TGF-signaling pathway
A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).
A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
Denervation technique
Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.
Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
References
1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.
2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.