A97-10 The Impact of an Investigational, First-in-class Natriuretic Peptide Receptor 1-blocking Monoclonal Antibody, REGN7544, in a Preclinical Model of Sepsis-induced Hypotension

Rationale Sepsis occurs as an exaggerated response to infection, and the resulting systemic inflammation causes hypotension, vascular leak, decreased tissue perfusion, and multiple organ dysfunction. Circulating brain natriuretic peptide (BNP) is a prognostic biomarker that correlates with increased mortality in sepsis. Engaged natriuretic peptide receptor 1 (NPR1) signaling by BNP results in decreased blood pressure (BP), suggesting that this pathway may play a key role in sepsis-induced hypotension. REGN7544, a fully human investigational monoclonal antibody that inhibits NPR1, has demonstrated durable BP increases in normotensive humanized-NPR1 (NPR1hu/hu) mice. Here, we investigated whether blocking NPR1 signaling with REGN7544 may increase BP and maintain hemodynamic stability in a mouse model of sepsis. Methods The hemodynamic effects of a single intravenous 25 mg/kg dose of REGN7544 were evaluated in a cecal ligation and puncture (CLP) model of sepsis using telemetered NPR1hu/hu mice. CLP or sham surgery was performed on Day 0, followed by administration of REGN7544 or isotype control. To benchmark the effects of REGN7544 against standard of care (SOC), another group of NPR1hu/hu mice underwent CLP or sham surgery and were treated with subcutaneous minipump-infused norepinephrine (5 mg/kg/day) or vehicle (saline). BP, heart rate, and body temperature were continuously recorded from 3 days before surgery through completion on Day 4. Serum N-terminal pro B-type natriuretic peptide (NT-proBNP) and inflammatory cytokines were assessed on Day 4. Vascular leak was assessed at 24 hours post-CLP (time of peak BP reduction). Results Thirty-two mice were tested to evaluate the impact of REGN7544 (n = 6 sham surgery and isotype control; n = 13 CLP and isotype control; n = 13 CLP and REGN7544), and 30 mice were tested to benchmark the SOC drug norepinephrine (n = 6 sham surgery and saline; n = 12 CLP and saline; n = 12 CLP and norepinephrine). NT-proBNP was significantly elevated in CLP-challenged mice versus sham controls (P<0.001). Treatment of CLP-challenged mice with REGN7544 resulted in significant increases in mean arterial pressure (MAP; P<0.01 after 12 hours post-dose) versus isotype control. CLP-challenged mice treated with isotype control remained persistently hypotensive (Figure). Additionally, CLP-challenged mice administered REGN7544 showed decreased systemic inflammation (IL6, TNF-α) and reduced vascular leak in the lungs, liver, and kidneys versus isotype control. CLP-challenged mice treated with norepinephrine demonstrated similar improvements in MAP (Figure) versus controls to CLP-challenged mice treated with REGN7544. However, norepinephrine infusion did not improve systemic inflammation. Conclusions The NPR1-blocking monoclonal antibody REGN7544 may be a novel mechanistic approach for the treatment of sepsis-induced hypotension.