Vericiguat

Abstract

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GENERIC NAME: VERICIGUAT

PROPRIETARY NAME: Verquvo (Merck & Co Inc)

APPROVAL RATING: 1P

THERAPEUTIC CLASS: Soluble Guanylate Cyclase Stimulator

SIMILAR DRUGS: Dapagliflozin, Riociguat, Sacubitril/Valsartan

SOUND-/LOOK-ALIKE NAMES: Venlafaxine

INDICATIONS: Vericiguat is approved by the Food and Drug Administration (FDA) to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following a hospitalization for HF or need for outpatient intravenous (IV) diuretics in adults with symptomatic chronic HF and ejection fraction less than 45%. ¹

CLINICAL PHARMACOLOGY: Vericiguat is a stimulator of soluble guanylate cyclase (sGC), an important enzyme in the nitric oxide (NO) signaling pathway. When NO binds to sGC, the enzyme catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP) production.^1-4 The increase in levels of cGMP activates effector molecules, with cGMP-dependent protein kinases (PKGs) and phosphodiesterases (PDEs) predominating in the cardiovascular system. The cGMP-PKG signaling within the vascular endothelium stimulates cell proliferation and increases permeability; in vascular smooth muscle, it inhibits cell proliferation and mediates vasorelaxation; and in cardiac myocardium, it inhibits hypertrophy and modulates contractility. cGMP-PKG signaling also mediates cellular apoptosis in all 3 of these tissues.^4,5 Cyclic nucleotide PDEs are also involved in the breakdown of cGMP into GMP. ⁴ Therefore, inhibition of PDEs to enhance cGMP signaling within the cardiovascular system is beneficial for the treatment of a variety of cardiovascular diseases, specifically in vascular endothelial and smooth muscle cells and in cardiac myocytes. ⁵

HF is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction. The increase in cGMP levels after administration of vericiguat can lead to smooth muscle relaxation and vasodilation and thus to improvement of the signs and symptoms of HF. ¹

The average reduction in systolic blood pressure was 1 to 2 mm Hg greater with vericiguat compared with placebo. Additionally, patients had a dose-dependent reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) after 12 weeks of vericiguat plus standard of care treatment; estimated reduction from baseline was greater with vericiguat than placebo at week 32. These beneficial changes occurred without any evidence of proarrhythmic risk or meaningful changes in QTc prolongation. ¹

PHARMACOKINETICS: Vericiguat is a low-soluble, low-clearance, highly permeable, and weakly basic Biopharmaceutics Classification System class II drug that demonstrates linear pharmacokinetics. It has high bioavailability and low variability when given with food. ⁶ Absolute bioavailability after administration with food is 93%. When administered with a high-fat, high-calorie meal, T_max was increased to 4 hours (from 1 hour in the fasted state), AUC increased by 44%, and C_max increased by 41%. If the tablet is crushed and mixed with water, bioavailability is unaltered. ¹

Mean volume of distribution is approximately 44 L in healthy subjects. Protein binding is 98%, mainly to serum albumin.^1,6

The mean total radioactivity of vericiguat recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). ⁶ The half-life of vericiguat is 30 hours in patients with HF. ¹ Vericiguat clearance was 1.6 L/hour in healthy volunteers and 1.3 L/hour in patients with HF with reduced ejection fraction.^1,6

In vitro studies have shown that glucuronidation of vericiguat is primarily mediated by UGT1A9 and 1A1 to form an inactive N-glucuronide metabolite; glucuronidation could be preferentially catalyzed via UGT1A9 more than via UGT1A1. These studies also showed that vericiguat is not a substrate of OATP1B1, OATP1B3, or OCT1. ⁶

In vitro and phase 1 drug-drug interaction studies show vericiguat has a low risk of acting as a perpetrator by inhibiting CYP-450, UGT isoforms, or major transport proteins, or by inducing CYP-450. Thus, the potential is low for vericiguat to cause drug-drug interactions when coadministered. ⁶

No clinically significant differences in the pharmacokinetics of vericiguat were observed based on age, sex, race/ethnicity (Black, White, Asian, Hispanic, Latino), body weight, or baseline NT-proBNP. ¹

Comparative Efficacy

Indication: Heart Failure with Reduced Ejection Fraction

Guidelines

Guideline: 2017 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) focused update of the 2013 American College of Cardiology Foundation (ACCF)/AHA guideline for the management of heart failure.

