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This study compared the pharmacokinetic (PK) profile of a new liquid formulation of mepolizumab with the established lyophilized formulation. In this open‐label, parallel‐group, single‐dose study (NCT03014674; GSK ID: 204958), healthy participants were randomized (1:1:1) to receive a single mepolizumab dose (100 mg) administered subcutaneously as liquid in a single‐use prefilled syringe or single‐use prefilled autoinjector, or as a lyophilized formulation. Maximum plasma concentration, area under the plasma concentration–time curve from time zero (predose) to time of last quantifiable concentration (AUC0–t), and AUC from time zero to infinity (AUC0–∞) as well as additional PK parameters, safety assessments, and blood eosinophil count were evaluated. In total, 244 participants received study drug. All PK parameters were similar across the 3 groups; 90% confidence intervals for maximum plasma concentration, AUC0–t, and AUC0–∞ treatment ratios (liquid prefilled syringe or autoinjector vs lyophilized formulation) were within conventional bioequivalence bounds (0.80‐1.25), demonstrating statistical PK comparability. On‐treatment adverse event incidence was 29% to 38%. Mepolizumab liquid formulation administered via prefilled syringe or autoinjector had similar PK properties to the lyophilized formulation, with no safety concerns identified.

Objectives There are no published reports for anti‐interleukin‐5 therapy in children

Aims GSK3511294 is a humanized anti-interleukin (IL)-5 monoclonal antibody (mAb) engineered for extended half-life and improved IL-5 affinity versus other anti-IL-5 mAbs. This study examined its safety, tolerability, pharmacokinetics (PK) and effect on blood eosinophil counts. Methods This was a double-blind, parallel-group, single-ascending-dose, multicenter, Phase 1 study (205722;NCT03287310) in patients with asthma and a blood eosinophil count ≥200 cells μL-1 . Patients were randomized 3:1 within dose cohorts to receive a single subcutaneous dose of GSK3511294 (2, 10, 30, 100 or 300 mg) or placebo and followed for up to 40 weeks to assess safety (primary endpoint), ratio to baseline in blood eosinophil count, plasma PK parameters and frequency/titers of binding antidrug antibodies (all secondary). Results Forty-eight patients received study drug and completed the study. Adverse events (AEs) occurred in 92% of placebo-treated and 81% of GSK3511294-treated patients. There were no AEs leading to study withdrawal or serious AEs; hypersensitivity (one event in one patient) and injection-site reaction (three events in two patients) occurred infrequently. Marked reductions (>48%) in blood eosinophil count were seen from 24 hours post-dose with all GSK3511294 doses but not placebo; suppression was maintained for longer with increasing dose (82% and 83% adjusted reductions vs placebo with 100 and 300 mg, respectively, at Week 26). PK were linear and dose proportional over the dose range; terminal half-life was 38-53 days. Conclusions GSK3511294 was well tolerated, with linear and dose proportional PK, extended half-life and blood eosinophil count reduction, supporting less frequent dosing versus other anti-IL-5 mAbs.

Assessment of efficacy in important subgroups – such as those defined by sex, age, race and region – in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non‐informative prior.

Objective: A liquid mepolizumab formulation in a single-use prefilled syringe (PFS) is under development. We evaluated the usability of mepolizumab self-injected via PFS by patients with severe eosinophilic asthma (SEA), or their caregivers, in clinic and at home. Methods: This open-label, single-arm, Phase IIIa study included patients with SEA, aged ≥12 years, and receiving mepolizumab (100 mg subcutaneously) every 4 weeks for ≥12 weeks prior to screening. Patients with SEA not receiving mepolizumab at screening who met additional criteria were also included. Patients/caregivers self-administered mepolizumab (100 mg subcutaneously) via PFS every 4 weeks for 12 weeks. The first (Week 0) and third (Week 8) dose were observed in clinic; the second dose (Week 4) was unobserved at home. Primary and secondary endpoints were the proportion of patients who successfully self-administered their third and second doses, respectively. Injection success was determined by investigator/site staff. Patient experience, mepolizumab trough concentrations, blood eosinophil counts, and safety were also assessed. Results: Of the 56 patients/caregivers who self-administered ≥1 dose of mepolizumab, 55 completed the study. All patients were reported to have successfully self-administered their third mepolizumab dose in clinic (N = 55, 100%); this was further evidenced by trough concentrations/blood eosinophil counts. Most patients/caregivers found the PFS easy and convenient to use with 75% (n = 42) expressing little/no anxiety about using the device at home. Incidence of on-treatment drug-related adverse events was low (4%); none were fatal. Conclusions: Patients/caregivers successfully self-administered mepolizumab via the PFS both in clinic and at home, with no new safety concerns identified.

