First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G-protein-biased sphingosine-1 phosphate receptor-1 agonist for endothelial protection.

AIMS: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P1 -desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization). METHODS: SAR247799 was administered orally to healthy subjects in a double-blind, randomized, placebo-controlled study with single (2.5-37.5 mg) or 2-week once-daily (0.5-15 mg) doses. An open-label single dose pilot food-interaction arm with 10 mg SAR247799 in cross-over design was also performed. RESULTS: SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose-dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose-proportional increases in exposure and was eliminated with an apparent terminal half-life of 31.2-33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7-23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub-lymphocyte-reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial-protective properties, had minimal-to-no heart rate reduction and displayed no marked safety findings. CONCLUSION: SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.

Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

AIMS: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODS: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. RESULTS: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. CONCLUSION: These data provide the first human evidence suggesting endothelial-protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.

An individual patient-based meta-analysis of the effects of dronedarone in patients with atrial fibrillation.

AIMS: Dronedarone is a non-iodinated benzofuran derivative with antiarrhythmic properties. In placebo-controlled atrial fibrillation (AF) trials, the drug was found to have divergent effects on endpoints such as cardiovascular death or hospitalization. The objective of this meta-analysis of all placebo-controlled studies was to provide insights on possible reasons for these divergent effects. METHODS AND RESULTS: Individual data on 9664 patients were used from all AF placebo-controlled studies. The primary outcome measure was cardiovascular death. Cardiovascular hospitalization and hospitalization for heart failure were secondary endpoints. Predefined procedures were used to reduce inter-study heterogeneity adjusting for important baseline variables using a Cox model. Despite adjustments, a significant inter-trial heterogeneity of the outcome of cardiovascular mortality persisted (P-value of 0.005 for the treatment effect × study interaction). Further analyses were conducted in subgroups based on baseline clinical criteria: digoxin co-prescription, advanced heart failure, coronary artery disease, or the presence of permanent AF. These analyses allowed the calculation of a global treatment effect in two important patient subgroups, those with permanent AF in whom there was harm with respect to cardiovascular mortality [hazard ratio (HR) = 2.32; 95% confidence interval (CI) 1.13-4.75] and hospitalization for heart failure (HR = 1.674; 95% CI 1.05-2.67); and those with non-permanent AF in whom there was benefit in terms of cardiovascular hospitalization [HR = 0.751 95% CI (0.68-0.83)]. CONCLUSION: This meta-analysis demonstrates significant heterogeneity of dronedarone treatment effects across the placebo-controlled randomized trials. The most important predictor of a harmful effect of dronedarone on cardiovascular death and heart failure hospitalization was the presence of permanent AF.

Efficacy and safety of celivarone, with amiodarone as calibrator, in patients with an implantable cardioverter-defibrillator for prevention of implantable cardioverter-defibrillator interventions or death: the ALPHEE study.

BACKGROUND: Celivarone is a new antiarrhythmic agent developed for the treatment of ventricular arrhythmias. This study investigated the efficacy and safety of celivarone in preventing implantable cardioverter-defibrillator (ICD) interventions or death. METHODS AND RESULTS: Celivarone (50, 100, or 300 mg/d) was assessed compared with placebo in this randomized, double-blind, placebo-controlled, parallel-group study. Amiodarone (200 mg/d after loading dose of 600 mg/d for 10 days) was used as a calibrator. A total of 486 patients with a left ventricular ejection fraction ≤40% and at least 1 ICD intervention for ventricular tachycardia or ventricular fibrillation in the previous month or ICD implantation in the previous month for documented ventricular tachycardia/ventricular fibrillation were randomized. Median treatment duration was 9 months. The primary efficacy end point was occurrence of ventricular tachycardia/ventricular fibrillation-triggered ICD interventions (shocks or antitachycardia pacing) or sudden death. The proportion of patients experiencing an appropriate ICD intervention or sudden death was 61.5% in the placebo group; 67.0%, 58.8%, and 54.9% in the celivarone 50-, 100-, and 300-mg groups, respectively; and 45.3% in the amiodarone group. Hazard ratios versus placebo for the primary end point ranged from 0.860 for celivarone 300 mg to 1.199 for celivarone 50 mg. None of the comparisons versus placebo were statistically significant. Celivarone had an acceptable safety profile. CONCLUSIONS: Celivarone was not effective for the prevention of ICD interventions or sudden death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00993382.

Celivarone for maintenance of sinus rhythm and conversion of atrial fibrillation/flutter.