Reference: Yancy et al. ⁷

Comments: Following diagnosis of HF with reduced ejection fraction, guideline-directed management, and therapy should be initiated. For patients with HF with reduced ejection fraction (New York Heart Association [NYHA] class I-IV), recommended pharmacologic treatment is an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker, with diuretics used as needed. The following patient scenarios should then be considered and guideline-directed management and therapy implemented: for those with NYHA class II to IV (provided CrCl is greater than 30 mL/minute and potassium level is less than 5 mEq/L), an aldosterone antagonist is recommended; in the case of NYHA class II to III HF and adequate blood pressure while on ACE inhibitor or ARB and no contraindication to ARB or sacubitril, the ACE inhibitor or ARB should be discontinued and angiotensin receptor–neprilysin inhibitor initiated; in Black patients with NYHA class III to IV, hydralazine and nitrates are recommended; and in patients with NYHA class II to III, normal sinus rhythm, and heart rate at least 70 beats per minute on maximally tolerated beta-blocker dose, ivabradine is recommended. Guideline-directed management and therapy should be continued, with serial reassessment and optimized dosing/adherence. When the guideline was developed, dapagliflozin and vericiguat were not FDA approved for the management of HF.

Guideline: Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices, and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology (ESC/HFA).

Reference: Seferovic et al. ⁸

Comments: The clinical practice update is not a formal guideline update or position statement, but is a report from the ESC/HFA workshop that contains new recommendations based on major trials published since 2016. The next European Society of Cardiology update guideline for the diagnosis and treatment of acute and chronic HF is planned for 2021. According to the report, empagliflozin, canagliflozin, or dapagliflozin should be considered for patients with type 2 diabetes mellitus who either have established cardiovascular disease or are at high cardiovascular disease risk, to prevent or delay onset of and hospitalization for HF. There is insufficient evidence for the use of canakinumab in patients with HF. Sacubitril/valsartan is recommended as a replacement for ACE inhibitors/ARBs to reduce the risk of HF hospitalization and death in ambulatory patients with HF with reduced ejection fraction who remain symptomatic despite optimal medical treatment with an ACE inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist. A beta-blocker may be considered for ambulatory patients with symptomatic HF with mid-range ejection fraction in sinus rhythm to reduce the risk of all-cause and cardiovascular death. Candesartan may be considered for ambulatory patients with symptomatic HF with mid-range ejection fraction to reduce the risk of HF hospitalization and cardiovascular death. Spironolactone may be considered for ambulatory patients with symptomatic HF with mid-range ejection fraction without contraindications to reduce the risk of HF hospitalization and cardiovascular death. Evidence is insufficient to provide recommendations regarding IV iron. Vericiguat was not approved at the time the guideline was published.

Studies

Drug: Vericiguat versus Placebo

Reference: Armstrong et al ² (VICTORIA trial)^9,10

Study Design: Phase 3, randomized, double-blind, placebo-controlled, multicenter trial

