Zamanian, Roham T.

Aberrant kinase signaling that involves platelet‐derived growth factor receptor (PDGFR) α/β, colony stimulating factor 1 receptor (CSF1R), and stem cell factor receptor (c‐KIT) pathways may be responsible for vascular remodeling in pulmonary arterial hypertension. Targeting these specific pathways may potentially reverse the pathological inflammation, cellular proliferation, and fibrosis associated with pulmonary arterial hypertension progression. Seralutinib (formerly known as GB002) is a novel, potent, clinical stage inhibitor of PDGFRα/β, CSF1R, and c‐KIT delivered via inhalation that is being developed for patients with pulmonary arterial hypertension. Here, we report on an ongoing Phase 2 randomized, double‐blind, placebo‐controlled trial (NCT04456998) evaluating the efficacy and safety of seralutinib in subjects with World Health Organization Group 1 Pulmonary Hypertension who are classified as Functional Class II or III. A total of 80 subjects will be enrolled and randomized to receive either study drug or placebo for 24 weeks followed by an optional 72‐week open‐label extension study. The primary endpoint is the change from baseline to Week 24 in pulmonary vascular resistance by right heart catheterization. The secondary endpoint is the change in distance from baseline to Week 24 achieved in the 6‐min walk test. A computerized tomography sub‐study will examine the effect of seralutinib on pulmonary vascular remodelling. A separate heart rate monitoring sub‐study will examine the effect of seralutinib on cardiac effort during the 6‐min walk test.

Abstract Rationale Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. Objectives To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. Methods The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Results Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (−5.4; 95% CI, −8.1 to −2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Conclusions Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.

Abstract Rationale Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) typically undergo frequent clinical evaluation. The incidence and outcomes of coronavirus disease (COVID-19) and its impact on routine management for patients with pulmonary vascular disease is currently unknown. Objectives To assess the cumulative incidence and outcomes of recognized COVID-19 for patients with PAH/CTEPH followed at accredited pulmonary hypertension centers, and to evaluate the pandemic's impact on clinic operations at these centers. Methods A survey was e-mailed to program directors of centers accredited by the Pulmonary Hypertension Association. Descriptive analyses and linear regression were used to analyze results. Results Seventy-seven center directors were successfully e-mailed a survey, and 58 responded (75%). The cumulative incidence of COVID-19 recognized in individuals with PAH/CTEPH was 2.9 cases per 1,000 patients, similar to the general U.S. population. In patients with PAH/CTEPH for whom COVID-19 was recognized, 30% were hospitalized and 12% died. These outcomes appear worse than the general population. A large impact on clinic operations was observed including fewer clinic visits and substantially increased use of telehealth. A majority of centers curtailed diagnostic testing and a minority limited new starts of medical therapy. Most centers did not use experimental therapies in patients with PAH/CTEPH diagnosed with COVID-19. Conclusions The cumulative incidence of COVID-19 recognized in patients with PAH/CTEPH appears similar to the broader population, although outcomes may be worse. Although the total number of patients with PAH/CTEPH recognized to have COVID-19 was small, the impact of COVID-19 on broader clinic operations, testing, and treatment was substantial.

Inhaled treprostinil (Tyvaso) has been shown to be a safe and effective addition to pulmonary arterial hypertension (PAH) oral therapies; however, the respiratory‐related safety profile of inhaled treprostinil required further elucidation in the setting of routine clinical care. The objectives of this study were to characterize respiratory‐related adverse events (AEs) associated with current or recent treatment with inhaled treprostinil and to compare the incidence of respiratory‐related AEs in PAH patients treated with inhaled treprostinil with that in patients treated with other Food and Drug Administration (FDA)–approved PAH therapies. This was a long‐term, prospective, observational study. All respiratory‐related AEs were recorded during the study. The number of PAH patients enrolled was 1,333, 666 treated with inhaled treprostinil and 667 controls (treated with an FDA‐approved PAH therapy other than inhaled treprostinil), for a total of 958 and 1,094 patient‐years of exposure, respectively. In the inhaled‐treprostinil group, 1,281 respiratory‐related AEs were reported in 403 patients (61%), and in the control group, 1,295 respiratory‐related AEs were reported in 388 patients (58%). Cough, throat irritation, nasal discomfort, and hemoptysis were the most common respiratory‐related AEs (occurring in ≥2% of patients in either treatment group) that demonstrated a higher number of events per patient‐year of exposure in the inhaled‐treprostinil group than in the control group (risk ratio [95% confidence interval]: 1.487 [1.172–1.887], 3.777 [2.050–6.956], 2.039 [1.072–3.879], and 1.957 [1.024–3.741], respectively). Overall, inhaled treprostinil was well tolerated by PAH patients in routine clinical care, with respiratory‐related AEs consistent with the known safety profile (trial registration: clinicaltrials.gov identifier: NCT01266265).