BibTex format
@article{Jones:2026:10.1126/scitranslmed.ads5175,
author = {Jones, RJ and De, Bie EMDD and Deliu, N and Ng, AYKC and Dunmore, BJ and Gr盲f, S and Guignabert, C and Humbert, M and Savale, L and Tu, L and Boucly, A and Newman, J and Polwarth, G and Upton, PD and Lawrie, A and Rhodes, CJ and Wilkins, MR and Binmahfooz, SK and Rothman, AMK and Hemnes, A and Villar, SS and West, J and UK, National Cohort Study of Idiopathic and Heritable PAH Consortium and Uniphy, Clinical Trials Network and Toshner, MR},
doi = {10.1126/scitranslmed.ads5175},
journal = {Sci Transl Med},
title = {Sotatercept reduces bone morphogenetic protein signaling in patients with pulmonary arterial hypertension.},
url = {http://dx.doi.org/10.1126/scitranslmed.ads5175},
volume = {18},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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.
AU - Jones,RJ
AU - De,Bie EMDD
AU - Deliu,N
AU - Ng,AYKC
AU - Dunmore,BJ
AU - Gr盲f,S
AU - Guignabert,C
AU - Humbert,M
AU - Savale,L
AU - Tu,L
AU - Boucly,A
AU - Newman,J
AU - Polwarth,G
AU - Upton,PD
AU - Lawrie,A
AU - Rhodes,CJ
AU - Wilkins,MR
AU - Binmahfooz,SK
AU - Rothman,AMK
AU - Hemnes,A
AU - Villar,SS
AU - West,J
AU - UK,National Cohort Study of Idiopathic and Heritable PAH Consortium
AU - Uniphy,Clinical Trials Network
AU - Toshner,MR
DO - 10.1126/scitranslmed.ads5175
PY - 2026///
TI - Sotatercept reduces bone morphogenetic protein signaling in patients with pulmonary arterial hypertension.
T2 - Sci Transl Med
UR - http://dx.doi.org/10.1126/scitranslmed.ads5175
UR - https://www.ncbi.nlm.nih.gov/pubmed/42160453
VL - 18
ER -