Bayer's First-in-Class sGC Stimulator Verquvo (Vericiguat) Approved in Japan for Chronic Heart Failure, Under Regulatory Review in China

June 24, 2021 /BioonBIOON/ --Bayer(Bayer) recently announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has approvedVerquvo (vericiguat, 2.5 mg, 5 mg, 10 mg tablets) is a soluble guanylate cyclase (sGC) stimulator indicated for the treatment of patients with chronic heart failure (CHF) who are receiving standard therapy for CHF, to reduce the risk of further worsening events.The approval was based on the results of the pivotal Phase 3 VICTORIA trial, which specifically targeted patients who had recently experienced a worsening heart failure event (recent hospitalization for heart failure or use of intravenous diuretics), with the corresponding data published in the *New England Journal of Medicine* (NEJM) in March 2020.

Vericiguat was jointly developed by Merck and Bayer. The two companies entered into a global collaboration in October 2014 to develop sGC stimulators. Merck holds the commercialization rights for vericiguat in the United States, while Bayer holds exclusive rights for the rest of the world.

This drug is an oral, once-daily, first-in-class soluble guanylate cyclase (sGC) stimulator. sGC is a key enzyme in the nitric oxide (NO) signaling pathway. When NO binds to sGC, the enzyme catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP). As a second messenger, cGMP plays a role in regulating vascular tone, cardiac contractility, and cardiac remodeling. Heart failure is associated with impaired NO synthesis and reduced sGC activity, which may lead to myocardial and vascular dysfunction. By directly stimulating sGC, vericiguat acts independently of and synergistically with NO to increase intracellular cGMP levels, thereby counteracting impaired cardiac and vascular function.

It is worth noting that,Vericiguat is the first sGC stimulator approved for the treatment of heart failure.In January this year, vericiguat received U.S.FDAApproved under the brand name Verquvo, it is indicated for patients with symptomatic chronic heart failure and an ejection fraction <45% to reduce the risk of cardiovascular death and heart failure hospitalization following a worsening heart failure event (defined as hospitalization for heart failure or outpatient intravenous [IV] diuretic therapy for heart failure without hospitalization). In May this year, vericiguat received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), recommending the granting of a marketing authorization for the treatment of adult patients with symptomatic chronic heart failure with reduced ejection fraction who have stabilized following a recent decompensation event requiring intravenous (IV) therapy.

Currently, vericiguat is also under regulatory 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.

Chemical structure of vericiguat (Image source: medchemexpress.com)

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

Regulatory approval of vericiguat, based on the results of the pivotal Phase III VICTORIA study. Data show that,Following a worsening heart failure event, vericiguat plus background therapy significantly reduced the composite risk of cardiovascular death or heart failure hospitalization compared with background therapy alone.The positive results of the Phase III VICTORIA trial were presented at the American College of Cardiology Annual Scientific Session held in March 2020Meeting/Presented at the World Congress of Cardiology (ACC.20/WCC Virtual) virtual conference and published in the premier international medical journal *The New England Journal of Medicine* (NEJM). The title of the article is:Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction。

It is worth noting that,VICTORIA is the first contemporary outcomes study specifically designed for patients with symptomatic chronic heart failure (ejection fraction < 45%) following a worsening event.. Data show,When used in combination with available heart failure medications, compared with placebo, a once-daily 10 mg dose of vericiguat significantly 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 can lead to clinical deterioration and a poor prognosis, with approximately 50% of patients unfortunately dying within 5 years of diagnosis. The VICTORIA trial was the first positive contemporary outcomes trial specifically targeting patients with symptomatic chronic heart failure with reduced ejection fraction and a prior history of worsening heart failure events. The findings of this study have opened up new possibilities for the treatment of chronic heart failure.

VICTORIAClinical Trial# Results

VICTORIA was a randomized, placebo-controlled, parallel-group, multicenter, double-blind Phase III study conducted at more than 600 clinical centers in 42 countries worldwide, enrolling 5,050 patients with symptomatic chronic heart failure who had experienced a heart failure worsening 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), in addition to 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 annualized placebo event rate for the primary endpoint was more than twofold higher, and baseline levels of the clinical prognostic biomarker (NT-proBNP) were also more than twofold higher, indicating a substantially higher risk of hospitalization or death in these patients.

The results showed that the study met its primary efficacy endpoint: when used in combination with available heart failure medications, a once-daily 10 mg dose of vericiguat, compared with placebo, 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 per 100 patient-years).

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

In the baseline NT-proBNP analysis, patients were divided into 4 quartiles. The overall treatment benefit was driven by patients in the lower 3 quartiles, among whom the relative risk reduction for the primary composite endpoint ranged from 18% to 27%.

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. (Bioon.com)

Original Source:Vericiguat approved in Japan to treat patients with chronic heart failure