A Phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma.

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 (205 722;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 the 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.

Assessing efficacy in important subgroups in confirmatory trials: An example using Bayesian dynamic borrowing.

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.

The Pharmacokinetics and Relative Bioavailability of Mepolizumab 100 mg Liquid Formulation Administered Subcutaneously to Healthy Participants: A Randomized Trial.

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.

Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.

OBJECTIVE: Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor, which is mainly expressed on eosinophils. Eosinophils are key cells in the inflammatory cascade of various diseases, including asthma. This study investigated the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between exposure of mepolizumab subcutaneous (SC) administration and blood eosinophil reduction compared with intravenous (IV) administration in adult subjects with asthma. METHODS: In this multi-center, randomized, open-label, parallel-group, repeat-dose study, 70 adult subjects received one of four possible treatment regimens: mepolizumab 12.5, 125, or 250 mg SC or 75 mg IV. In addition to analyzing the dose and PK/PD relationship, absolute bioavailability, safety, tolerability, and incidence of anti-mepolizumab antibodies were evaluated. RESULTS: Blood eosinophil levels decreased in a dose-dependent manner with the lowest (12.5 mg) dose clearly differentiating from the other doses. A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50% and 90% of maximal blood eosinophil inhibition were 11 mg (95% confidence interval (CI): 5.19 - 16.85) and 99 mg (95% CI: 47 - 152), respectively. The route of administration did not affect the exposure-response relationship. The estimated mepolizumab SC absolute bioavailability (arm) was 74% (90% CI: 54 - 102%). The safety profile of mepolizumab was favorable. CONCLUSIONS: A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed. The subcutaneous absolute bioavailability was 74%. The route of administration did not affect the mepolizumab exposure eosinophil response relationship.

Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial.

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 FEV1 (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.

Safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects: two randomized studies.

BACKGROUND: 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. OBJECTIVE: To characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies.

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.

Metabolism and disposition of the antihypertensive agent moxonidine in humans.

The metabolism and pharmacokinetics of moxonidine, a potent central-acting antihypertensive agent, were studied in four healthy subjects after a single oral administration of approximately 1 mg (approximately 60 muCi) of [(14)C(3)]moxonidine. Moxonidine was rapidly absorbed, with peak plasma concentration achieved between 0.5 to 2 h postdose. The maximal plasma concentration and the area under the curve of unchanged moxonidine are lower than those determined for radioactivity, indicating presence of circulating metabolite(s). The total recovery of radiocarbon over 120 h ranged from 99.6 to 105.2%, with 92.3 to 103.3% of the radioactivity excreted in the urine and only 1.9 to 7.3% of the dose excreted in the feces. Thus, renal elimination represented the principal route of excretion of radioactivity. Metabolites of moxonidine were identified in urine and plasma samples by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Oxidation of moxonidine on the methyl group or on the imidazoline ring resulted in the formation of hydroxymethyl moxonidine, hydroxy moxonidine, dihydroxy moxonidine, and dehydrogenated moxonidine. Metabolite profiling results indicated that parent moxonidine was the most abundant component in the urine. The dehydrogenated moxonidine was the major urinary metabolite as well as the major circulating metabolite. Moxonidine also underwent phase II metabolism, generating a cysteine conjugate. In summary, moxonidine is well absorbed after oral administration. The major clearance pathway for moxonidine in humans is via renal elimination. Furthermore, seven metabolites were identified with three metabolites unique to humans.

Quinidine does not affect the renal clearance of moxonidine.

AIMS: To test the hypothesis that the renal clearance of moxonidine decreases when dosed with quinidine. METHODS: A randomized, two-period study was conducted with six healthy, male subjects orally dosed with either 0.2 mg moxonidine alone or 1 h after 400 mg quinidine sulphate. Pharmacokinetic parameters were calculated using a noncompartmental analysis method. RESULTS: When coadministered, quinidine significantly increased moxonidine AUC and t1/2 by 11% and 15%, respectively, and decreased CL/F by 10% compared with the control dosing. CLR and Aeur were not significantly different. Clinically, both treatments were well tolerated. CONCLUSIONS: Quinidine does not affect the renal clearance of moxonidine. The decrease in apparent total clearance of moxonidine with quinidine coadministration was possibly due to metabolic inhibition, though not likely to be clinically significant.