Verquvo (Vericiguat): First-in-Class Soluble Guanylate Cyclase (sGC) Stimulator Approved for Heart Failure Treatment

       Bayer（Bayer recently announced that the European Commission (EC) has approved Verquvo (vericiguat, 2.5 mg, 5 mg, and 10 mg tablets), a soluble guanylate cyclase (sGC) stimulator, for adult patients with symptomatic chronic heart failure with reduced ejection fraction who have stabilized following a recent decompensation event requiring intravenous (IV) therapy. The approval of Verquvo is based on the results of the pivotal Phase 3 VICTORIA trial, which specifically focused on patients who recently experienced a worsening heart failure event (recent hospitalization for heart failure or use of intravenous diuretics). The results showed, following a worsening heart failure event, Verquvo in combination with background therapy significantly reduced the composite risk of cardiovascular death or hospitalization for heart failure compared with background therapy alone.

Verquvo is administered orally once daily. Its active pharmaceutical ingredient, vericiguat, is a first-in-class soluble guanylate cyclase (sGC) stimulator. Although sGC is essential for both vascular and cardiac function, in patients with heart failure, impaired nitric oxide (NO) availability leads to insufficient sGC stimulation, resulting in myocardial and vascular dysfunction. Vericiguat was jointly developed by Merck and Bayer, following a global collaboration agreement reached in October 2014 to develop sGC modulators. Merck holds the commercialization rights for vericiguat in the United States, while Bayer holds exclusive rights for the rest of the world.

Verquvo's mechanism of action differs from existing heart failure treatments, providing a unique approach to managing patients with chronic heart failure following a decompensation event (also known as a worsening event).. Current treatments counteract the deleterious effects of endogenous neurohormonal systems, which are activated by the myocardial and vascular dysfunction that occurs in heart failure. Verquvo works synergistically with existing therapies through a distinct mechanism of action, specifically restoring the impaired NO-sGC-cGMP pathway, which plays a critical role in the progression of heart failure and the worsening of disease symptoms.

Verquvo is the first soluble guanylate cyclase (sGC) stimulator approved for the treatment of heart failure. In January this year, Verquvo was approved in the United States to reduce the risk of cardiovascular death and heart failure hospitalization following a worsening heart failure event (defined as hospitalization for heart failure or requiring outpatient intravenous [IV] diuretic therapy for heart failure without hospitalization) in symptomatic patients with chronic heart failure and an ejection fraction <45%. In June this year, Verquvo was approved in Japan to reduce the risk of further worsening events in patients with chronic heart failure (CHF) receiving standard therapy for CHF. Currently, vericiguat is also under review in China and other countries. In China, Bayer submitted a marketing authorization application for vericiguat to the National Medical Products Administration (NMPA) in late August 2020.

Dr. Michael Devoy, Chief Medical Officer and Head of Medical Affairs and Pharmacovigilance at Bayer’s Pharmaceuticals Division, stated: “The approval of Verquvo in the European Union represents a major breakthrough for patients with heart failure. Heart failure is the leading cause of hospitalization in Europe. Given that half of patients are readmitted within 30 days of hospitalization or initiation of intravenous diuretic therapy, we believe the market launch of Verquvo will provide clinicians with a much-needed new option to help reduce the substantial burden of chronic heart failure.”

Vericiguat molecular structure (Image source: medchemexpress.com)

Patients with symptomatic chronic heart failure and reduced ejection fraction are at high risk of hospitalization following an episode of heart failure symptoms requiring outpatient intravenous diuretic therapy or hospitalization. It is estimated that more than half of patients are readmitted within one month after discharge due to worsening heart failure, and approximately one-fifth of patientsDeath within 2 years. Following the launch of vericiguat, it will provide a welcome new option for physicians, healthcare professionals, and patients.

