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Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs.

Danirixin (GSK1325756) is a small, high-affinity, selective and reversible CXCR2 antagonist in development for treatment of chronic obstructive pulmonary disease. The objective of the study was to evaluate the relative bioavailability, including the inter-subject variability, of a conventional immediate-release (IR) formulation and two prototype bioenhanced formulations of danirixin during gastric acid suppression in a healthy, elderly population. A single-centre, crossover study in healthy male and female volunteers aged 65–80 years was conducted. Subjects were randomised to receive danirixin 50 mg IR in the fed and fasted states and danirixin 50 mg Bioenhanced Formulation 1 and 2 in the fasted state. All subjects also received omeprazole 20 mg each morning beginning 4 days prior to the first treatment period and continuing through danirixin dosing in the final treatment period. Twenty subjects were randomised and completed the study. Bioenhanced Formulation 2 in the fasted state demonstrated the highest adjusted geometric means for AUC(0–t), AUC(0–inf), AUC(0–24) and Cmax. Danirixin IR demonstrated adjusted means that were higher in the fed state compared with the fasted state. For all formulations tested, there was substantial inter-subject variability (CVb >100 % for all formulations). The overall incidences of adverse events (AEs) were 10 % for danirixin IR (both in the fed and fasted states) and 15–20 % for the bioenhanced formulations. The majority of AEs were mild in intensity. There were no serious AEs. Concomitant use of omeprazole resulted in large inter-subject variability in the exposure to danirixin. Bioenhanced formulation strategies could not overcome the effect of omeprazole on exposure and variability between subjects.

Abstract Background: Loxapine, a first-generation antipsychotic, delivered with a novel inhalation delivery device developed for the acute treatment of agitation in patients with schizophrenia or bipolar disorder was evaluated in subjects with asthma or chronic obstructive pulmonary disease (COPD). Methods: Separate randomized, double-blind, parallel-arm, placebo-controlled trials compared two administrations of inhaled loxapine (10 mg) 10 hr apart with placebo in 52 subjects with asthma and in 53 subjects with COPD. A thermally-generated drug aerosol of loxapine was delivered to the deep lung for rapid systemic absorption. Controller medications were continued throughout the study, but quick-relief bronchodilators were withheld from 6–8 hr before through 34 hr after dose 1, unless indicated as rescue. Results: All airway adverse events (AEs) were of mild or moderate severity. Symptomatic bronchospasm occurred in 53.8% of subjects with asthma after inhaled loxapine and 11.5% after placebo; and in 19.2% of COPD subjects after inhaled loxapine and 11.1% after placebo. Subjects required inhaled albuterol as follows: asthma: 53.8% after inhaled loxapine and 11.5% after placebo; and COPD: 23.1% after inhaled loxapine and 14.8% after placebo. Respiratory signs/symptoms requiring treatment responded to rescue bronchodilator [forced expiratory volume in 1 sec (FEV1) return to within 10% of baseline] within 1 hr in 11 of 15 events in asthma subjects and four of seven events in COPD subjects, the remainder by the last spirometry. Conclusions: In subjects with either asthma or COPD, FEV1 decline and bronchospasm can occur following inhaled loxapine, but more frequently in asthmatic subjects. Most subjects with bronchospasm responded to rescue bronchodilator within 1 hr. No treatment-related serious AE occurred. Although inhaled loxapine is contraindicated in patients with active airways disease per the current approved US labeling, these studies demonstrated that rescue bronchodilator mitigated the symptomatic bronchospasms that may occur in case of inadvertent use.

