A Phase 2 Randomized Controlled Study of Tralokinumab in Subjects with Idiopathic Pulmonary Fibrosis.

RATIONALE: IL-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease. OBJECTIVES: Investigate efficacy and safety of tralokinumab, a human anti-IL-13 monoclonal antibody, in subjects with mild to moderate IPF. METHODS: Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention-to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median. MEASUREMENTS AND MAIN RESULTS: The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least-squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: -1.77 (-4.13 to 0.59) (P = 0.140) and -1.41 (-3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC greater than or equal to 10% at Week 52 was numerically greater for tralokinumab-treated subjects compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively. CONCLUSIONS: Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).

A randomized trial of benralizumab, an antiinterleukin 5 receptor α monoclonal antibody, after acute asthma.

BACKGROUND: Patients with frequent asthma exacerbations resulting in emergency department (ED) visits are at increased risk for future exacerbations. We examined the ability of 1 dose of benralizumab, an investigational antiinterleukin 5 receptor α monoclonal antibody, to reduce recurrence after acute asthma exacerbations. METHODS: In this randomized, double-blind, placebo-controlled study, eligible subjects presented to the ED with an asthma exacerbation, had partial response to treatment, and greater than or equal to 1 additional exacerbation within the previous year. Subjects received 1 intravenous infusion of placebo (n = 38) or benralizumab (0.3 mg/kg, n = 36 or 1.0 mg/kg, n = 36) added to outpatient management. The primary outcome was the proportion of subjects with greater than or equal to 1 exacerbation at 12 weeks in placebo vs the combined benralizumab groups. Other outcomes included the time-weighted rate of exacerbations at week 12, adverse events, blood eosinophil counts, asthma symptom changes, and health care resource utilization. RESULTS: The proportion of subjects with greater than or equal to 1 asthma exacerbation at 12 weeks was not different between placebo and the combined benralizumab groups (38.9% vs 33.3%; P = .67). However, compared with placebo, benralizumab reduced asthma exacerbation rates by 49% (3.59 vs 1.82; P = .01) and exacerbations resulting in hospitalization by 60% (1.62 vs 0.65; P = .02) in the combined groups. Benralizumab reduced blood eosinophil counts but did not affect other outcomes, while demonstrating an acceptable safety profile. CONCLUSIONS: When added to usual care, 1 dose of benralizumab reduced the rate and severity of exacerbations experienced over 12 weeks by subjects who presented to the ED with acute asthma.

Acute exposure to thyroid hormone increases Na+ current and intracellular Ca2+ in cat atrial myocytes.

Whole-cell recording methods and fluorescence microscopy were used to study the effects of acute exposure to thyroid hormone (T(3)) on cat atrial myocytes. Acute exposure ( approximately 5 min) to 10 nM T(3) significantly increased tetrodotoxin (TTX)-sensitive inward Na(+) current (I(Na)) at voltages between -40 and +20 mV. At maximal I(Na) activation (-40 mV) T(3) increased peak I(Na) by 32 %. T(3) had no effect on the time course of I(Na) decay, voltage dependence of activation, inactivation, or recovery from inactivation. Comparable exposures to reverse T(3) (rT(3)) or T(4) had no effect on I(Na). L-type Ca2+ current was unaffected by acute exposure to T(3). T(3)-induced increases in I(Na) were unaffected by 50 microM nickel, a blocker of T-type Ca2+ current. T(3) significantly increased cell shortening (+62 %) and could elicit spontaneous action potentials arising from Ca2+ -mediated after-depolarizations. T(3) (but not rT(3)) significantly increased baseline intracellular Ca2+, release of Ca2+ from sarcoplasmic reticulum (SR) and caffeine (10 mM)-induced release of SR Ca2+. We conclude that acute T(3) exposure increases Na(+) influx via I(Na) and thereby stimulates reverse-mode Na(+)-Ca2+ exchange to increase intracellular Ca2+ content and release. As a result, T(3) increases contraction strength, and can initiate Ca2+ -mediated arrhythmic activity. Acute non-genomic effects of T(3) can contribute to the positive inotropy and sinus (atrial) tachycardia traditionally attributed to chronic, genomic effects of elevated thyroid hormone on atrial muscle.