BMPR-II biomarkers for testing therapeutic efficacy in pulmonary arterial hypertension: The StratosPHere 1 study.

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where deficiency of the TGF/BMP pathways have causal roles in hereditary and idiopathic forms. It is an attractive candidate for therapeutic intervention but there is an unmet need for clinically-relevant and practical biomarkers that can measure target engagement. A major challenge has been the inaccessibility of lung tissue in disease for molecular profiling. Here we explore the surrogate capacity of peripheral blood BMP pathway-specific markers. We demonstrate that BMPR-II in flow cytometrically characterised white blood cell subsets is reduced in a proportion of patients, however proteomic analysis demonstrates pleiotropic alterations of TGF{beta}/BMP modulators. Downstream BMPR-II canonical and non-canonical signalling is impacted and measurable in whole blood. We present discovery and international replication cohorts for a transcriptomic BMPR-II signalling signature. The composite biomarker panel is repeatable, reproducible, longitudinally stable and expressed in correlated gene modules in PAH which associate with clinical outcomes. The assay performance characteristics of the biomarker panel make it feasible for early phase, target engagement clinical trials and an adaptive three arm study of two pre- clinically validated modulators of BMPR-II is underway. One Sentence SummaryThe first demonstration of clinically-relevant BMP biomarker panels validated in international populations of patients with PAH.