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Background and PurposeWe conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT‐1303), a second‐generation sphingosine 1‐phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators.Experimental ApproachThe selectivity of the active metabolite amiselimod phosphate (amiselimod‐P) for human S1P receptors and activation of G‐protein‐coupled inwardly rectifying K+ (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans.Key ResultsAmiselimod‐P showed potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five‐fold weaker GIRK activation than fingolimod‐P. After oral administration of amiselimod or fingolimod at 1 mg·kg−1, the concentration of amiselimod‐P in rat heart tissue was lower than that of fingolimod‐P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study.Conclusions and ImplicationsAmiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

AimAmiselimod (MT‐1303) is a selective sphingosine 1‐phosphate 1 (S1P1) receptor modulator which is currently being developed for the treatment of various autoimmune diseases. Unlike some other S1P receptor modulators, amiselimod seemed to show a favourable cardiac safety profile in preclinical, phase I and II studies. The aim of the current study was to characterize the cardiac effects of amiselimod by directly comparing it with fingolimod and placebo.MethodsA total of 81 healthy subjects aged 18–55 years were equally randomized to receive amiselimod 0.4 mg, amiselimod 0.8 mg, placebo or fingolimod 0.5 mg once daily for 28 days. The chronotropic/dromotropic and inotropic effects were evaluated using intensive Holter electrocardiogram and echocardiography.ResultsUnlike fingolimod, neither amiselimod dose exerted acute (1–6 h) negative chronotropic effects on Days 1 and 2. The lowest nadir mean hourly heart rate was observed on Day 14 in the amiselimod 0.4 mg group (least squares mean difference: −4.40 bpm, 95% confidence interval −7.15, −1.66) and Day 7 in the 0.8 mg group [−3.85 bpm (−6.58, −1.11)] compared with placebo, but these changes were smaller than those with fingolimod on Day 1 [−6.49 bpm (−8.95, −4.02)]. No clinically significant bradyarrhythmia or cardiac functional abnormalities were observed in either amiselimod group. Both amiselimod doses were well tolerated and no serious adverse events were reported. Fingolimod was also generally well tolerated, although one subject was withdrawn owing to highly frequent 2:1 atrioventricular blocks on Day 1.ConclusionThe study demonstrated a more favourable cardiac safety profile for amiselimod than fingolimod when administered over 28 days in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• New drugs are expected to undergo rigorous clinical electrocardiographic evaluation ('thorough QT/QTc study') during their early clinical development in order to determine any affect on cardiac repolarization. • The fluoroquinolone antibiotic moxifloxacin (400 mg) has been used as a positive comparator for thorough QT/QTc studies due to its QT prolongation (QTcF) of between 6 and 10 ms. • Positive comparators that are able to produce mean changes close to the regulatory guidelines of 5 ms, and which can be detected by the assay in use, would enable a more rigorous evaluation of the assay conditions used in evaluating new chemical entities. WHAT THIS STUDY ADDS• This thorough QT/QTc study directly compares the effects of two doses of levofloxacin and moxifloxacin on QTc in the same healthy subjects.• Mean QTc was prolonged in subjects receiving levofloxacin compared with placebo as determined by both individual and Fridericia's heart rate correction methods.• The largest time-matched differences in QTc for two doses of levofloxacin compared with placebo suggest the potential for using levofloxacin in more rigorous QT/QTc studies, providing a robust evaluation of the assay conditions used in determining potential effects on cardiac repolarization.• There is evidence to suggest that levofloxacin moderately increases heart rate in a dose-dependent fashion. AIMSTo characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. METHODSHealthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. RESULTSMean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. CONCLUSIONSBoth levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a thres...

Background:Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis.Objective:To assess safety and efficacy of amiselimod over 96 weeks.Methods:After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results.Results:Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: ‘headache’, ‘lymphocyte count decreased’, ‘nasopharyngitis’ and ‘MS relapse’ were most common (14.7%–16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12-lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug.Conclusion:For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity.

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Background Of patients receiving moderate emetic risk chemotherapy (MEC), 30–90% experience chemotherapy-induced nausea and vomiting (CINV); however, the optimal antiemetic treatment remains controversial. Methods In this multicenter, prospective, observational study of adults treated with MEC while receiving chemotherapy for various cancer types in Japan, the enrolled patients kept diaries documenting CINV. All participants received a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. Results Of the 400 patients enrolled from May 2013 to January 2015, 386 were eligible for evaluation. The median age was 64 (range, 26–84). The overall complete response (CR; no emetic events and no antiemetic measures) rate was 64%. The proportion of patients showing CR was low in the carboplatin (CBDCA)- and oxaliplatin-based chemotherapy groups, especially among women. We showed that the CR rates in men were high in the CBDCA (AUC5) + etoposide (ETP) (80%), capecitabine plus oxaliplatin (CAPOX) (78%), and CBDCA+ paclitaxel (PTX) groups for lung cancer (73%). Total control (TC; no emetic events, no antiemetic measures, and no nausea) and complete control (CC; no emetic events, no antiemetic measures, and less than mild nausea) were achieved in 51 and 61% of patients, respectively. Logistic regression analysis revealed history of motion sickness, history of pregnancy-associated vomiting and CBDCA-based chemotherapy as risk factors for CR and history of motion sickness and history of pregnancy-associated vomiting as risk factors for TC. Additional, Ages ≥65 years is an independent predictive factor for achieving TC. Conclusions Our data showed that two antiemetics were insufficient to control CINV in patients receiving CBDCA- or oxaliplatin-based chemotherapy. However, two antiemetics may be sufficiently effective for elderly male patients receiving CBDCA (AUC5) + ETP, CBDCA+PTX for lung cancer, or CAPOX. Additionally, we consider that three antiemetics are necessary for women with colorectal cancer receiving CAPOX. Risk factor analysis related to CR showed that CINV prophylaxis in patients treated with CBDCA-based chemotherapy was generally supportive of the guideline-recommended three antiemetics. However, the control of nausea in patients receiving non-CBDCA-based chemotherapy is a key point to note. The further individualization of antiemetic regimens for patients receiving MEC based on both types of chemotherapy regimens and sex is needed.

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