Sustained effect of seralutinib on circulating biomarkers: Lessons from the TORREY phase 2 open-label extension study

<bold>Background:</bold> Seralutinib is an inhaled PDGFRα/β, CSF1R and c-KIT kinase inhibitor targeting pathways driving vascular remodeling in pulmonary arterial hypertension (PAH). The TORREY phase 2 study met its primary endpoint, demonstrating a significant reduction in pulmonary vascular resistance in patients with PAH (<ext-link>NCT04456998</ext-link>). An exploratory analysis of TORREY identified 223 circulating biomarkers associated with seralutinib treatment relative to placebo at week 24. We present changes in these biomarkers following long-term treatment in patients participating in an open-label extension (<ext-link>NCT04816604</ext-link>). <bold>Methods:</bold> Olink proteomics data were generated for 21 placebo-to-seralutinib and 22 continued seralutinib patients treated for 48 or 72 weeks, respectively. One-sided Wilcoxon signed-rank tests were used to assess biomarker changes over the treatment period. <bold>Results:</bold> In the placebo-to-seralutinib arm, 87/223 (39%) of the previously identified protein changes were recapitulated at nominal significance (p < 0.05). In the continued seralutinib arm, 105/223 (47%) 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. <bold>Conclusion:</bold> The observed long-term biomarker changes support a sustained effect of seralutinib on pathways relevant to PAH pathogenesis.