Interleukin 5 (IL‐5) and eosinophils are thought to play an important role in the pathology of asthma. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of mepolizumab, a humanized anti‐IL5 IgG1 monoclonal antibody, in development for the treatment of severe eosinophilic asthma. This single‐blind study randomized 35 healthy Japanese male subjects (3:1) to receive either a single mepolizumab intravenous dose (10, 75, 250, or 750 mg) or placebo. Subjects were observed for up to 151 days postdose, depending on the dose administered. Blood samples were collected to measure mepolizumab concentrations, blood eosinophils, IL‐5, and antibodies to mepolizumab. Mepolizumab exhibited dose‐proportional pharmacokinetics. The terminal phase half‐life was 19.7–34.6 days, independent of dose. Higher mepolizumab plasma concentrations were associated with lower blood eosinophil counts. Mepolizumab 75–750 mg reduced blood eosinophils for ≥3 months postdose. Mepolizumab demonstrated a favorable safety profile: of 41 reported adverse events, most were mild in severity and none were serious. No neutralizing antibodies to mepolizumab were detected. Sustained reduction in blood eosinophils after single intravenous mepolizumab doses ≥ 75 mg, along with mepolizumab pharmacokinetics and a favorable tolerability profile in healthy Japanese subjects, provides a solid foundation for future studies with mepolizumab in Japanese patients with asthma.

Chronic obstructive pulmonary disease (COPD) has a significant negative impact on quality of life and increases the risk of premature death. Umeclidinium is a long-acting muscarinic receptor antagonist in development for the treatment of COPD with the aim to broaden treatment options for clinicians and patients by providing improved symptom control. To characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects. Two randomized, placebo-controlled, ascending-dose studies were conducted in healthy ipratropium bromide-responsive subjects. In the single-dose study, subjects (n = 20) received umeclidinium (10–350 μg), tiotropium bromide 18 μg and placebo in a crossover dosing schedule. In this study, lung function was assessed for 24 h by measuring specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1). In the repeat-dose study, subjects (n = 36) received umeclidinium (250–1,000 μg) and placebo for 14 days in a parallel-group schedule. Adverse events (AEs) were reported in five subjects (single-dose study) and 23 subjects (repeat-dose study); none were serious. In both studies, no abnormalities in 12-lead electrocardiogram parameters, 24-h Holter monitoring or lead II monitoring were reported as AEs. Umeclidinium was rapidly absorbed following single-dose administration [time to reach the maximum plasma concentration (tmax) 5–15 min] and repeat-dose administration (tmax 5–7 min). Following repeat dosing, the geometric mean plasma elimination half-life was approximately 27 h and statistically significant accumulation was observed for the area under the plasma concentration–time curve, maximum plasma concentration and cumulative amount of unchanged drug excreted into the urine at 24 h (range 1.5- to 4.5-fold). Umeclidinium at doses of 100 μg and above, and tiotropium bromide demonstrated statistically significant bronchodilatory effects relative to placebo at 12 h post-dosing, which lasted up to 24 h for umeclidinium 350 μg and for tiotropium bromide. Relative to placebo, these increases in sGaw were 24–34 % at 12 h post-dose and 13 % at 24 h post-dose. Increases in FEV1 achieved statistical significance at 12 and 24 h for umeclidinium 100 μg and 350 μg compared with placebo. Umeclidinium was well tolerated and demonstrated bronchodilatory effects in healthy subjects for up to 24 h. These bronchodilatory effects can be potentially clinically important in patients with airway obstruction such as COPD. The data obtained have informed dose selection for subsequent trials in subjects with COPD.

To characterise the safety, tolerability, pharmacodynamics (bronchodilatory effect) and pharmacokinetics of inhaled umeclidinium in patients with chronic obstructive pulmonary disease (COPD). The first investigation was a single dose, randomised, double-blind, placebo-controlled study (clinicaltrials.gov: NCT00515502) in which ipratropium bromide-sensitive patients received umeclidinium (250μg, 500μg, and 1000μg), tiotropium bromide 18μg or placebo. Patients were randomised to receive four out of five possible treatments as an incomplete block four-way cross-over. A subsequent study (clinicaltrials.gov: NCT700732472) was focused on assessment of safety, tolerability and pharmacokinetics of umeclidinium (250μg and 1000μg) administered once-daily for 7 days in a randomised, double-blind, placebo-controlled, parallel-group design. Of the 24 patients randomised for the single dose study, 20 completed; 31 out of 38 patients completed the repeat dose study. Most adverse events were mild-to-moderate and transient. Examination of heart rate, QTc interval, blood pressure and clinical laboratory assessments raised no concern over the safety of umeclidinium. Evidence of pharmacology was demonstrated in first study by statistically significant increases in specific airway conductance (sGaw) for up to 24h for all active treatments compared with placebo. Increases in forced expiratory volume in 1s were also observed. Pharmacokinetic analysis demonstrated that maximum observed plasma umeclidinium concentration (Cmax) was reached rapidly (time to Cmax: ∼5-15min) after single and repeat doses; 1.5-1.9-fold accumulation was observed after repeat-dosing. Single and repeat doses of umeclidinium were well tolerated and produced clinically relevant lung function improvements over 24h in patients with COPD.