Study Funding: Merck; Bayer

Patients: Five thousand fifty adults (at least 18 years of age) with chronic HF (NYHA class II, III, or IV), reduced left ejection fraction less than 45% within 12 months before randomization, and an elevated natriuretic peptide level within 30 days before randomization. For patients in sinus rhythm, criteria included a plasma B-type natriuretic peptide (BNP) level at least 300 pg/mL or an NT-proBNP level of at least 1000 pg/mL. For patients in atrial fibrillation, criteria included a BNP level of at least 500 pg/mL or an NT-proBNP level of at least 1600 pg/mL. Patients had to have evidence of worsening HF and were categorized into 3 cohorts based on timing of deterioration: those hospitalized within 3 months before randomization; those hospitalized 3 to 6 months before randomization; and those receiving IV diuretic therapy, without hospitalization, within the previous 3 months. The percentage of patients with an eGFR of 15 to 30 mL/minute/1.73m² of body surface area was capped at 15%. All patients received guideline-based background medical therapy in addition to the study drug. Exclusion criteria included systolic blood pressure less than 100 mm Hg or symptomatic hypotension; concurrent or anticipated use of long-acting nitrates, sGC stimulators (eg, riociguat for pulmonary hypertension), or phosphodiesterase type 5 (PDE-5) inhibitors (eg, sildenafil); use of IV inotropes or has/anticipates an implantable left ventricular assist device; severe renal impairment (eGFR less than 15 mL/minute) or requiring chronic dialysis; severe hepatic insufficiency; or other significant cardiac or noncardiac comorbidities. A total of 2526 patients were randomly assigned to receive vericiguat, and 2524 were assigned to receive placebo; 7 patients and 9 patients, respectively, did not receive the assigned vericiguat or placebo. Mean patient age was 67.3 years; 76.1% of patients were male, and 23.9% were female; 64.1% were White, 4.9% were Black, 22.4% were Asian, and 8.5% were other races. Patients were enrolled from 5 geographic regions: Eastern Europe (33.5%), Western Europe (17.6%), Asia-Pacific (24.4%), Latin America (14.3%), and North America (11.1%). Rate of hospitalization for HF in the previous 3 months was 66.9%, rate of hospitalization for HF in the previous 3 to 6 months was 17.2%, and 15.9% of patients required IV diuretic therapy for HF (without hospitalization) in the previous 3 months. Incidence of baseline ejection fraction less than 40% was 85.7%; 59% of patients had NYHA class II HF, 39.7% had NYHA class III HF, and 1.3% had NYHA class IV HF. The percentage of HF patients receiving triple therapy (a beta-blocker and a mineralocorticoid antagonist combined with either an ACE inhibitor, an ARB, or sacubitril/valsartan) was 59.7%; nearly 90% of patients were receiving 2 HF medications, and 15% were receiving an angiotensin receptor–neprilysin inhibitor.

Intervention: Patients were randomized (1:1) to receive vericiguat 10 mg orally once daily or placebo. The starting vericiguat dosage was 2.5 mg orally once daily for 2 weeks. The dosage was then increased to 5 mg orally once daily for 2 weeks. The target, and maximum allowable, dosage was 10 mg daily based on patient blood pressure and clinical HF symptoms. The systolic blood pressure criteria for study treatment dose modification were as follows: If patient systolic blood pressure was 100 mm Hg or higher, the dose could be increased to the target 10 mg dose, or maintained at 10 mg if already receiving the target dose; if systolic blood pressure was 90 to less than 100 mm Hg, the 10 mg dose was maintained; if systolic blood pressure was less than 90 mm Hg and the patient was asymptomatic, current doses of 5 or 10 mg could be reduced, or therapy interrupted if the current vericiguat dose was 2.5 mg; and if systolic blood pressure was less than 90 mm Hg and the patient was symptomatic, the dose was interrupted. Patients were stratified by geographic region, as well as by race in the North American cohort. All patients continued to receive guideline-based background therapy for their HF.

Results

Primary End Point(s):

• Composite of death from cardiovascular causes or first hospitalization for HF event occurred in 35.5% of the vericiguat group and 38.5% of the placebo group; hazard ratio (HR) was 0.9 (95% CI, 0.82-0.98; P = .02).

Secondary End Point(s):

• Death from cardiovascular causes occurred in 16.4% of the vericiguat group and 17.5% of the placebo group; HR was 0.93 (95% CI, 0.81-1.06).

• Hospitalization for HF occurred in 27.4% of the vericiguat group and 29.6% of the placebo group; HR was 0.9 (95% CI, 0.81-1).

• Total hospitalization for HF: 38.3 events per 100 patient-years with vericiguat and 42.4 events per 100 patient-years with placebo; HR was 0.91 (95% CI, 0.84-0.99; P = .02).

