Journal Article Ppublish 1 citation
PubMed: 42160453 DOI: 10.1126/scitranslmed.ads5175
Sotatercept reduces bone morphogenetic protein signaling in patients with pulmonary arterial hypertension.
Sci Transl Med 18(850):eads5175
Authors: Rowena J Jones, Eckart M D D De Bie, Nina Deliu, Anthony Y K C Ng, Benjamin J Dunmore, Stefan Gräf, Christophe Guignabert, Marc Humbert, Laurent Savale, Ly Tu, Athénäis Boucly, Joseph Newman, Gary Polwarth, Paul D Upton, Allan Lawrie, Christopher J Rhodes, Martin R Wilkins, Sarah K Binmahfooz, Alexander M K Rothman, Anna Hemnes, Sofía S Villar, James West, Mark R Toshner
Affiliations
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
- Royal Papworth Hospital, Cambridge, UK.
- MRC Biostatistics Unit, University of Cambridge, Biomedical Campus, Cambridge, UK.
- MEMOTEF, Sapienza University of Rome, Rome, Italy.
- Université Paris-Saclay, Hypertension Pulmonaire: Physiopathology and Innovation Thérapeutique, HPPIT, Faculté de Médecine, Le Kremlin-Bicêtre, France.
- INSERM UMR_S 999, HPPIT, Le Kremlin-Bicêtre, France.
- Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre (Assistance Publique-Hôpitaux de Paris), Le Kremlin-Bicêtre, France.
- National Heart and Lung Institute, Imperial College London, London, UK.
- University of Sheffield, Sheffield, UK.
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
- Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Abstract
Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where imbalances in the transforming growth factor-β (TGF-β) and bone morphogenetic protein receptor type II (BMPR-II) superfamily pathways have causal roles in hereditary and idiopathic forms of the disease. These pathways are emerging attractive candidates for therapeutic intervention, but there is an unmet need for clinically relevant and practical biomarkers that can measure target engagement, partly because of the inaccessibility of lung tissue in disease for molecular profiling. Here, we explored the surrogate capacity of peripheral blood bone morphogenetic protein (BMP) pathway-specific markers using samples collected in the StratosPHere 1 study using both cell surface assessment of BMPR-II receptor levels and quantitative PCR for the assessment of downstream target engagement. Downstream BMPR-II canonical and noncanonical signaling was measurable and altered in whole blood in both discovery and international replication cohorts, and transcriptomic signatures were clustered by discrete gene modules that associated with clinical outcomes and mortality. We derived a transcriptomic biomarker panel that was repeatable, reproducible, and longitudinally stable for use in early phase, target engagement clinical trials. The biomarker panel was used in a pilot study of nine sotatercept-treated patients with PAH to test the effect of the therapy on the BMP pathway; analysis suggested that sotatercept did not rebalance or increase BMPR-II pathway signaling but rather led to a reduction, possibly due to depletion of circulating BMP9 and BMP10.
MeSH
Bone Morphogenetic Proteins, Genes, Hypertension, Blood, Bone Morphogenetic Protein Receptors, Type Ii, Biomarkers, Pulmonary Arterial Hypertension, Therapeutics