Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug-Drug Interactions in Healthy Participants.

Seralutinib, an inhaled, small-molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter-based drug-drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P-gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor.

Safety and efficacy of rodatristat ethyl for the treatment of pulmonary arterial hypertension (ELEVATE-2): a dose-ranging, randomised, multicentre, phase 2b trial.

Background: The role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results.

Methods: ELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America.

Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

Background: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways.

A Phase-2 Exploratory Randomized Controlled Trial of INOpulse in Patients with Fibrotic Interstitial Lung Disease Requiring Oxygen.

Patients with fibrotic interstitial lung disease often progress to the point of requiring supplemental oxygen. This is invariably accompanied by an impaired quality of life and limitations on activities of daily living. This study aimed to assess the improvement in physical activity in patients with interstitial lung disease requiring supplemental oxygen treated with pulsed inhaled nitric oxide via INOpulse (Bellerophon Therapeutics).

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea.

Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes.

Comparative bioavailability of inhaled treprostinil administered as LIQ861 and Tyvaso® in healthy subjects.

Introduction: Treprostinil is a synthetic prostacyclin analogue approved for inhalation administration to patients with pulmonary arterial hypertension (PAH) via nebulized Tyvaso® inhalation solution. LIQ861 is an inhaled, dry-powder formulation of treprostinil produced using Print® (Particle Replication in Nonwetting Templates) technology, a proprietary process for designing and producing highly uniform drug particles.

Methods: We conducted comparative bioavailability analyses of treprostinil exposure from LIQ861 (79.

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction.

Background: Pulmonary hypertension (PH) is associated with poor outcomes, yet specific treatments only exist for a small subset of patients. The most common form of PH is that associated with left heart disease (Group 2), for which there is no approved therapy. Nitrite has shown efficacy in preclinical animal models of Group 1 and 2 PH, as well as in patients with left heart failure with preserved ejection fraction (HFpEF).

Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects.

Introduction: The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models.

Methods: Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively.

A 26-Week Toxicity Assessment of AIR001 (Sodium Nitrite) by Inhalation Exposure in Rats and by Intravenous Administration in Dogs.

Historically, nitrogen oxides (NO) in food, drinking water, as well as in the atmosphere have been believed to be associated with adverse health consequences. More recently, NO have been implicated in normal homeostatic regulation, and exogenous administration has been associated with health benefits. One such potential health benefit is the prospect that inhaled nitrite will lower pulmonary blood pressure (BP) in patients with pulmonary arterial hypertension (PAH), a disease with poor prognosis due to the lack of effective treatment.

Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease.

Rationale: The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear.

Objectives: A second year of follow-up was performed to determine if these effects persisted after stopping treatment.

Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: results from the scleroderma lung study.

Objective: To assess the impact of cyclophosphamide (CYC) on the health-related quality of life (HRQOL) of patients with scleroderma after 12 months of treatment.

Methods: One hundred fifty-eight subjects participated in the Scleroderma Lung Study, with 79 each randomized to CYC and placebo arms. The study evaluated the results of 3 measures of health status: the Short Form 36 (SF-36), the Health Assessment Questionnaire (HAQ) disability index (DI), and Mahler's dyspnea index, and the results of 1 preference-based measure, the SF-6D.

Cyclophosphamide versus placebo in scleroderma lung disease.

Background: We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease.

Methods: At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year.

Alveolar macrophages from systemic sclerosis patients: evidence for IL-4-mediated phenotype changes.

The mechanism of chronic lung inflammation leading to lung fibrosis is unknown and does not have a characteristic inflammatory macrophage phenotype. This study was undertaken to determine whether a change in macrophage phenotype could account for chronic lung inflammation. In this study, human alveolar macrophages (AM) from subjects with systemic sclerosis (SSc) were obtained from bronchoalveolar lavage (BAL) and characterized on the basis of function (response to LPS), phenotype, and relative cell-surface B7 expression.