Background: Pulmonary arterial hypertension is a rare, life-limiting disease where the protein BMPRII has a causal role in hereditary and idiopathic forms making it an attractive candidate for therapeutic intervention. However, challenges remain in translating our preclinical understanding of the pathway into clinical trials. One major challenge is the development of practical biomarkers of target engagement suitable for use as endpoints.

Aim: Here we present the preliminary data on studies aimed at developing a simple, minimally invasive biomarker for determining target engagement using qPCR in whole blood RNA, suitable for adoption in upcoming planned trials.

Method: We tested different blood-based biomarker strategies for measuring BMPRII pathway activity. Microarray and RNAseq data were used to develop and validate a list of putative BMPRII target genes with further validation using qPCR. In a prospective study, PAH patients (n=20) were recruited and sampled to 16 weeks. Biomarkers were assessed for assay repeatability, independent reproducibility, and temporal stability.

Result: An eventual panel of 8 qPCR biomarkers were identified which met required criteria of acceptable variation and statistical power when used as an endpoint for adaptation for an early phase clinical trial in a rare disease population.

Conclusion: Biomarkers identified here will be used in the upcoming Stratosphere Phase 2a trial to directly inform the primary endpoint of adaptation based on target engagement. Whilst little is known about BMPRII signalling in whole blood, we feel that the genes within our panel cover a broad range of canonical and non-canonical targets that may be induced by multiple BMP ligands.