in primary progressive multiple sclerosis informs a phase 3 randomised double blind placebo controlled trial
    The Lancet, 2016
    Co-Authors: Fred D Lublin, Hanspeter Hartung, Xavier Montalban, Jerry S Wolinsky, David H Miller, Mark S Freedman, Bruce A C Cree, Howard L Weiner, Catherine Lubetzki, Bernard M J Uitdehaag
    Abstract:

    Summary Background No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of Fingolimod in patients with primary progressive multiple sclerosis. Methods In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral Fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to Fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to Fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive Fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25–65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2–10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. Findings 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to Fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to Fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to Fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the Fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87–82·51) of patients in the Fingolimod group versus 80·3% (73·31–87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80–1·12; p=0·544). Safety results were generally consistent with those of studies of Fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the Fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one ( Interpretation The anti-inflammatory effects of Fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. Funding Novartis Pharma AG.

  • Fingolimod in multiple sclerosis mechanisms of action and clinical efficacy
    Clinical Immunology, 2012
    Co-Authors: Jens Ingwersen, Orhan Aktas, Patrick Kuery, Bernd C Kieseier, Alexey Boyko, Hanspeter Hartung
    Abstract:

    Abstract Fingolimod, also known as FTY720, has recently been approved by the regulatory authorities in the US, EU, Australia, Russia, among others, for the treatment of relapsing–remitting multiple sclerosis. Fingolimod therefore represents the first oral drug for the treatment of this autoimmune disease of the central nervous system. Fingolimod modulates sphingosine-1 phosphate receptors and has unique immunoregulatory properties. Mechanistic studies from animal models have shown that Fingolimod prevents immune cells from exiting from the lymphoid tissue and reaching the inflammatory tissue. Indeed, two phase III studies that laid the basis for Fingolimod's approval demonstrated that Fingolimod efficiently improves the relapse rate compared to both placebo and one of the standard MS medications. In this review, we will summarize the immunological profile of Fingolimod, discuss the possible direct neurobiological effects that have been suggested recently and present the clinical data regarding the efficacy and safety profiles of this promising new drug.

  • comparison of Fingolimod with interferon beta 1a in relapsing remitting multiple sclerosis a randomised extension of the transforms study
    Lancet Neurology, 2011
    Co-Authors: Bhupendra Khatri, Giancarlo Comi, Ludwig Kappos, Frederik Barkhof, Hanspeter Hartung, Xavier Montalban, Jean Pelletier, Tracy Stites, Stacy Wu, Fred Holdbrook
    Abstract:

    Summary Background In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, Fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to Fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with Fingolimod. Methods Patients randomly assigned to receive 0·5 mg or 1·25 mg daily oral Fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0·5 mg or 1·25 mg Fingolimod. The initial randomisation and dose of Fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834. Findings 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous Fingolimod showed persistent benefits in ARR (0·5 mg Fingolimod [n=356], 0·12 [95% CI 0·08–0·17] in months 0–12 vs 0·11 [0·08–0·16] in months 13–24; 1·25 mg Fingolimod [n=330], 0·15 [0·10–0·21] vs 0·11 [0·08–0·16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to Fingolimod compared with the previous 12 months (interferon beta-1a to 0·5 mg Fingolimod [n=167], 0·31 [95% CI 0·22–0·43] in months 0–12 vs 0·22 [0·15–0·31], in months 13–24 p=0·049; interferon beta-1a to 1·25 mg Fingolimod [n=174], 0·29 [0·20–0·40] vs 0·18 [0·12–0·27], p=0·024). After switching to Fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p vs switch group; p=0·002 for 1·25 mg Fingolimod vs switch group). There was no benefit on disability progression. Interpretation Switching from interferon beta-1a to Fingolimod led to enhanced efficacy with no unexpected safety concerns. Compared with patients switched from interferon beta-1a to Fingolimod, continuous treatment with Fingolimod for 2 years provides a sustained treatment effect with improved clinical and MRI outcomes. Funding Novartis Pharma AG.

  • mechanism of action of oral Fingolimod fty720 in multiple sclerosis
    Clinical Neuropharmacology, 2010
    Co-Authors: Jerold Chun, Hanspeter Hartung
    Abstract:

    Fingolimod (FTY720) is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (MS). In vivo, Fingolimod is phosphorylated to form Fingolimod-phosphate, which resembles naturally occurring sphingosine 1-phosphate (S1P), an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors. There are at least 5 S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), 4 of which bind Fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS. S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system (CNS). S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology, and migration. Fingolimod crosses the blood-brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies. Prophylactic administration of Fingolimod to animals with experimental autoimmune encephalitis (EAE), a model of MS, completely prevents development of EAE features, whereas therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and 3 trials involving patients with relapsing or relapsing-remitting MS.

Giancarlo Comi - One of the best experts on this subject based on the ideXlab platform.

