Anthony Cahn

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.

A phase 1, randomized, placebo‐controlled, dose‐escalation study of an anti‐IL‐13 monoclonal antibody in healthy subjects and mild asthmatics

AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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.

Safety and efficacy of dual therapy with GSK233705 and salmeterol versus monotherapy with salmeterol, tiotropium, or placebo in a crossover pilot study in partially reversible COPD patients

Background GSK233705 is an inhaled, long-acting muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This study was performed to see if the addition of GSK233705 to salmeterol would provide greater bronchodilation than salmeterol or tiotropium alone in COPD. Methods In an incomplete-block, three-period, crossover design, dually responsive patients received three of the following five treatments: GSK233705 20 μg plus salmeterol 50 μg twice-daily; GSK233705 50 μg plus salmeterol 50 μg twice-daily; salmeterol 50 μg or placebo, each twice-daily; and tiotropium 18 μg or placebo once-daily for 7 days. Each treatment period was separated by a 14-day washout. The primary efficacy endpoint was morning (trough) forced expiratory volume in 1 second (FEV1) on Day 8, following 7 days of treatment. Secondary endpoints included pulmonary function, plethysmography, pharmacokinetics of GSK233705 and salmeterol, adverse events (AEs), electrocardiograms (ECGs), vital signs, and laboratory parameters. Results A total of 47 patients were randomized. The mean % predicted normal postbronchodilator FEV1 was 55% at screening. Compared with placebo (n = 24), the adjusted mean change from baseline in trough FEV1 on Day 8 was 215 mL higher with GSK233705 20 μg + salmeterol (n = 23) and 203 mL higher with GSK233705 50 μg + salmeterol (n = 27), whereas with salmeterol (n = 27) and tiotropium (n = 28) the changes were 101 mL and 118 mL higher, respectively. The primary efficacy results were supported by the results from the other secondary lung function assessments. AEs were reported by similar proportions of patients across the treatment groups, with headache the most frequently reported treatment-related AE reported by one subject receiving each of GSK233705 20 μg + salmeterol, tiotropium, and placebo. No significant differences were seen in vital signs, ECGs, or laboratory parameters between the groups. Conclusion The addition of GSK233705 to salmeterol in partially reversible COPD patients resulted in greater bronchodilation than salmeterol or tiotropium alone and was well tolerated.

Randomized trial of allergen-induced asthmatic response in smokers and non-smokers: effects of inhaled corticosteroids.

It is thought that asthmatics who smoke cigarettes respond less well to inhaled corticosteroid (ICS) therapy than asthmatics who do not smoke.

Systemic Exposure and Urinary Cortisol Effects of Fluticasone Propionate Formulated With Hydrofluoroalkane in 4- to 11-Year-Olds With Asthma

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluorocarbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24‐hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open‐label, 2‐way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 μg twice a day or fluticasone propionate chlorofluorocarbon 88 μg twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 μg twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUClast (area under the plasma fluticasone propionate concentration–time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24‐hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24‐hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic–pituitary–adrenal axis effects as measured by 24‐hour urinary cortisol excretion.

Safety, Tolerability, and Pharmacokinetics of Single and Repeat Doses of Nemiralisib Administered via the Ellipta Dry Powder Inhaler to Healthy Subjects

PURPOSE Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability. METHODS This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 μg) and repeat (200 μg for 10 days) doses of inhaled nemiralisib in parts A (n = 12) and B (n = 12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n = 6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days. FINDINGS 21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma Cmax dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma Cmax and AUC0-24 values were 174.3 pg/mL (96.9-313.3) and 694.6 pg·h/mL (503.5-958.2) for 100 μg and 398.9 pg/mL (318.3-500.1) and 1699.6 pg·h/mL (1273.3-2268.7) for 200 μg, respectively. Repeat dosing for 10 days showed exposures ∼2- to 4-fold higher than on the single dose (peak, trough, and AUC0-24 levels), achieving steady-state by day 6. Mean AUC0-24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non-drug-related adverse events were observed; neither was serious or resulted in withdrawal. IMPLICATIONS Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ∼23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325.