Abstract Rationale The most effective approach to teaching respiratory inhaler technique is unknown. Objectives To evaluate the relative effects of two different educational strategies (teach-to-goal instruction vs. brief verbal instruction) in adults hospitalized with asthma or chronic obstructive pulmonary disease. Methods We conducted a randomized clinical trial at two urban academic hospitals. Participants received teach-to-goal or brief instruction in the hospital and were followed for 90 days after discharge. Inhaler technique was assessed using standardized checklists; misuse was defined as 75% steps or less correct (≤9 of 12 steps). The primary outcome was metered-dose inhaler misuse 30 days postdischarge. Secondary outcomes included Diskus technique; acute care events at 30 and 90 days; and associations with adherence, health literacy, site, and patient risk (near-fatal event). Measurements and Main Results: Of 120 participants, 73% were female and 90% were African American. Before education, metered-dose inhaler misuse was similarly common in the teach-to-goal and brief intervention groups (92% vs. 84%, respectively; P = 0.2). Metered-dose inhaler misuse was not significantly less common in the teach-to-goal group than in the brief instruction group at 30 days (54% vs. 70%, respectively; P = 0.11), but it was immediately after education (11% vs. 60%, respectively; P < 0.001) and at 90 days (48% vs. 76%, respectively; P = 0.003). Similar results were found with the Diskus device. Participants did not differ across education groups with regard to rescue metered-dose inhaler use or Diskus device adherence at 30 or 90 days. Acute care events were less common among teach-to-goal participants than brief intervention participants at 30 days (17% vs. 36%, respectively; P = 0.02), but not at 90 days (34% vs. 38%, respectively; P = 0.6). Participants with low health literacy receiving teach-to-goal instruction were less likely than brief instruction participants to report acute care events within 30 days (15% vs. 70%, respectively; P = 0.008). No differences existed by site or patient risk at 30 or 90 days (P > 0.05). Conclusions In adults hospitalized with asthma or chronic obstructive pulmonary disease, in-hospital teach-to-goal instruction in inhaler technique did not reduce inhaler misuse at 30 days, but it was associated with fewer acute care events within 30 days after discharge. Inpatient treatment-to-goal education may be an important first step toward improving self-management and health outcomes for hospitalized patients with asthma or chronic obstructive pulmonary disease, especially among patients with lower levels of health literacy. Clinical trial registered with www.clinicaltrials.gov (NCT01426581).

With greater interest in delivery of protein and peptide-based drugs to the lungs for topical and systemic activity, a range of new devices and formulations are being investigated. While a great deal of recent research has focused on the development of novel devices, attention must now be paid to the formulation of these macromolecular drugs. The emphasis in this review will be on targeting of protein/peptide drugs by inhalation using carriers and ligands.

Acute exacerbation (AE) is an important outcome of idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). Recombinant human soluble thrombomodulin (rhTM) is a new drug for the treatment of disseminated intravascular coagulation in Japan. The objective of this study was to evaluate the efficacy of rhTM for AE of IPF/NSIP. Twenty-two patients with AE-idiopathic interstitial pneumonia (16 patients with IPF and six patients with NSIP) were enrolled in our study. Among them, eleven patients were treated with rhTM (rhTM group), and eleven patients were treated without rhTM (non-rhTM group). Patients admitted to our hospital prior to December 2013 were treated with rhTM, while those admitted after January 2014 were treated without rhTM. The primary endpoint was mortality at 90 days after AE treatment. The secondary endpoint was the safety of rhTM for AE-IPF/AE-NSIP. In addition, we examined prognostic factors of AE-IPF/AE-NSIP. The mortality rate was significantly lower in the rhTM group than in the non-rhTM group (mortality rate at 90 days: 36% vs 90%, P=0.023; median survival time: not reached vs 15.0 days, P=0.019). A univariate analysis revealed the respiratory rate (hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.00-1.18, P=0.039) and rhTM administration (HR 0.21, 95% CI 0.06-0.77, P=0.013) as predictors of mortality at 90 days, and a multivariate analysis identified rhTM administration (HR 0.025, 95% CI 0.0006-0.94, P=0.046) as an independent predictor of mortality at 90 days. No serious adverse events were observed. The administration of rhTM is associated with reductions in mortality in patients with AE-IPF/NSIP, without causing adverse events.

Treating symptoms and preventing exacerbations are key components of chronic obstructive pulmonary disease (COPD) long-term management. Recently, a more tailored treatment approach has been proposed, in particular for two well-established clinical phenotypes, frequent exacerbators and chronic bronchitis-dominant COPD. ELOM-080 has demonstrated clinical efficacy in treating symptoms and preventing exacerbations in subjects with chronic bronchitis. However, little is known about the potential effects of ELOM-080 in COPD patients. To evaluate the effect on exacerbation, cough sputum, and general state of health of long-term treatment with ELOM-080 in COPD patients with an exacerbation history and chronic bronchitis. We performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled parallel-group clinical trial of a 6-month treatment with ELOM-080 (3×300 mg) in patients with chronic bronchitis and concomitant COPD. The primary outcome was the proportion of subjects with at least one exacerbation over the 6-month study period. Secondary outcomes included the total number of exacerbations (ie, cumulative occurrence of exacerbations during the study period) and the proportion of acute exacerbations necessitating an antibiotic treatment, monthly evaluations of sputum and cough symptoms, and the general state of health and a safety analysis. Of 260 randomized subjects, 64 patients fulfilled the inclusion criteria for COPD (ELOM-080: 35, placebo: 29). Compared to placebo, ELOM-080 reduced the percentage of subjects with at least one exacerbation (29% versus 55%, =0.031) and a reduction in the overall occurrence of exacerbations (ELOM-080: 10, placebo: 21, =0.012) during the winter season. The percentage of asymptomatic or mildly symptomatic patients (sputum/expectoration and cough) was consistently higher in the ELOM-080 group compared to placebo, with statistical significant differences after 2 and 3 months of treatment (2 months: ELOM-080 25%, placebo 11%, <0.005; 3 months: ELOM-080 26%, placebo 14%, <0.05). Likewise the subjective rating of general health status was better in the ELOM-080 group with statistically significant superiority after 2 and 3 months of treatment (2-month treatment: =0.015; 3-month treatment: =0.024). Tolerability results were comparable between ELOM-080 and placebo. ELOM-080 is efficacious in patients with COPD and a chronic bronchitis phenotype. Prophylactic use reduces the rate of exacerbations and improves the key symptoms of sputum and cough with a favorable long-term tolerability profile.