  • Effectiveness of Fingolimod in real-world relapsing-remitting multiple sclerosis Italian patients: the GENIUS study
    Neurological Sciences, 2020
    Co-Authors: Giancarlo Comi, Francesca Sangalli, Vincenzo Brescia Morra, Carlo Pozzilli, Antonio Bertolotto, Luca Prosperini, Antonio Carotenuto, Pietro Iaffaldano, Marco Capobianco, Delia Colombo
    Abstract:

    Background Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate Fingolimod effectiveness in a real-world sample of RRMS patients. Methods A retrospective, multicentre study in patients treated with Fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of Fingolimod. Results Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before Fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%). Conclusions Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up.

  • long term up to 4 5 years treatment with Fingolimod in multiple sclerosis results from the extension of the randomised transforms study
    Journal of Neurology Neurosurgery and Psychiatry, 2016
    Co-Authors: Jeffrey A. Cohen, Giancarlo Comi, Frederik Barkhof, Hanspeter Hartung, Xavier Montalban, Jean Pelletier, Tracy Stites, Bhupendra O Khatri, Shannon Ritter, Philipp Von Rosenstiel
    Abstract:

    OBJECTIVE: The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of Fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. METHODS: Patients randomised to Fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-Fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to Fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-Fingolimod 0.5 mg and pooled IFN-switch groups. RESULTS: Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-Fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to Fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to Fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. CONCLUSIONS: These results support a continued effect of long-term Fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to Fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834.

  • A real world experience with Fingolimod in active RRMS patients naïve to second-line agents: a 2 years, intention-to-treat, observational, single center study
    Multiple Sclerosis and Demyelinating Disorders, 2016
    Co-Authors: D. Baroncini, P. O. Annovazzi, Marco Zaffaroni, Giorgio Minonzio, Sanzio Baldini, A Bianchi, Giancarlo Comi, Antonio Ghezzi
    Abstract:

    BackgroundFingolimod is approved by EMA as a second-line treatment for relapsing-remitting multiple sclerosis (RRMS). Experience with Fingolimod in real life is still limited. Aim of our study was to report data on Fingolimod effectiveness in a real life cohort of Italian active RRMS patients, naïve to second-line agents, followed for 2 years. Fingolimod was a part of the patients’ regular treatment and is produced by Novartis.MethodsWe included all consecutive RRMS patients starting Fingolimod at our center according to EMA criteria before January 1st 2013. Exclusion criteria were a previous treatment with natalizumab or an immunosuppressant therapy in the previous 12 months. All patients were clinically evaluated quarterly, and performed brain MRI yearly. Definition of “no evidence of disease activity” (NEDA-3): no relapses, no brain MRI activity and no 6-months confirmed worsening in EDSS score.ResultsWe included 38 RRMS patients, 35 switched from first-line injectable therapies. Six patients were also previously treated with immunosuppressants (5 mitoxantrone, 1 cyclophosphamide). At 24th month 34 patients continued Fingolimod treatment. Main adverse events were infections (18 %), liver-enzymes elevation (8 %), and leukopenia (8 %). After 12 and 24 months 79 and 63 % of patients were relapses-free. Fingolimod significantly reduced ARR compared to the previous year (0.3 ± 0.6 vs 1.2 ± 0.5; p 

  • safety of the first dose of Fingolimod for multiple sclerosis results of an open label clinical trial
    BMC Neurology, 2014
    Co-Authors: Alice Laroni, Alessandra Lugaresi, Giancarlo Comi, Davide Brogi, Vincenzo Brescia Morra, Leonello Guidi, Carlo Pozzilli, Renato Turrini, Debora Raimondi, Antonio Uccelli
    Abstract:

    Background In patients with relapsing-remitting MS (RRMS) Fingolimod prevents disease relapses and delays disability progression. First dose administration of Fingolimod is associated with a transient, dose-dependent decrease in heart rate (HR) in the 6 hours after drug intake. The aim of the study is to to assess safety and tolerability of the first dose of Fingolimod in a cohort of Italian patients with RRMS without alternative therapeutic options.

  • Fingolimod versus intramuscular interferon in patient subgroups from transforms
    Journal of Neurology, 2013
    Co-Authors: Jeffrey A. Cohen, Guillermo Izquierdo, Giancarlo Comi, Bhupendra Khatri, Frederik Barkhof, Xavier Montalban, Jean Pelletier, B Eckert, Dieter A Haring, Gordon Francis
    Abstract:

    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.

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  • randomized trial of vaccination in Fingolimod treated patients with multiple sclerosis
    Neurology, 2015
    Co-Authors: Ludwig Kappos, Guillermo Izquierdo, Matthias Mehling, Krzysztof Selmaj, Rafael Arroyo, Valentina Curovicperisic, Astrid Keil, M Bijarnia, Arun Singh, Philipp Von Rosenstiel
    Abstract:

    Objective: To evaluate immune responses in Fingolimod-treated patients with multiple sclerosis (MS) against influenza vaccine (to test for responses against anticipated novel antigens in seronegative patients) and recall (tetanus toxoid [TT] booster dose) antigens. Methods: This was a blinded, randomized, multicenter, placebo-controlled study. Patients aged 18 to 55 years with relapsing MS were randomized (2:1) to Fingolimod 0.5 mg or placebo for 12 weeks. At week 6, patients received seasonal influenza vaccine (containing antigens of California, Perth, and Brisbane virus strains) and TT booster dose. Antibody titers against influenza and TT were estimated at baseline (prevaccination) and 3 and 6 weeks postvaccination. The primary efficacy variable was responder rate (proportion of patients showing seroconversion or significant increase [≥4-fold] in antibody titers against at least one influenza virus strain) at 3 weeks postvaccination and vs placebo. Results: Of 138 randomized patients (Fingolimod 95, placebo 43), 136 completed the study (2 discontinued in Fingolimod group). The responder rates (odds ratio; 95% confidence interval) for influenza vaccine (Fingolimod vs placebo) were 54% vs 85% (0.21; 0.08–0.54) at 3 weeks and 43% vs 75% (0.25; 0.11–0.57) at 6 weeks postvaccination. For TT, responder rates were 40% vs 61% (0.43; 0.20–0.92) at 3 weeks and 38% vs 49% (0.62; 0.29–1.33) at 6 weeks postvaccination. Adverse events were reported in 86.3% and 79.1% of patients receiving Fingolimod and placebo, respectively. Conclusion: Most Fingolimod-treated patients with MS were able to mount immune responses against novel and recall antigens and the majority met regulatory criteria indicating seroprotection. However, response rates were reduced compared with placebo-treated patients. This should be kept in mind when vaccinating patients on Fingolimod. Classification of evidence: This study provides Class I evidence that in some patients with MS receiving immunizations, concurrent Fingolimod treatment in comparison to placebo decreases vaccination-induced immune responses.

  • Fingolimod for multiple sclerosis mechanism of action clinical outcomes and future directions
    Current Neurology and Neuroscience Reports, 2011
    Co-Authors: Matthias Mehling, Ludwig Kappos, Tobias Derfuss
    Abstract:

    The oral sphingosine 1-phosphate receptor (S1PR) modulator Fingolimod functionally antagonizes S1PR hereby blocking lymphocyte egress from secondary lymphoid organs to the peripheral blood circulation. This results in a reduction in peripheral lymphocyte counts, including potentially encephalitogenic T cells. In patients with relapsing multiple sclerosis Fingolimod has been shown to be an effective treatment. In phase 2 and phase 3 studies Fingolimod-treated patients had reduced disease activity clinically and in MRI. Although severe infectious complications occurred in single cases treated with Fingolimod, the frequency of overall infections was comparable in Fingolimod-treated patients and controls. Overall, in clinical studies Fingolimod was well tolerated and had a favorable safety profile. In follow-up studies with continuous Fingolimod, treatment showed sustained efficacy while being well tolerated.

  • clinical immunology of the sphingosine 1 phosphate receptor modulator Fingolimod fty720 in multiple sclerosis
    Neurology, 2011
    Co-Authors: Matthias Mehling, Ludwig Kappos, Trina A Johnson, J Antel, Amit Baror
    Abstract:

    The oral sphingosine 1-phosphate (S1P) receptor (S1PR) modulator Fingolimod has been shown to be effective in the treatment of patients with relapsing multiple sclerosis (MS). The drug binds with high affinity to 4 of the 5 G-protein-coupled S1P receptors (S1P(1-5)). After binding, the receptors are internalized, degraded, and thus functionally antagonized by Fingolimod. Under physiologic conditions, S1P(1) mediates the egress of lymphocytes from secondary lymphoid organs to the peripheral circulation. Functional antagonism of S1P(1) by Fingolimod results in a reduction in peripheral lymphocyte counts by inhibiting egress of lymphocytes, including potentially encephalitogenic T cells and their naive progenitors that would otherwise be present within the circulation. Despite the Fingolimod-mediated reduction of lymphocyte counts, Fingolimod-treated patients with MS have been shown to have few infections and related complications and were able to mount antigen-specific immune responses in vaccination studies.

  • antigen specific adaptive immune responses in Fingolimod treated multiple sclerosis patients
    Annals of Neurology, 2011
    Co-Authors: Matthias Mehling, Jens Kuhle, Raija L P Lindberg, Patricia Hilbert, Stefanie Fritz, Bojana Durovic, Dominik Eichin, Olivier Gasser, Thomas Klimkait, Ludwig Kappos
    Abstract:

    T cells exit secondary lymphoid organs along a sphingosine1-phosphate (S1P) gradient and, accordingly, are reduced in blood upon Fingolimod-mediated S1P-receptor (S1PR)-blockade. Serving as a model of adaptive immunity, we characterized cellular and humoral immune responses to influenza vaccine in Fingolimod-treated patients with multiple sclerosis (MS) and in untreated healthy controls. Although the mode of action of Fingolimod might predict reduced immunity, vaccine-triggered T cells accumulated normally in blood despite efficient S1PR-blockade. Concentrations of anti-influenza A/B immunoglobulin (Ig)M and IgG also increased similarly in both groups. These results indicate that Fingolimod-treated individuals can mount vaccine-specific adaptive immune responses comparable to healthy controls.