INTRODUCTION: Celivarone, a new noniodinated benzofuran derivative pharmacologically related to dronedarone and amiodarone, has been shown to have antiarrhythmic properties at a molecular level. The purpose of the 2 trials presented here (MAIA and CORYFEE) was to assess celivarone efficacy in the maintenance of sinus rhythm postcardioversion and for the conversion of atrial fibrillation (AF)/atrial flutter (AFL). METHODS AND RESULTS: In the MAIA trial, 673 patients with AF/AFL recently converted to sinus rhythm were randomly assigned to receive 50, 100, 200, or 300 mg once-daily dosing of celivarone; 200 mg daily of amiodarone preceded by a loading dose of 600 mg for 10 days; or placebo. At 3 months' follow up, no significant difference was observed in time to AF/AFL relapse among the various celivarone groups and placebo. However, fewer symptomatic AF/AFL recurrences were observed in the lower-dose celivarone groups (26.6% for celivarone 50 mg [P = 0.022] and 25.2% for celivarone 100 mg [P = 0.018] vs 40.5% for placebo at 90 days). Fewer adverse events were observed with the use of celivarone and placebo than amiodarone. In the CORYFEE study, 150 patients with AF/AFL were randomly assigned to once-daily celivarone dosing of 300 or 600 mg, or placebo, for a 2-day treatment period. There was no significant difference in the rate of spontaneous conversion to sinus rhythm between the treatment and control groups. CONCLUSIONS: In these studies, celivarone does not appear to be efficacious in the maintenance of sinus rhythm in AF/AFL patients or for the conversion of AF/AFL patients.

Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter.

BACKGROUND: Amiodarone is effective in maintaining sinus rhythm in atrial fibrillation but is associated with potentially serious toxic effects. Dronedarone is a new antiarrhythmic agent pharmacologically related to amiodarone but developed to reduce the risk of side effects. METHODS: In two identical multicenter, double-blind, randomized trials, one conducted in Europe (ClinicalTrials.gov number, NCT00259428 [ClinicalTrials.gov] ) and one conducted in the United States, Canada, Australia, South Africa, and Argentina (termed the non-European trial, NCT00259376 [ClinicalTrials.gov] ), we evaluated the efficacy of dronedarone, with 828 patients receiving 400 mg of the drug twice daily and 409 patients receiving placebo. Rhythm was monitored transtelephonically on days 2, 3, and 5; at 3, 5, 7, and 10 months; during recurrence of arrhythmia; and at nine scheduled visits during a 12-month period. The primary end point was the time to the first recurrence of atrial fibrillation or flutter. RESULTS: In the European trial, the median times to the recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01). The corresponding durations in the non-European trial were 59 and 158 days (P=0.002). At the recurrence of arrhythmia in the European trial, the mean (+/-SD) ventricular rate was 117.5+/-29.1 beats per minute in the placebo group and 102.3+/-24.7 beats per minute in the dronedarone group (P<0.001); the corresponding rates in the non-European trial were 116.6+/-31.9 and 104.6+/-27.1 beats per minute (P<0.001). Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group. CONCLUSIONS: Dronedarone was significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia.

A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study.

INTRODUCTION: We compared the efficacy and safety of amiodarone and dronedarone in patients with persistent atrial fibrillation (AF). METHODS: Five hundred and four amiodarone-naïve patients were randomized to receive dronedarone 400 mg bid (n = 249) or amiodarone 600 mg qd for 28 days then 200 mg qd (n = 255) for at least 6 months. Primary composite endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion and no electrical cardioversion) or premature study discontinuation. Main safety endpoint (MSE) was occurrence of thyroid-, hepatic-, pulmonary-, neurologic-, skin-, eye-, or gastrointestinal-specific events, or premature study drug discontinuation following an adverse event. RESULTS: Median treatment duration was 7 months. The primary composite endpoint was 75.1 and 58.8% with dronedarone and amiodarone, respectively, at 12 months (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.28-1.98; P < 0.0001), mainly driven by AF recurrence with dronedarone compared with amiodarone (63.5 vs 42.0%). AF recurrence after successful cardioversion was 36.5 and 24.3% with dronedarone and amiodarone, respectively. Premature drug discontinuation tended to be less frequent with dronedarone (10.4 vs 13.3%). MSE was 39.3 and 44.5% with dronedarone and amiodarone, respectively, at 12 months (HR = 0.80; 95% CI 0.60-1.07; P = 0.129), and mainly driven by fewer thyroid, neurologic, skin, and ocular events in the dronedarone group. CONCLUSION: In this short-term study, dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants.

Effect of dronedarone on exercise capacity and cardiac function in patients with severe left ventricular dysfunction and compensated stable heart failure.

