Novel biomarkers for BMPR2 target engagement have significant effects upon mortality in pulmonary arterial hypertension.

<bold>Background:</bold> Pulmonary arterial hypertension is a rare, life-limiting disease where the protein BMPR2 has a causal role in hereditary and idiopathic forms, making it an attractive candidate for therapeutic intervention. However, a challenge remaining in translation into clinical trials is the development of practical biomarkers of target engagement that have clinical relevance. <bold>Aim:</bold> We have previously presented a panel of 8 genes associated with BMPR2 pathway engagement in peripheral blood samples which are readily and robustly detectable by qPCR. Here, we describe how these genes cluster into BMP signalling ‘modules’ with significant relevance to clinical outcomes. <bold>Method:</bold> Whole blood RNAseq data from the UK National PAH cohort (n=355) for 8 BMPR2 biomarker genes (<italic>ARL4c, ID2, ID3, NOTCH1, NOTCH2, PTGS2, SMAD1</italic> and <italic>SMAD5</italic>) were used to perform consensus clustering of PAH patients. Overall survival between patient clusters were compared using Kaplan Meier survival estimators and Cox proportional hazard modelling after correction for age at diagnosis and sex. Clinical differences were also compared. <bold>Result:</bold> BMPR2 biomarker gene expression grouped into 3 discrete clusters with distinct biomarker gene expression levels. Patient cluster identity related to BMPR2 signalling ‘modules’. The cluster associated with lowest canonical signalling (ID2,ID3) also associated with significantly worse survival. <bold>Conclusion:</bold> Biomarkers characterised here will be used in the upcoming StratosPHere 2 trial as readouts of target engagement. Consensus clustering of these biomarkers shows significant association with survival outcomes, highlighting the clinical relevance of their usage.