IL-33 receptor inhibition in subjects with uncontrolled asthma: A randomized, placebo-controlled trial.

Background: Most biologics for severe asthma target only type 2 immunity. Inhibition of IL-33 signaling has the potential to target type 2 and non-type 2 pathways. Objective: This multicenter phase IIA study evaluated the safety and efficacy of GSK3772847, a human mAb directed against the IL-33 receptor (IL-33R) in subjects with moderate-to-severe uncontrolled asthma. Methods: Adults with uncontrolled asthma despite inhaled corticosteroid/long-acting ß2-agonist therapy received equivalent replacement medication (open-label fluticasone propionate/salmeterol [500/50 µg, twice daily]) for 2 weeks before randomization at week 0. At weeks 0, 4, 8, and 12, participants were administered blinded placebo or 10 mg/kg of intravenous GSK3772847. At week 2, salmeterol was discontinued; thereafter, fluticasone propionate was titrated by approximately 50% on weeks 4, 6, 8, and 10. Asthma control was assessed until week 16. Participants with loss of asthma control discontinued treatment. The primary end point was loss of asthma control; secondary end points were the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of GSK3772847. Results: At week 16, 56 participants (81%) and 45 (66%) receiving placebo and GSK3772847, respectively, had loss of asthma control (an 18% reduction [95% credible interval = 2%-35%]). Early loss of asthma control prevented full analysis of the secondary efficacy end points after week 4. The most frequent classes of treatment-related adverse events were cardiac disorders (n = 3 [4%] in both groups) and musculoskeletal/connective tissue disorders (with GSK3772847, n = 3 [4%]; with placebo n = 0). Target engagement of IL-33R by GSK3772847 was demonstrated. Conclusion: Treatment with GSK3772847 may be beneficial for patients with uncontrolled asthma. Further studies are warranted.

Effect of once-daily fluticasone furoate/vilanterol versus vilanterol alone on bone mineral density in patients with COPD: a randomized, controlled trial.

BACKGROUND: The relationship between inhaled corticosteroids and bone mineral density (BMD) remains uncertain despite extensive research. METHODS: This was an international, multicenter, randomized, double-blind, parallel-group, 3-year noninferiority study. Patients with chronic obstructive pulmonary disease (COPD) (⩾40 years of age; smoking history ⩾10 pack years) and at least one native hip evaluable for BMD were enrolled and randomized 1:1, stratified by sex, to treatment with vilanterol (VI) 25 µg or fluticasone furoate/vilanterol (FF/VI) 100 µg/25 µg. BMD measurements were taken via dual-energy X-ray absorptiometry every 6 months. The primary endpoint was assessment of the noninferiority of change from baseline in total hip BMD per year at the -1% noninferiority level. Change from baseline in BMD at the lumbar spine and BMD measurements by sex were secondary endpoints. Incidences of COPD exacerbations and bone fractures throughout the study were also recorded. RESULTS: Of 283 randomized patients, 170 (60%) completed the study. Noninferiority was demonstrated for FF/VI versus VI with regards to change from baseline in total hip BMD per year, with changes of -0.27% and 0.18%, respectively, and a treatment difference of -0.46% per year [95% confidence interval (CI) -0.97 to 0.06]. The treatment difference for FF/VI versus VI regarding lumbar spine BMD was -0.51% per year (95% CI -1.11 to 0.10). COPD exacerbations and bone fracture rates were similar between treatment groups. CONCLUSION: FF/VI showed noninferiority to VI for change from baseline in total hip BMD per year, when assessed at the -1% noninferiority margin in a combined sample of men and women with COPD.The reviews of this paper are available via the supplemental material section.

A Semi-automated and Scalable 3D Spheroid Assay to Study Neuroblast Migration.

The subventricular zone of the mammalian brain is the major source of adult born neurons. These neuroblasts normally migrate long distances to the olfactory bulbs but can be re-routed to locations of injury and promote neuroregeneration. Mechanistic understanding and pharmacological targets regulating neuroblast migration is sparse. Furthermore, lack of migration assays limits development of pharmaceutical interventions targeting neuroblast recruitment. We therefore developed a physiologically relevant 3D neuroblast spheroid migration assay that permits the investigation of large numbers of interventions. To verify the assay, 1,012 kinase inhibitors were screened for their effects on migration. Several induced significant increases or decreases in migration. MuSK and PIK3CB were selected as putative targets and their knockdown validated increased neuroblast migration. Thus, compounds identified through this assay system could be explored for their potential in augmenting neuroblast recruitment to sites of injury for neuroregeneration, or for decreasing malignant invasion.

ELLIPTA Versus DISKUS plus HandiHaler in COPD: A Randomized, Open-Label, Crossover Study in a Clinical Trial Setting.

BACKGROUND: Inhaler errors among patients with chronic obstructive pulmonary disease (COPD) can reduce treatment efficacy. METHODS: This randomized, open-label, crossover study evaluated correct use of ELLIPTA versus DISKUS plus HandiHaler. Participants with COPD attended at least 3 study visits (Day 1 [Visit 1], Day 28 [Visit 2], and Day 56 [Visit 3]). Inhalers contained placebo; usual maintenance medication was continued. Participants were randomized to an inhaler sequence (ELLIPTA then DISKUS plus HandiHaler, or the reverse) and preference questionnaire at Visit 1. Participants read the instructions for use in the approved prescribing information for their inhaler(s) and correct use was assessed at Visit 1 (verbal guidance provided if required). Correct use was reassessed at Visit 2, and with the next inhaler(s) at Visit 3. Primary endpoint was the proportion of participants demonstrating correct use (0 errors) with the assigned inhaler(s) after 28 days. RESULTS: A greater proportion of study participants (n = 217) correctly used ELLIPTA (96%) versus DISKUS plus HandiHaler (87%) after 28 days. The odds of demonstrating correct use with ELLIPTA were 6.88 times that of DISKUS plus HandiHaler (p < 0.001). Overall, > 99% of participants made 0 critical errors (errors leading to no or significantly reduced medication inhaled) with ELLIPTA versus 89% with DISKUS plus HandiHaler after 28 days. ELLIPTA was the patient-preferred option versus DISKUS plus HandiHaler or no preference (p < 0.001). CONCLUSIONS: Delivery of COPD maintenance therapy via ELLIPTA demonstrates higher correct use rates and lower critical error rates compared with DISKUS plus HandiHaler.