Vericiguat, a novel sGC stimulator: Mechanism of action, clinical, and translational science

Abstract

Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for the treatment of heart failure (HF) with reduced ejection fraction (HFrEF). Decreased nitric oxide (NO) availability, sGC desensitization to NO, sGC deficiency, and reduced cyclic guanosine monophosphate (cGMP) signaling are potential contributing factors for HF disease progression. Vericiguat works via stimulation of sGC in the critical NO-sGC-cGMP pathway. Vericiguat is primarily metabolized by glucuronidation via uridine diphosphate-glucuronosyltransferase (UGT) isoforms UGT1A1 and UGT1A9. Urinary excretion and renal clearance of vericiguat are low. No intrinsic factor had a clinically relevant effect on vericiguat exposure. Vericiguat has low drug-drug interaction potential with no clinically relevant pharmacokinetic or pharmacodynamic interactions observed with warfarin, digoxin, aspirin, or sacubitril/valsartan. The global phase III study VICTORIA included patients with HFrEF who had a recent HF hospitalization or intravenous diuretic treatment for HF. Treatment with vericiguat on top of standard of care resulted in a 10% relative reduction in the primary composite outcome of death from cardiovascular causes or first hospitalization for HF. Vericiguat was well-tolerated with low incidence of symptomatic hypotension and syncope compared to placebo. Given its positive benefit-risk profile, vericiguat is an important option for high-risk patients with HFrEF who are already on guideline-directed medical therapy and had recent worsening of HF. Future efforts to develop additional effective therapies are needed to further reduce morbidity and mortality in patients with HF.

FIGURE 1

Mechanism of action of vericiguat. In heart failure (orange), oxidative stress and inflammation contribute to endothelial dysfunction in part through decreases in eNOS resulting in decreased NO availability. This decrease in NO leads to decreases in sGC activity and cGMP production. cGMP deficiency leads to myocardial and vascular dysfunction. Treatment with vericiguat (green) both increases the sensitivity of sGC to activation by NO and directly stimulates sGC activity, ameliorating the deficiency in cGMP, thereby improving cardiovascular functions. From Armstrong PW et al. Copyright © 2018, with permission from Elsevier. cGMP, cyclic guanylate monophosphate; eNOS, endothelial nitric oxide synthase; GTP, guanosine‐5′‐triphosphate; NO, nitric oxide; sGC, soluble guanylate cyclase.

FIGURE 2

Key clinical trials of vericiguat throughout phases of development. HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; PD, pharmacodynamics; PK, pharmacokinetics. ^aA study to assess vericiguat as victim of PK drug–drug interactions. ^bA study to assess vericiguat as perpetrator of PK drug–drug interactions.

FIGURE 3

Estimates of the cumulative incidence of the primary outcome of the VICTORIA study. The primary outcome in VICTORIA was a composite of death from cardiovascular causes or first hospitalization for heart failure. The inset is the same data plotted on an enlarged y‐axis. From Armstrong PW et al. Copyright © 2020 Massachusetts Medical Society, with permission from Massachusetts Medical Society. CI, confidence interval.