PURPOSE: Dronedarone is a novel multichannel blocker with antiadrenergic and vasodilatory properties. The aim of this study was to investigate the effects of dronedarone on functional capacity in patients with severe left ventricular (LV) dysfunction and compensated stable heart failure (HF). METHODS: This was a multicentre, double-blind, randomized, placebo-controlled, dose-escalating study. Patients in sinus rhythm with impaired LV function (LV ejection fraction [LVEF] ≤ 30%) and compensated HF (New York Heart Association [NYHA] class I-II), who would continue to receive cardiovascular treatment (excluding antiarrhythmic agents), were eligible. A total of 124 patients were randomized to receive dronedarone (400 mg or 800 mg once daily or 600 mg twice daily) or placebo for 30 days. The primary objective was assessment of the effects of dronedarone on functional capacity, using the 6 min walk test. Secondary objectives included the effects of dronedarone on LVEF, cardiothoracic ratio, NYHA status, and Holter parameters. RESULTS: A total of 111 patients completed the study. There were no significant differences between dronedarone and placebo with respect to walking distance and LVEF. The cardiothoracic ratio was similar in all treatment groups throughout the study, and the NYHA status did not change in the majority of patients. Dronedarone was well tolerated and, as expected, decreased heart rate. No new arrhythmic events or torsades de pointes were reported. CONCLUSIONS: Short-term treatment with dronedarone did not affect exercise capacity and did not decrease LVEF in patients with severe LV dysfunction and compensated HF.

Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study.

BACKGROUND: Dronedarone is a new multichannel blocker for atrial fibrillation (AF) previously demonstrated to have both rhythm and rate control properties in paroxysmal and persistent AF. The Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) trial assessed the efficacy of dronedarone in the control of ventricular rate in patients with permanent AF, when added to standard therapy. METHODS: In this randomized, double-blind, multinational trial, dronedarone, 400 mg twice a day (n = 85), or matching placebo (n = 89) was administered for 6 months to adult patients with permanent AF, in addition to standard therapy. The primary end point was the change in mean ventricular rate between baseline and day 14, as assessed by 24-hour Holter. Ventricular rate was also assessed during submaximal and maximal exercise. RESULTS: Dronedarone significantly decreased mean 24-hour ventricular rate. Compared with placebo, the mean treatment effect at day 14 was a reduction of 11.7 beats per minute (beat/min; P < .0001). Comparable reductions were sustained throughout the 6-month trial. During maximal exercise and compared to placebo, there was a mean reduction of 24.5 beat/min (P < .0001), without any reduction in exercise tolerance as measured by maximal exercise duration. The effects of dronedarone were additive to those of other rate-control agents, including beta-blockers, calcium antagonists, and digoxin. Dronedarone was well tolerated, with no organ toxicities or proarrhythmia. CONCLUSION: In addition to its reported rhythm-targeting and rate-targeting therapeutic actions in paroxysmal and persistent AF, dronedarone improves ventricular rate control in patients with permanent AF. Dronedarone was well tolerated with no evidence of organ toxicities or proarrhythmias in this short-term study.

Dose-dependent effects of oral dronedarone on the circadian variation of RR and QT intervals in healthy subjects: implications for antiarrhythmic actions.

Dronedarone, a non-iodinated benzofuran derivative, was developed as a potentially less toxic alternative to amiodarone. This study describes Holter data of dronedarone in humans. Five groups of healthy subjects were given 1 of 5 oral doses of dronedarone in a twice-daily regimen or placebo. Holter recordings of circadian rhythmicity of RR and QT intervals were evaluated. Dronedarone prolonged RR and QT intervals as a function of dose, without effect on circadian patterns. The relative prolongation of QT, QTc, and RR by dronedarone was significant. The QTc interval did not exhibit a clearly recognizable circadian pattern, suggesting that the circadian pattern of the QT interval was mostly a reflection of circadian changes in the RR interval in the study population. Dronedarone resembled amiodarone in class III and sympatholytic effects, indicating its potential as a unique antiarrhythmic compound seemingly devoid of the side effects mediated by iodine in amiodarone.

Interaction between digoxin and dronedarone in the PALLAS trial.

BACKGROUND: Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the dronedarone-digoxin interaction might explain these adverse outcomes. METHODS AND RESULTS: Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events. CONCLUSIONS: In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death, but not on occurrence of heart failure. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01151137.

Efficacy and safety of dronedarone in patients previously treated with other antiarrhythmic agents.