Recurrence of acute exacerbations has a major impact on patients with COPD. Therefore, effective prevention and treatment of exacerbation is crucial in the management of COPD, especially for patients with moderate to severe disease. This study evaluated the effectiveness of YuPingFeng granule administration in preventing exacerbation and improving symptom score, as well as its long-term (1 year) safety profile, in patients with COPD. This was a randomized, double-blind, parallel, placebo-controlled study of 240 patients from eight centers in China. Participants were eligible if they had mild to severe COPD as defined by Global Initiative for Chronic Obstructive Lung Disease, had a history of at least two COPD exacerbations or one hospitalization within the previous year, and had remained clinically stable for over 4 weeks before the study. They were randomly assigned to receive 5 g of YuPingFeng or placebo, three times per day, for 1 year. The primary end point was the exacerbation rate over 1 year, and the analysis was by intention to treat. Secondary end points included symptom score, which was assessed by COPD assessment test (CAT) score and safety profiles. This trial was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn; registration number: ChiCTR-IPR-15007023). The YuPingFeng group had a significantly lower exacerbation rate than the placebo group (1.15 vs 1.55; risk ratio=0.677 [95% CI 0.531-0.863]; =0.002) and a significantly reduced risk of second exacerbation (95% CI 0.326-0.772; =0.002). After treatment, the mean change in the CAT score in the YuPingFeng group (-4.41±7.01) differed significantly from that in the placebo group (-2.49±5.31; =0.001). YuPingFeng was well tolerated. YuPingFeng granules can be considered as a treatment option for COPD; this treatment prevents acute exacerbations of COPD and has a good safety profile.

To assess the comparative efficacy of short-acting muscarinic antagonists (SAMAs), long-acting muscarinic antagonists (LAMAs), LAMA in combination with long-acting beta-agonists (LABAs; LAMA/LABAs) and inhaled corticosteroids (ICS) in combination with LABA (ICS/LABAs) for the maintenance treatment of COPD. We systematically reviewed 74 randomized controlled trials (74,832 participants) published up to 15 November 2017, which compared any of the interventions (SAMA [ipratropium], LAMA [aclidinium, glycopyrronium, tiotropium, umeclidinium], LAMA/LABA [aclidinium/formoterol, indacaterol/glycopyrronium, tiotropium/olodaterol, umeclidinium/vilanterol] and ICS/LABA [fluticasone/vilanterol, budesonide/formoterol, salmeterol/fluticasone]) with each other or with placebo. A random-effects network meta-analysis combining direct and indirect evidence was conducted to examine the change from baseline in trough FEV , transition dyspnea index, St George's Respiratory Questionnaire and frequency of adverse events at weeks 12 and 24. Inconsistency models were not statistically significant for all outcomes. LAMAs, LAMA/LABAs and ICS/LABAs led to a significantly greater improvement in trough FEV compared with placebo and SAMA monotherapy at weeks 12 and 24. All LAMA/LABAs, except aclidinium/formoterol, were statistically significantly better than LAMA monotherapy and ICS/LABAs in improving trough FEV . Among the LAMAs, umeclidinium showed statistically significant improvement in trough FEV at week 12 compared to tiotropium and glycopyrronium, but the results were not clinically significant. LAMA/LABAs had the highest probabilities of being ranked the best agents in FEV improvement. Similar trends were observed for the transition dyspnea index and St George's Respiratory Questionnaire outcomes. There were no significant differences in the incidences of adverse events among all treatment options. LAMA/LABA showed the greatest improvement in trough FEV at weeks 12 and 24 compared with the other inhaled drug classes, while SAMA showed the least improvement. There were no significant differences among the LAMAs and LAMA/LABAs within their respective classes.