Bayer’s First-in-Class sGC Stimulator Verquvo (vericiguat) Approved in EU for Heart Failure, Under Regulatory Review in China

July 22, 2021 /BioonBIOON/ --Bayer(Bayer) recently announced that the European Commission (EC) has approved Verquvo (vericiguat, 2.5 mg, 5 mg, 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 targeted patients who experienced a recent heart failure worsening event (recent hospitalization for heart failure or use of intravenous diuretics). Results showed that,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, impaired nitric oxide (NO) availability in patients with heart failure leads to insufficient sGC stimulation, resulting in myocardial and vascular dysfunction. vericiguat was co-developed by Merck and Bayer, following a global collaboration agreement established 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.

The mechanism of action of Verquvo differs from existing heart failure treatments, offering a distinct approach to managing patients with chronic heart failure following a decompensation event (also known as a worsening event). Current treatments counteract the detrimental effects of the endogenous neurohormonal systems, which are activated by myocardial and vascular dysfunction occurring 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 key 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 of this year, Verquvo was approved in the United States for symptomatic patients with 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 receiving outpatient intravenous [IV] diuretic therapy for heart failure without being hospitalized). In June of this year, Verquvo was approved in Japan 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. 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.

Dr. Michael Devoy, Chief Medical Officer and Head of Medical Affairs and Pharmacovigilance at Bayer's Pharmaceuticals Division, said: “The approval of Verquvo in the EU marks a major breakthrough for patients with heart failure. Heart failure is the leading cause of hospitalization in Europe. With half of all patients readmitted within 30 days of hospitalization or the initiation of intravenous diuretics, we believe that the launch of Verquvo will provide clinicians with a much-needed new option to help reduce the significant burden of chronic heart failure.”

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

Patients with symptomatic chronic heart failure and reduced ejection fraction are at high risk of hospitalization after experiencing heart failure symptoms that require outpatient intravenous diuretic therapy or inpatient treatment. It is estimated that more than half of patients are readmitted within one month of discharge due to clinical deterioration, and approximately one-fifth of patients die within two years. Following its market launch, vericiguat 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 III VICTORIA trial. Data demonstrated that, following a worsening heart failure event, vericiguat in combination with background therapy significantly reduced the composite risk of cardiovascular death or hospitalization for heart failure compared with background therapy alone. The positive results from the Phase III VICTORIA trial were presented at the American College of Cardiology Annual Scientific Session held in March 2020.Conference/ presented at the virtual World Congress of Cardiology (ACC.20/WCC Virtual) 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。

VICTORIA was the first contemporary outcomes trial specifically targeting patients with symptomatic chronic heart failure (ejection fraction <45%) following a worsening event. Data showed that, when used in combination with available heart failure medications, vericiguat at a dose of 10 mg once daily, compared with placebo,`Significantly reduced the relative risk of the composite endpoint of hospitalization for heart failure and cardiovascular death following a worsening event by 10%`(HR=0.90; 95% CI: 0.82-0.98; p=0.019), 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 five 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 who had previously experienced a worsening heart failure event. The findings of this trial open up new possibilities for the treatment of chronic heart failure.

Dr. Burkert Pieske, Principal Investigator of the pivotal Phase 3 VICTORIA trial and Professor of Internal Medicine and Cardiology at Charité – Universitätsmedizin Berlin, Germany, stated: “With this latest approval, we have the potential to bring new hope to patients with heart failure by breaking the cycle of decompensation events (worsening events) and reducing the risk of rehospitalization. Rehospitalization has a significant impact on both patients and their families, and even while receiving guideline-directed medical therapy, many patients continue to experience progressive worsening of symptoms. Therefore, the availability of a new therapy specifically developed for these patients is highly welcome news.”

VICTORIAClinical TrialResults

VICTORIA was a randomized, placebo-controlled, parallel-group, multicenter, double-blind phase III study conducted at more than 600 clinical centers across 42 countries worldwide, enrolling 5,050 patients with symptomatic chronic heart failure, an ejection fraction of less than 45%, and a recent heart failure worsening event. In the study, patients were randomized to receive vericiguat once daily (titrated to 10 mg; n=2,526) or placebo (n=2,524) in addition to standard heart failure pharmacotherapy. The primary endpoint was a composite of cardiovascular death or heart failure hospitalization. Compared with recent heart failure outcomes trials, the annual placebo event rate for the primary endpoint was more than twofold higher, and baseline levels of the clinical prognostic marker NT-proBNP were also more than twofold higher, indicating a substantially elevated risk of hospitalization or death in this patient population.

The results showed that the study met its primary efficacy endpoint: when used in combination with available heart failure medications, compared with placebo, a once-daily 10 mg dose of vericiguat willThe composite risk of hospitalization for heart failure and cardiovascular death was significantly reduced by 10% following worsening events.(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 in most pre-specified subgroups., including patients who received or did not receive Entresto (sacubitril/valsartan). Baseline NT-proBNP levels and age were associated with treatment efficacy. In this study, data suggest that most patients with NT-proBNP levels in the lower quartile range and those aged under 75 years may have derived greater benefit.

In the baseline NT-proBNP analysis, patients were divided into four quartiles. The overall treatment benefit was driven by patients in the lower three 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:Bayer’s new symptomatic chronic heart failure treatment Verquvo™ (vericiguat) approved in EU