BACKGROUND: Currently available antiarrhythmic drugs (AADs) for the prevention of atrial fibrillation (AF)/atrial flutter (AFL) suffer from incomplete efficacy and poor tolerability. HYPOTHESIS: Dronedarone could represent an effective and safe option in patients previously treated with AADs, especially class Ic AADs and sotalol. METHODS: Retrospective analysis of 2 double-blind, parallel-group trials (EURIDIS [European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm] and ADONIS [American-Australian-African Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm]) comparing the efficacy and safety of dronedarone with placebo over 12 months. The primary end point was AF/AFL recurrence in patients previously treated with another AAD that was discontinued for whatever reason prior to randomization. RESULTS: In patients previously treated with any AADs, dronedarone decreased the risk of AF recurrence by 30.4% vs placebo (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.59-0.82; P < 0.001). In patients previously treated with a class Ic agent, dronedarone decreased the risk of recurrence by 31.4% (HR: 0.69; 95% CI: 0.53-0.89; P = 0.004), whereas in patients previously treated with sotalol, dronedarone showed a trend toward a decrease of risk of recurrence (HR: 0.86; 95% CI: 0.67-1.11; P = 0.244). Dronedarone was equally effective irrespective of whether class Ic or sotalol were stopped for lack of efficacy or adverse events (AEs). Discontinuation rates were similar in the 2 groups (55.9% vs 43.1%), as were incidence of AEs and serious AEs. CONCLUSIONS: Dronedarone seems to be effective in preventing AF recurrences in patients without permanent AF previously treated with other AADs, even if those were discontinued for lack of efficacy. Dronedarone appears to be well tolerated even in patients who already had tolerability issues with AADs.

Effects of dronedarone started rapidly after amiodarone discontinuation.

BACKGROUND: Multiple studies have shown that amiodarone is effective in treating atrial fibrillation (AF), but is associated with a relatively high incidence of side effects; however, due to amiodarone's long elimination half-life (20-100 days), physicians may hesitate to start other drugs until it has fully cleared. HYPOTHESIS: A rapid switch from amiodarone to dronedarone is feasible. METHODS: EURIDIS and ADONIS were double-blind, multinational, parallel-group trials comparing the efficacy and safety of dronedarone with placebo over 12 months. This retrospective subanalysis of EURIDIS/ADONIS compared the effects of dronedarone in patients discontinuing amiodarone within 2 days before randomization ("rapid switch") with results in patients who had received no amiodarone during the 2 months preceding randomization. RESULTS: In total, 1237 patients were enrolled ("rapid switch", n = 154; "no amiodarone", n = 1014). In both the "rapid switch" and the "no amiodarone" groups, dronedarone users had significantly lower AF recurrence than patients receiving placebo (HR = 0.64, 95% CI, 0.44-0.95; P = 0.0224 and HR = 0.79, 95% CI, 0.67-0.92; P = 0.0027, respectively). Dronedarone users had a higher incidence of bradyarrhythmic events than placebo-treated patients. A "rapid switch" from amiodarone to dronedarone was associated with a higher incidence of serious heart failure events and heart failure hospitalizations versus all other groups. Overall event rates were low and there was no significant difference in total adverse event rates or deaths between groups. CONCLUSION: In this patient population, a switch from amiodarone to dronedarone within a 2-day time frame might be feasible in certain patient categories, but further investigation is warranted.

Celivarone in patients with an implantable cardioverter-defibrillator: adjunctive therapy for the reduction of ventricular arrhythmia-triggered implantable cardioverter-defibrillator interventions.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) remain the treatment of choice for the prevention of life-threatening arrhythmias. However, many patients with ICDs require additional antiarrhythmic therapy to reduce the morbidity associated with recurrent arrhythmia-triggered ICD interventions. OBJECTIVE: Our study aimed to evaluate the safety and efficacy of celivarone in reducing these interventions. METHODS: A total of 153 eligible ICD recipients were randomized to receive either placebo or celivarone 100 or 300 mg once daily for 6 months. The primary end point was the prevention of arrhythmia-triggered ICD therapies. RESULTS: Fewer ventricular tachycardia and ventricular fibrillation episodes were observed in the 300-mg celivarone group than in the placebo group, with a relative risk reduction of 46%, which was not statistically significant. The analysis of all-cause shocks showed a trend toward a decreased number of events in the celivarone 300-mg group. A post hoc analysis of the primary end point in a subgroup of patients in the celivarone 300-mg group, who had received ICD therapy within 1 month of randomization, showed a significant benefit (P = .032). Celivarone was not associated with an increased risk of torsades de pointes, thyroid dysfunction, or pulmonary events. More heart failure events were reported in the celivarone groups than in the placebo group, but the difference was not statistically significant. CONCLUSION: Celivarone tends to reduce ventricular tachycardia-/ventricular fibrillation-triggered ICD therapies. This effect was not statistically significant. There was a trend toward greater efficacy in the 300-mg group, especially in patients undergoing ICD therapy within 30 days prior to randomization. Overall, celivarone was well tolerated.