• Death from any cause or first hospitalization for HF (a composite secondary outcome) occurred in 37.9% of the vericiguat group and 40.9% of the placebo group; HR was 0.9 (95% CI, 0.83-0.98; P = .02).

• Death from any cause occurred in 20.3% of the vericiguat group and 21.2% of the placebo group; HR was 0.95 (95% CI, 0.84-1.07; P = .38).

Other End Point(s):

• Adverse events (serious and nonserious) occurred in 80.5% of patients receiving vericiguat and in 81% of those receiving placebo.

• Symptomatic hypotension occurred in 9.1% of patients in the vericiguat group and in 7.9% of those in the placebo group (P =. 12).

• Syncope occurred in 4% of patients in the vericiguat group and in 3.5% of those in the placebo group (P = .3).

• Anemia developed in more patients in the vericiguat group than in the placebo group (7.6% vs 5.7%); of these cases, 1.6% (in the vericiguat group) and 0.9% (in the placebo group) were considered serious adverse events. The baseline mean hemoglobin level was 13.3 g/dL in the vericiguat group and 13.4 g/dL in the placebo group, and the change from baseline in hemoglobin level at week 16 was −0.38 and −0.14 g/dL, respectively.

Comments: Patients were enrolled at 616 sites in approximately 40 countries. Efficacy outcomes were reported using the intention-to-treat cohort, with use of time-to-event analyses and censoring for those who withdrew or were lost to follow-up. Adherence of 80% or higher was achieved in 93.8% of the vericiguat group and 93.4% of the placebo group. The median dose of study medication was 9.2 mg in the vericiguat group and 9.2 mg in the placebo group. After approximately 12 months, 89.2% of the vericiguat group and 91.4% of the placebo group were receiving the target dose. The median follow-up period was 10.8 months.

Based on the absolute risk reduction, the number needed to treat with vericiguat for 1 year to prevent a primary outcome event is approximately 34. Subgroup analysis based on sex, age, race, geographic region, race in North America, index event, NYHA class, use of sacubitril/valsartan, eGFR, and ejection fraction showed that the effect of vericiguat on the primary outcome was consistent among most prespecified subgroups. Incidence of death from cardiovascular cause or hospitalization for HF was lower among those who received vericiguat than among those who received placebo. When vericiguat was added to background therapy, it reduced the risk of worsening HF and improved survival.

Limitations: Only 11% of study participants were from North America; 14.5% were concomitantly receiving an angiotensin receptor–neprilysin inhibitor (sacubitril/valsartan), and 59.7% were receiving 3 HF therapies. Beta-blocker use (93.1%) was reported by drug class and not by the individual drug (eg, carvedilol, metoprolol). The study did not report the average dose of each drug treatment or whether all background therapies had been optimized. The study duration was less than 1 year (median follow-up, 10.8 months); therefore, prolonged efficacy is unknown.

Results from the VICTORIA trial confirm observations from 3 phase 2 studies (SOCRATES-REDUCED [in patients with LVEF less than 45%], SOCRATES-PRESERVED [in those with LVEF 45% or higher], and VITALITY-HFpEF).^11-17

Contraindications, Warnings, and Precautions

CONTRAINDICATIONS: Vericiguat is contraindicated with concomitant use of other sGC stimulators (eg, riociguat). ¹

Vericiguat is contraindicated in pregnancy. ¹

Though not stated in the product labeling, a potential contraindication is hypersensitivity to vericiguat or any of its inactive ingredients (tablets: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate; film coating: hypromellose, talc, titanium dioxide, ferric oxide red [5 mg tablet], or ferric oxide yellow [10 mg tablet]). ¹

WARNINGS AND PRECAUTIONS: Vericiguat product labeling includes a boxed warning regarding the risk of embryo-fetal harm if used during pregnancy. Based on animal reproductive studies, vericiguat may cause fetal harm when administered to a pregnant woman and must be avoided during pregnancy. Pregnancy must be ruled out prior to the start of treatment. Advise females of reproductive potential to use effective forms of contraception during treatment and for 1 month after the final dose. ¹

There are no data regarding the presence of vericiguat or its metabolites in human milk, or their effects on breastfeeding infants or milk production. Because of the potential for serious adverse reactions in a breastfeeding infant, the manufacturer recommends that women be advised not to breastfeed during treatment. ¹

Safety and effectiveness of vericiguat have not been established in pediatric patients. ¹

ADVERSE REACTIONS: The most common adverse reactions associated with vericiguat include symptomatic hypotension, anemia, and dizziness (see Table 1).^1,2

Table 1.