Purpose: The purpose of this study was to investigate the safety and tolerability of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered p.o. alone and in combination with doxorubicin and to determine whether Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in peripheral blood natural killer lymphocytes. Experimental Design: Patients with advanced nonhematological malignancies were eligible for this Phase I trial. Zosuquidar.3HCl and doxorubicin were administered separately during the first cycle of therapy and then administered concurrently. Zosuquidar.3HCl was administered over 4 days, with doses escalated until the occurrence of dose-limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75 mg/m 2 . Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were analyzed, and dual fluorescence cytometry was used to determine the effects of Zosuquidar.3HCl on Pgp function in natural killer cells. Results: A total of 38 patients were treated at nine dose levels. Neurotoxicity was dose-limiting for oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations, and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered every 12 h for 4 days is 300 mg/m 2 . Zosuquidar.3HCl did not affect doxorubicin myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were similar in the absence and presence of doxorubicin. Higher plasma concentrations of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer cells. Conclusion: Zosuquidar.3HCl can be coadministered with doxorubicin using a 4-day oral dosing schedule, with little effect on doxorubicin toxicity or pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling should be explored to optimize Pgp inhibition while minimizing cerebellar toxicity.

Background Approximately 5% to 10% of asthmatic patients achieve incomplete symptom control on current therapies. The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity suggests a potential benefit of anti–IL-13 therapy in refractory asthma. GSK679586, a humanized mAb, inhibits IL-13 binding to both IL-13 receptor α1 and α2. Objectives We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids. Methods Patients who remained symptomatic (Asthma Control Questionnaire score ≥1.5) after uptitration to 1000 μg/d fluticasone propionate or greater were randomized to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 (n = 99) or placebo (n = 99). Results Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Questionnaire symptom scores (the primary end point; GSK679586 = −0.31, placebo = −0.17, P = .058) and FEV 1 (GSK679586 = −0.01, placebo = 0.03, P = .276). Similar analyses in patients with increased serum IgE levels, blood eosinophil counts, or both were also negative. Incidence of asthma exacerbations was similar between treatments. Most adverse events were nonserious and unrelated to treatment. Two GSK679586-treated patients had treatment-related serious adverse events (lethargy and supraventricular extrasystoles). Conclusions Although well tolerated, GSK679586 did not demonstrate clinically meaningful improvements in asthma control, pulmonary function, or exacerbations in patients with severe asthma. Further studies are needed to determine whether therapies targeting IL-13, the functionally related IL-4 cytokine, or both can provide clinical benefit in patients with severe refractory asthma or a subpopulation of these patients beyond that achievable with high-dose corticosteroids.

IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586.In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg(-1)) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg(-1)) or placebo.GSK679586 displayed approximately linear pharmacokinetics (based on AUC and C(max)) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586-IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg(-1) doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs.GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.

The purpose of this study was to investigate the safety and tolerability of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered p.o. alone and in combination with doxorubicin and to determine whether Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in peripheral blood natural killer lymphocytes.Patients with advanced nonhematological malignancies were eligible for this Phase I trial. Zosuquidar.3HCl and doxorubicin were administered separately during the first cycle of therapy and then administered concurrently. Zosuquidar.3HCl was administered over 4 days, with doses escalated until the occurrence of dose-limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75 mg/m(2). Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were analyzed, and dual fluorescence cytometry was used to determine the effects of Zosuquidar.3HCl on Pgp function in natural killer cells.A total of 38 patients were treated at nine dose levels. Neurotoxicity was dose-limiting for oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations, and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered every 12 h for 4 days is 300 mg/m(2). Zosuquidar.3HCl did not affect doxorubicin myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were similar in the absence and presence of doxorubicin. Higher plasma concentrations of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer cells.Zosuquidar.3HCl can be coadministered with doxorubicin using a 4-day oral dosing schedule, with little effect on doxorubicin toxicity or pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling should be explored to optimize Pgp inhibition while minimizing cerebellar toxicity.