FDA Clears Vericiguat to Treat Heart Failure Following Hospitalization

FDA clears Verquvo, Vericiguat, Heart failure drug.

January 25, 2021 — The U.S. Food and Drug Administration (FDA) approved Merck's Verquvo (vericiguat). It is the first treatment for chronic heart failure approved specifically for patients following a hospitalization for heart failure or need for outpatient IV diuretics.

The drug is supposed to reduce the risk of cardiovascular death and heart failure hospitalization in indicated patients with symptomatic chronic heart failure and ejection fraction less than 45%. Vericiguat is a soluble guanylate cyclase (sGC) stimulator, and is the first drug in this class ro be cleared by the FDA for heart failure.

The approval of vericiguat by the FDA is based on the results of the pivotal Phase 3 VICTORIA trial and follows a priority regulatory review. Vericiguat 2.5 mg, 5 mg, and 10 mg tablets is being jointly developed with Bayer AG.

“Patients with symptomatic chronic heart failure and reduced ejection fraction have a high risk for hospitalization after experiencing symptoms of heart failure requiring outpatient IV diuretic treatment or hospitalization. By some estimates, more than half of these patients are rehospitalized within a month of discharge due to a worsening event and approximately one in five die within two years,” said Paul W. Armstrong, M.D., cardiologist and distinguished university professor of medicine at the Canadian Vigour Centre, University of Alberta, and study chair of the VICTORIA trial. “The approval of vericiguat provides doctors, health care professionals, and patients with a welcome new option to current available therapies.”

VICTORIA Trial Paves Way to Vericiguat Clearance

The approval of vericiguat was based on data from VICTORIA (NCT02861534),[1] a randomized, parallel-group, placebo-controlled, double-blind, event-driven, multi-center clinical trial comparing vericiguat to placebo in 5,050 adult patients with symptomatic chronic heart failure (New York Heart Association [NYHA] class II-IV) and left ventricular ejection fraction (LVEF) less than 45%, following a worsening heart failure event. A worsening heart failure event was defined as heart failure hospitalization within six months or less prior to randomization or use of outpatient IV diuretics for heart failure within three months or less prior to randomization.

In VICTORIA, the primary efficacy objective was to determine whether vericiguat is superior to placebo, both in combination with other heart failure therapies, in reducing the risk of cardiovascular death or heart failure hospitalization in adults with symptomatic chronic heart failure and ejection fraction less than 45% following a worsening heart failure event.

In VICTORIA, the primary endpoint was a composite of time to first event of cardiovascular death or hospitalization for heart failure. The median follow-up for the primary endpoint was 11 months. Verquvo was superior to placebo in reducing the risk of cardiovascular death or heart failure hospitalization based on a time-to-event analysis.

Vericiguat met the primary efficacy objective based on a time-to-event analysis (hazard ratio [HR]: 0.90, 95% confidence interval [CI], 0.82-0.98; p=0.019). Over the course of the study, there was a 4.2% reduction in annualized absolute risk with vericiguat compared with placebo. Therefore, 24 patients would need to be treated over an average of one year to prevent one primary endpoint event.

Patients received up to the target maintenance dose of vericiguat 10 mg once daily or matching placebo. Therapy was initiated at vericiguat 2.5 mg once daily and increased in approximately two-week intervals to 5 mg once daily and then 10 mg once daily, as tolerated. Placebo doses were similarly adjusted. After approximately one year, 90% of patients in both the vericiguat and placebo arms were treated with the 10 mg target maintenance dose.

Study participants were: 76% male, 64% Caucasian, 22% Asian, and 5% Black. The mean age was 67 years. At randomization, 59% of patients were NYHA Class II, 40% were NYHA Class III and 1% were NYHA Class IV. The mean LVEF was 29%. Approximately half of all patients had an EF less than 30%, and 14% of patients had an EF between 40% and 45%. Sixty-seven percent of the patients in VICTORIA were enrolled within three months of a heart failure hospitalization index event; 17% were enrolled within three to six months of heart failure hospitalization, and 16% were enrolled within three months of outpatient treatment with IV diuretics for worsening heart failure. The median NT-pro B-type natriuretic peptide (NT-proBNP) level was 2800 pg/mL at randomization.

Study participants were on standard of care. At baseline, 93% of patients were receiving a beta-blocker, 73% were receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), 70% were receiving a mineralocorticoid receptor antagonist (MRA), 15% were receiving a combination of an angiotensin receptor and neprilysin inhibitor (ARNI), 28% had an implantable cardiac defibrillator and 15% had a biventricular pacemaker. Ninety-one percent of patients were treated with two or more heart failure medications (beta blocker, any renin-angiotensin system [RAS] inhibitor or MRA) and 60% of patients were treated with all three. At baseline, 6% of patients were receiving ivabradine and 3% a sodium glucose co-transporter 2 (SGLT2) inhibitor.

In the VICTORIA trial, vericiguat demonstrated an adverse event profile similar to placebo. The adverse drug reactions occurring more commonly with vericiguat than placebo and in greater than or equal to 5% of patients treated with vericiguat in VICTORIA were hypotension (16% vs 15%) and anemia (10% vs 7%). The VICTORIA trial included a total of 2,519 patients treated with vericiguat (up to 10 mg once daily). The mean duration of vericiguat exposure was one year, and the maximum duration was 2.6 years.

About vericiguat tablets for once daily oral use (2.5 mg, 5 mg and 10 mg)

First sGC Drug Approvaled for Heart Failure

Soluble guanylate cyclase (sGC) is a key enzyme of the nitric oxide (NO) signaling pathway. A decade ago it attracted rapidly growing interest as a therapeutic target in cardiopulmonary disease, with several sGC agonists in clinical development. Upon binding of NO to a prosthetic heme group on sGC, the enzyme catalyzes synthesis of the second messenger cyclic guanosine monophosphate (cGMP), which produces vasorelaxation and inhibits smooth muscle proliferation, leukocyte recruitment and platelet aggregation through a number of downstream mechanisms.[1]

Riociguat was the first sGC stimulator approved in the United States in 2013 for the treatment of pulmonary arterial hypertension (PAH) and the treatment of chronic thromboembolic pulmonary hypertension.

Vericiguat is a stimulator of sGC. When NO binds to sGC, the enzyme catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP), a second messenger that plays a role in the regulation of vascular tone, cardiac contractility, and cardiac remodeling. Heart failure is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction. By directly stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cGMP, leading to smooth muscle relaxation and vasodilation.

About Heart Failure with Reduced Ejection Fraction

Heart failure with reduced ejection fraction (HFrEF), formerly known as systolic heart failure, is characterized by the compromised ability of the heart to pump blood sufficiently during its contraction phase. In the U.S., approximately 6.2 million adults (20 years of age and older) have heart failure, and approximately 50% of heart failure patients have HFrEF. An observational, cohort analysis of PINNACLE registry data showed that approximately half of patients with worsening chronic HFrEF are rehospitalized within 30 days of a worsening event, and an estimated one in five patients with worsening chronic HFrEF will die within two years.

The vericiguat label contains a boxed warning that indicates that vericiguat should not be administered to pregnant females because it may cause fetal harm. Link to Verquvo Safety Information.

Prescribing Information, including Boxed Warning