Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated. METHODS: This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14-69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose. The primary efficacy analysis was a logistic regression evaluating the contribution of artefenomel exposure to Day 28 PCR-adjusted adequate clinical and parasitological response (ACPR). Safety was also evaluated. RESULTS: The randomized population included 140 patients. For the primary analysis in the pharmacokinetic/pharmacodynamic efficacy population (N = 121), the contribution of artefenomel AUC0-∞ to Day 28 PCR-adjusted ACPR was not demonstrated when accounting for ferroquine AUC0-d28, baseline parasitaemia, and other model covariates: odds ratio 1.1 (95% CI 0.98, 1.2; P = 0.245). In the per-protocol population, Day 28 PCR-adjusted ACPR was 80.8% (21/26; 95% CI 60.6, 93.4) with ferroquine alone and 90.3% (28/31; 95% CI 74.2, 98.0), 90.9% (30/33; 95% CI 75.7, 98.1) and 87.1% (27/31; 95% CI 70.2, 96.4) with 300, 600, and 1000 mg artefenomel, respectively. Median time to parasite clearance (Kaplan-Meier) was 56.1 h with ferroquine, more rapid with artefenomel, but similar for all doses (30.0 h). There were no deaths. Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively. All AEs were of mild-to-moderate severity, and consistent with the known profiles of the compounds. Vomiting was the most reported AE. There were no cases of QTcF prolongation ≥ 500 ms or > 60 ms from baseline. CONCLUSION: The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03660839 (7 September, 2018).

Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma.

BACKGROUND: Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear. METHODS: In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety. RESULTS: A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups. CONCLUSIONS: Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.).

A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. RESULTS: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.

Prognostic significance of elevated creatine kinase MB after coronary bypass surgery and after an acute coronary syndrome: results from the GUARDIAN trial.

OBJECTIVE: To determine if the correlation between magnitude of creatine kinase-myocardial band release after coronary artery bypass surgery and 6-month mortality is comparable to that of patients admitted with an acute coronary syndrome. METHODS: The GUARDIAN trial tested the efficacy of cariporide, an Na+/H+ exchange inhibitor, on reduction of myocardial ischemia or death in high-risk patients. We compared 6-month survival in a cohort of 2332 GUARDIAN patients scheduled for coronary artery bypass surgery at entry with 4233 acute coronary syndrome patients stratified by level of creatine kinase-myocardial band release. Cumulative 6-month survival by creatine kinase-myocardial band categories was performed using life table analysis, adjusting for variables known to impact prognosis using Cox regression. RESULTS: The 6-month mortality rates for coronary artery bypass surgery patients with peak creatine kinase-myocardial band ratios of <1, > or =1 and <5, > or =5 and <10, and > or =10 upper limits of normal (ULN) were 5.8, 2.8, 5.9, and 12.0%, respectively (P <.0001). The 6-month mortality rates for acute coronary syndrome patients with peak creatine kinase-myocardial band ratios of <1, > or =1 and <5, > or =5 and <10, and > or =10 ULN were 6.3, 9.8, 10.0, and 12.3%, respectively (P <.0001). Patients with coronary artery bypass surgery or acute coronary syndrome had similar adjusted 6-month survival estimates at normal creatine kinase-myocardial band levels and when the creatine kinase-myocardial band level was > or =10 ULN. Patients with coronary artery bypass surgery had significantly better survival at intermediate enzyme levels (> or =1 and <10 ULN; P <.001). CONCLUSIONS: Modest elevations of creatine kinase-myocardial band release (> or =1 and <10 ULN) after coronary artery bypass surgery are not associated with adverse 6-month survival, in contrast to that seen in acute coronary syndrome patients. Routine creatine kinase-myocardial band sampling should be considered in all higher-risk patients undergoing coronary artery bypass surgery procedures to identify the sizable cohort of patients with creatine kinase-myocardial band release > or =10 ULN; these patients may benefit from postoperative angiotensin-converting enzyme inhibitor and beta-blocker therapy. Newer cardioprotective agents that reduce the number of patients with marked creatine kinase-myocardial band release are currently being tested in large randomized controlled clinical trials.

Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: results of the CABG surgery cohort of the GUARDIAN study.

