Dados do Trabalho

Título

SUSTAINED EFFECT OF SERALUTINIB ON CIRCULATING BIOMARKERS IN THE TORREY PHASE 2 OPEN-LABEL EXTENSION STUDY (OLE)

Introdução

Seralutinib is an inhaled PDGFRα/β, CSF1R and c-KIT kinase inhibitor targeting pathways driving vascular remodeling in pulmonary arterial hypertension (PAH). The phase 2 TORREY study met its primary endpoint, demonstrating a significant reduction in pulmonary vascular resistance in patients with PAH (NCT04456998). An exploratory analysis of TORREY identified 380 circulating proteins altered by seralutinib following 12 and/or 24 weeks of treatment, relative to placebo. Many of the proteins and associated pathways relate to PAH disease biology and/or the seralutinib mechanism of action.

Objetivo

To characterize changes in these biomarkers following long-term seralutinib treatment in patients participating in an OLE (NCT04816604).

Método

Longitudinal plasma samples from PAH patients in TORREY and OLE studies were prospectively collected. Olink® proteomics data were generated for 22 placebo-to-seralutinib (P-S) and 23 continued-seralutinib (S-S) patients treated for 48 or 72 weeks, respectively. One-sided Wilcoxon signed-rank tests were used to assess biomarker changes of the 380 seralutinib-associated proteins identified in TORREY over the treatment period.

Resultados

In the P-S arm, 152/380 (40%) of the previously identified protein changes were recapitulated at nominal significance (p < 0.05). In the S-S arm, 169/380 (45%) protein changes were maintained after long-term treatment. Decreasing proteins include extracellular matrix (COL1A1, ITGB2, FAP), chemokines (CCL3,7) and RAS related proteins. Increasing proteins include anti-inflammatory factors (IL10, SCGB3A2) and metalloproteinase regulators (TIMP4). The directionality of the observed changes, as in the TORREY study, was consistent with anti-fibrotic, anti-inflammatory, and anti-proliferative effects. For the subset of proteins changing in TORREY and OLE, a StringDB network analysis was performed to identify proteins highly interconnected with each other and with seralutinib targets. Functional enrichment analysis of this network supports that pathways relevant to PDGFR signaling, proliferation, migration, and remodeling are downregulated by seralutinib.

Conclusão

The observed long-term biomarker changes support a sustained effect of seralutinib on proteins and pathways relevant to PAH pathogenesis. Protein changes relate to proliferation, inflammation, and matrix remodeling, and support the seralutinib MOA observed in preclinical studies.