The regulatory approval of Verquvo is based on the results of the pivotal Phase 3 VICTORIA trial. The data showed that, following a worsening heart failure event, vericiguat in combination with background therapy significantly reduced the risk of cardiovascularThe composite risk of cardiovascular death or hospitalization for heart failure. The positive results of the Phase III VICTORIA trial were presented at the virtual American College of Cardiology Annual Scientific Session & World Congress of Cardiology (ACC.20/WCC Virtual) in March 2020 and published in the premier international medical journal *The New England Journal of Medicine* (NEJM). The article is titled: "Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction."

VICTORIA is the first contemporary outcomes study specifically targeting patients with symptomatic chronic heart failure (ejection fraction <45%) following a worsening event. Data show that when used in combination with available heart failure medications, compared with placebo, vericiguat at a dose of 10 mg once dailySignificantly reduced the relative risk of the composite endpoint of heart failure hospitalization and cardiovascular death following a worsening event by 10% (HR=0.90; 95% CI: 0.82-0.98; p=0.019), with an absolute risk reduction of 4.2 per 100 patient-years.

For many patients with heart failure, worsening events may lead to clinical deterioration and a poor prognosis, approximatelyUnfortunately, 50% of patients die within 5 years of diagnosis. The VICTORIA trial is the first positive contemporary outcomes trial specifically targeting a patient population with symptomatic chronic heart failure with reduced ejection fraction and a history of worsening heart failure events. The findings of this study open up new possibilities for the treatment of chronic heart failure.

KeyDr. Burkert Pieske, Chief Investigator of the Phase 3 VICTORIA study and Professor of Internal Medicine and Cardiology at Charité Hospital in Berlin, Germany, stated: “With this latest approval, we have the potential to bring new hope to heart failure patients by breaking the cycle of decompensation (worsening) events and reducing the risk of rehospitalization. Rehospitalization has a significant impact on patients and their families, and even while receiving guideline-directed therapy, many patients’ symptoms continue to gradually worsen. Therefore, having access to a new therapy specifically developed for these patients is very welcome news.”

VICTORIAClinical Trial# Results

VICTORIA is a randomized, placebo-controlled, parallel-group, multicenter, double-blind Phase IIConducted at over 600 clinical sites across 42 countries worldwide, the Phase I study enrolled a total of 5,050 patients with symptomatic chronic heart failure who had experienced a worsening heart failure event and had an ejection fraction of less than 45%. In the study, patients were randomized to receive once-daily vericiguat (titrated to 10 mg, n=2,526) or placebo (n=2,524), alongside available heart failure pharmacotherapy. The primary endpoint was a composite of cardiovascular death or hospitalization for heart failure. Compared with recent heart failure outcome trials, the annual placebo event rate for the primary endpoint was more than twofold higher, and baseline levels of the clinical prognostic biomarker (NT-proBNP) were twice as high, indicating an elevated risk of hospitalization or death in this patient population.

Results showed, the study met its primary efficacy endpoint: when used in combination with standard heart failure therapies, compared with placebo, a once-daily 10 mg dose of vericiguat significantly reduced the composite risk of heart failure hospitalization and cardiovascular death following a worsening event by 10% (relative risk reduction: HR=0.90, 95% CI: 0.82-0.98, p=0.019); absolute risk reduction [ARR]: 4.2/100 patient-years).

This effect was consistent across most prespecified subgroups, including patients who received or did not receive Entresto (sacubitril/valsartan). Baseline NT-proBNP levels and age and treatment effassociated with outcomes. In this study, the data indicated that most patients with NT-proBNP levels in the lower quartile range and patients under 75 years of age may have derived greater benefit.

at baselineIn the NT-proBNP analysis, patients were divided into four quartiles. The overall treatment benefit was driven by patients in the lower three quartiles, with a relative risk reduction of 18–27% for the primary composite endpoint.

In the study,Vericiguat was well tolerated, consistent with the safety profile observed in previous vericiguat studies. The overall incidence of serious adverse events was similar between the vericiguat and placebo groups (32.8% vs 34.8%); symptomatic hypotension (9.1% vs 7.9%) and syncope (4.0% vs 3.5%) were more common in the vericiguat group than in the placebo group, but the differences were not statistically significant.