A multicentre, randomised, double-blind, placebo-controlled, crossover study to investigate the efficacy, safety, tolerability and pharmacokinetics of repeat doses of inhaled nemiralisib in adults with persistent, uncontrolled asthma

Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3Kδ has been linked to airway inflammation and asthma pathogenesis. This randomized, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability, and pharmacokinetics of a PI3Kδ inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients (n = 50) received once-daily inhaled nemiralisib (1000 µg) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period. Spirometry demonstrated no discernible difference in trough forced expiratory volume in 1 second (FEV1) from baseline (adjusted posterior median 7 ml; 95% credible interval −83, 102 ml) between nemiralisib and placebo treatment at day 28 (primary endpoint). These results were supported by most secondary endpoints, including weighted mean FEV1 (0–4 hours) and change in trough forced vital capacity at day 28. Nemiralisib was generally well-tolerated, with few side effects except for post-inhalation cough (nemiralisib: 35%; placebo: 9%). At day 14, sputum interleukin (IL)-5, IL-13, IL-6, and IL-8 levels were reduced by a median of 17%, 7%, 15%, and 8%, respectively, when comparing nemiralisib with placebo [n = 15 (IL-5, IL-8) or 16 (IL-6, IL-13); posterior probability of a true ratio >0%: 78%, 64%, 76%, and 63%, respectively]. These results suggest that nemiralisib inhibited PI3Kδ locally; however, this did not translate into meaningful clinical improvement. Further studies will investigate the potential efficacy of nemiralisib in patients with asthma with other specific more severe phenotypes, including those who are colonized with bacteria and frequently exacerbate.

Functional respiratory imaging: heterogeneity of acute exacerbations of COPD

Background Exacerbations of COPD are a major burden to patients, and yet little is understood about heterogeneity. It contributes to the current persistent one-size-fits-all treatment. To replace this treatment by more personalized, precision medicine, new insights are required. We assessed the heterogeneity of exacerbations by functional respiratory imaging (FRI) in 3-dimensional models of airways and lungs. Methods The trial was designed as a multicenter trial of patients with an acute exacerbation of COPD who were assessed by FRI, pulmonary function tests, and patient-reported outcomes, both in the acute stage and during resolution. Results Forty seven patients were assessed. FRI analyses showed significant improvements in hyperinflation (a decrease in total volume at functional residual capacity of −0.25±0.61 L, p≤0.01), airway volume at total lung capacity (+1.70±4.65 L, p=0.02), and airway resistance. As expected, these improvements correlated partially with changes in the quality of life and in conventional lung function test parameters. Patients with the same changes in pulmonary function differ in regional disease activity measured by FRI. Conclusion FRI is a useful tool to get a better insight into exacerbations of COPD, and significant improvements in its indices can be demonstrated from the acute phase to resolution even in relatively small groups. It clearly visualizes the marked variability within and between individuals in ventilation and resistance during exacerbations and is a tool for the assessment of the heterogeneity of COPD exacerbations.

Evaluation of the Safety, Tolerability, and Pharmacokinetics of GSK2269557 (Nemiralisib) Administered Via Dry Powder Inhaler to Healthy Japanese Subjects

The aim of the study was to assess the safety, tolerability, and pharmacokinetics of single and repeat doses of nemiralisib administered via a dry powder inhaler to healthy Japanese subjects. This was a single‐center, double‐blind, randomized, placebo‐controlled, parallel, single‐ and repeat‐ascending‐dose study. Thirty‐six healthy Japanese male subjects were randomized to receive either 1 dose strength of nemiralisib or placebo. The study consisted of a screening period, a single‐dose session (session 1), a repeat‐dose session (session 2), a 10‐day washout period between the sessions, and then a follow‐up visit 10 ± 1 days after the last dose of session 2. No serious adverse events were reported. No clinically significant abnormalities were found in clinical laboratory results, vital signs, or spirometry results. Generally, exposure (maximum observed plasma concentration [Cmax] and area under the concentration‐time curve [AUC]) increased with dose in an approximately proportional manner. Plasma Tmax was achieved rapidly at approximately 0.08 hours, and the terminal elimination half‐life (T1/2) was approximately 40 hours. Tmax and T1/2 did not change between days or doses in the single‐ and repeat‐dose sessions. Following 10 daily doses of 200, 500, and 700 μg nemiralisib, accumulation was observed, and the ratios (session 2, day 10:session 1) for Ro(AUC0‐24) and R(Cmax) were 2.4‐3.0 and 1.5‐1.7, respectively. Steady state was achieved by 6‐7 days, based on trough observed plasma drug concentration (Ctrough) values.