A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.

BACKGROUND: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. METHODS: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. RESULTS: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. CONCLUSIONS: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Metabolism and disposition of vilanterol, a long-acting ß(2)-adrenoceptor agonist for inhalation use in humans.

The metabolism and disposition of vilanterol, a novel long-acting ß(2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 µg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 µg of [(14)C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 µg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration.

Effect of once-daily fluticasone furoate/vilanterol on 24-hour pulmonary function in patients with chronic obstructive pulmonary disease: a randomized, three-way, incomplete block, crossover study.

BACKGROUND: Available inhaled corticosteroid/long-acting ß(2)-agonist combinations for chronic obstructive pulmonary disease (COPD) require twice-daily administration. The combination of fluticasone furoate (FF) and vilanterol (VI) FF/VI is being developed in a novel dry powder inhaler for the treatment of COPD and asthma with the potential for once-daily dosing. Results from Phase II studies have shown clinically and statistically significant improvements over placebo in trough (24-hour postdose) forced expiratory volume in 1 second (FEV(1)) after once-daily dosing with FF or VI (VI concurrently with an inhaled corticosteroid) in asthma and VI in COPD. OBJECTIVES: This Phase III, multicenter, randomized, double-blind, placebo-controlled study was designed based on guidance from drug regulators with the goal of evaluating the 24-hour spirometric effect of once-daily FF/VI in patients with COPD. METHODS: Patients (aged ≥40 years) who completed a 2-week placebo run-in period were randomized to 1 of 18 three-course sequences of placebo and 2 of 3 dose combinations of FF/VI (50/25 µg, 100/25 µg, and 200/25 µg), dosed once daily in the morning. Each 28-day treatment period was separated by a 2-week, single-blind, placebo washout period. The primary end point was time-adjusted (weighted mean) 0 to 24-hour FEV(1) (AUC) at the end of each 28-day treatment period (period days 28-29). Safety profile assessments included incidence of adverse events (AEs) (defined according to the Medical Dictionary for Regulatory Activities), 12-lead ECG outputs, vital signs (pulse rate, diastolic and systolic blood pressure) and clinical laboratory assessments (including fasting serum glucose and potassium) and 24-hour serum cortisol. The pharmacokinetics of FF and VI were assessed at the end of each 28-day treatment period with FF/VI. RESULTS: Eighty-seven patients were screened; 54 completed run-in and were randomized to double-blind treatment. The mean patient age was 57.9 years, and 46% were male. The majority of patients were current smokers (83%) and were receiving short-acting ß(2)-agonists within the 3 months before screening (63%). All 3 strengths of once-daily FF/VI demonstrated significantly higher 0 to 24-hour (period days 28-29) change from period baseline weighted mean FEV(1) than placebo: adjusted mean improvements from placebo in FEV(1) for FF/VI were 220 to 236 mL (all, P < 0.001). Improvements versus placebo in change from period baseline serial FEV(1) measures were observed at each time-point and with each strength of FF/VI over the 0 to 25-hour period (period days 28-29), indicating sustained bronchodilation. The overall incidence of on-treatment AEs was low (10%-12% with FF/VI; 4% with placebo); 2 serious AEs were reported during washout periods (1 AE after FF/VI 50/25 µg and 1 AE after placebo) but neither was considered treatment related. No serious AEs were reported during the treatment periods or during the follow-up period. No clinically or statistically significant differences from placebo were reported for serum glucose or potassium. No significant effects on vital signs, ECG, or 24-hour serial serum cortisol were reported. The extent of systemic exposure to FF and VI at steady state was low for all strengths of FF/VI. CONCLUSIONS: FF/VI inhaled once daily in the morning for 28 days produced significant improvements in pulmonary function with a prolonged (>24 hours') duration of action in this population of patients with COPD. The combination was well tolerated. ClinicalTrials.gov identifier: NCT01072149.