SUN-257 - Lorundrostat Modulates Heart Failure Risk Biomarkers in Participants with Uncontrolled Hypertension

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, cardiometabolic disease, and often involves maladaptive activation of the renin-angiotensin-aldosterone system. Given the recently demonstrated ability of the aldosterone synthase inhibition in reducing systolic blood pressure in uncontrolled or treatment-resistant hypertension (LAUNCH-HTN and ADVANCE-HTN trials), we sought to characterize systemic pharmacodynamic effects and modulation of pathways implicated in HF pathophysiology.

Methods: Circulating protein biomarkers (SomaScan, 1,053 analytes) were measured from serum at baseline and 12 weeks in 986 participants randomized to lorundrostat or placebo from LAUNCH-HTN and ADVANCE-HTN. Placebo-adjusted treatment effects were estimated using linear mixed models within each trial and meta-analyzed across trials using inverse-variance fixed effects. Finally, we mapped modules of coordinated longitudinal protein changes and identified hub proteins within each module using Weighted Gene Co-expression Network Analysis (WGCNA).

Results: Lorundrostat significantly modulated 191 analytes (FDR < 0.05), decreasing angiotensinogen and increasing renin, confirming target engagement. Notably, lorundrostat produced significant placebo-adjusted relative reductions in risk biomarkers with Mendelian randomization support for causal effects on incident HF, including NT-proBNP (-11.5%), MFAP4 (-18.1%), SVEP1 (-11.7%), NRP1 (-8.9%), and SPON1 (-4.0%). We observed concomitant reductions in biomarkers linked to extracellular matrix (ECM) remodeling (e.g., Collagen Types I, III, and IV, MMP-2, Laminin-2) and vascular activation (e.g., Endothelin, sTie-2, VEGF, sE-selectin, PDGFRA, PDGFRB, Notch-3), and increases in biomarkers involved in hemostasis (e.g., tPA) and protease inhibitor activity (e.g., SERPIND1, α-1-microglobulin, SLPI). Finally, WGCNA identified several protein co-change modules associated with treatment, including one defined by highly correlated ECM-related hub proteins (Laminin-2, Notch-3, MMP-2). This module contained several of the reduced incident HF risk biomarkers alongside other proteoglycans, suggesting that the reduction of these risk markers is coupled to modulation of a core ECM remodeling network.

Conclusions: Proteomic analyses suggest that lorundrostat is associated with favorable broad, system-level effects on vascular biology and matrix remodeling networks implicated in HF. Although based on circulating biomarkers rather than clinical HF outcomes, these results provide biological plausibility and support further evaluation of the therapeutic potential of lorundrostat in HFpEF.

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