OBJECTIVES: To evaluate the effects of cariporide on all-cause mortality or myocardial infarction at 36 days in patients at risk of myocardial necrosis after coronary artery bypass graft surgery. METHODS: In the coronary artery bypass graft cohort of the GUARD During Ischemia Against Necrosis trial, patients > or =18 years who required urgent coronary artery bypass graft, repeat coronary artery bypass graft, or had a history of unstable angina and > or =2 risk factors (age >65 years, female gender, diabetes mellitus, ejection fraction <35%, or left main or 3-vessel disease) were randomized to placebo (n = 743) or cariporide 20 mg (n = 736), 80 mg (n = 705), or 120 mg (n = 734). A 1-hour intravenous infusion was initiated shortly before surgery and administered every 8 hours for 2 to 7 days. Patients were followed up for 6 months. A nonparametric covariance analysis was used to calculate the primary efficacy endpoint. RESULTS: Baseline characteristics were similar between treatment groups. The cariporide 20- and 80-mg groups had event rates similar to placebo. The endpoint of all-cause mortality or myocardial infarction at day 36 was significant with cariporide 120 mg versus placebo (event rate 12.2% vs 16.2%; P =.027). The risk reduction was evident on postoperative day 1 (3.3% vs 6.5%; P =.005) and was maintained at 6 months (event rate 15.0% vs 18.6%; P =.033). Cariporide was well tolerated, and most adverse events were mild and transient in this high-risk population. CONCLUSIONS: Clinical benefit with cariporide 120 mg was observed early after treatment initiation and continued for 6 months postsurgery, suggesting that sodium-hydrogen exchange inhibition with cariporide is cardioprotective in patients undergoing high-risk coronary artery bypass graft surgery.

Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection.

Although the mechanisms underlying ischemia/reperfusion injury remain elusive, evidence supports the etiologic role of intracellular calcium overload and oxidative stress induced by reactive oxygen species. Activation of the sodium hydrogen exchanger (NHE) is associated with intracellular calcium accumulation. Inhibition of the NHE-1 isoform may attenuate the consequences of this injury. Although there is strong preclinical and early clinical evidence that NHE inhibitors may be cardioprotective, definitive proof of this concept in humans awaits the results of ongoing clinical trials.

Lessons learned from a phase III population pharmacokinetic study of cariporide in coronary artery bypass graft surgery.

BACKGROUND: Cariporide (HOE642) is a recently developed inhibitor of the myocardial sodium-hydrogen exchange system. The clinical effects of sodium-hydrogen exchange inhibition in patients at high risk for myocardial cell necrosis were investigated in the GUARDIAN trial (n = 11,590 patients). Although the trial did not show a significant benefit of cariporide over placebo in the overall population, a 25% relative risk reduction in the primary end point of death or myocardial infarction (12.1% for the highest tested cariporide dose of 120 mg 3 times a day versus 16.2% for placebo; P =.03) was observed in the subpopulation of patients who underwent bypass surgery. OBJECTIVE: Our objective was to identify an optimal dosing regimen that might offer increased protection during the period of highest risk. METHODS: A population pharmacokinetic model of cariporide was developed with use of data from phase I studies. After adequate predictability was shown for the patients in the pharmacokinetic substudy of the GUARDIAN trial (n = 269 patients), the model was used to predict the individual pharmacokinetic profile in the remaining patients. These predicted concentrations were used to calculate the mean concentration during the period of coronary artery bypass graft surgery (the acute risk period in patients who receive coronary artery bypass grafts), and this mean concentration was used as predictor variable in a time-to-event analysis. RESULTS: A mixture of two Weibull functions adequately described the time course of the observed sum of the acute and chronic hazard rate. The calculated mean concentration during the period of surgery was an adequate predictor for the probability of an event in the acute risk period. The estimated minimal effective mean concentration was 0.5 mg/L. CONCLUSIONS: A dosing regimen with a loading dose of an infusion of 120 mg/h for 1 hour followed by an infusion of 20 mg/h for 47 hours should achieve stable exposure above the estimated minimal effective concentration in more than 95% of patients during and after coronary artery bypass graft surgery.

Design of a trial evaluating myocardial cell protection with cariporide, an inhibitor of the transmembrane sodium-hydrogen exchanger: the Guard During Ischemia Against Necrosis (GUARDIAN) trial.

Inhibition of the sodium-hydrogen exchanger (NHE) is a powerful experimental tool to inhibit sodium and calcium accumulation within the ischemic myocyte and halt progression of cell ischemia to cell necrosis. This paper describes the protocol and rationale of a first large-scale clinical trial designed to evaluate the safety and efficacy of cariporide, a novel specific and potent inhibitor of the exchanger.