Adverse Reactions (Incidence ≥5%) Reported in the VICTORIA Study. ²

Adverse reaction	Vericiguat (n = 2519) (%)	Placebo (n = 2515) (%)
Hypotension	15.4	14.1
Symptomatic hypotension	9.1	7.9
Cardiac failure	8.9	9.9
Anemia	7.6	5.7
Dizziness	6.7	6
Acute kidney injury	5.3	5
Dyspnea	5.3	5.1
Diarrhea	5.2	4.9

DRUG INTERACTIONS: Vericiguat is contraindicated with concomitant use of other sGC stimulators (eg, riociguat). ¹

Concurrent use with sildenafil may result in increased exposure (up to 22.4%) to sildenafil and may increase the risk of symptomatic hypotension. Concomitant use of vericiguat and PDE-5 inhibitors, such as sildenafil, is not recommended.^1,6

Pre- or coadministration of vericiguat with proton pump inhibitors or antacids may result in reduced AUC (approximately 30%); however, no dose adjustment is recommended. ⁶

Coadministration with CYP, UGT, and transporter protein inducers and inhibitors resulted in non-clinically significant increases or reductions in vericiguat AUC and C_max. ⁶

Vericiguat has a low risk of acting as a perpetrator that causes serious drug-drug interactions. No significant differences were observed when vericiguat was given alone in comparison with its coadministration with warfarin, aspirin, digoxin (P-gp substrate), mefenamic acid (UGT1A9 inhibitor), ketoconazole (multipathway CYP and transporter inhibitor), atazanavir (UGT1A1 inhibitor), rifampin (inducer), midazolam (CYP3A substrate), sacubitril/valsartan, or sildenafil.^1,6 No clinically significant changes in bleeding time or platelet aggregation were observed when a single vericiguat dose (15 mg) was coadministered with aspirin 500 mg; no significant differences were observed in prothrombin time or activities of factors II, VII, and X when multiple doses of vericiguat 10 mg once daily were coadministered with a single dose of warfarin 25 mg. In vitro, vericiguat is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and is not an inducer of CYP1A2, 2B6, or 3A4. Vericiguat is not an inhibitor of UGT1A1, 1A4, 1A6, 1A9, 2B4, or 2B7. Vericiguat is a substrate of P-gp and BCRP but is not a substrate of OCT1 or OATP1B1 and OATP1B3. Vericiguat is not an inhibitor of P-gp, BCRP, BSEP, OATP1B1/1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K. ¹

Coadministration of vericiguat and nitroglycerin is generally well tolerated and is unlikely to cause adverse effects beyond those known for nitroglycerin.^1,18 There were no differences in seated blood pressure in healthy subjects given sacubitril/valsartan concomitantly with vericiguat. ¹

RECOMMENDED MONITORING: No special monitoring is required.

DOSING: The recommended initial vericiguat dosage is 2.5 mg orally once daily with food. The dosage can be increased at 2-week intervals, as tolerated by the patient, up to the target maximum maintenance dosage of 10 mg once daily.^1,2 In the VICTORIA study, the dose was adjusted based on patient systolic blood pressure and tolerability. ⁹

No dosage adjustments are recommended for patients with an eGFR greater than or equal to 15 mL/minute/1.73 m² who are not on dialysis, or for those with mild or moderate hepatic impairment (eg, Child-Pugh class A or B). Vericiguat has not been studied in patients with eGFR less than 15 mL/minute/1.73 m² at treatment initiation or who are on dialysis, or in patients with severe hepatic impairment (eg, Child-Pugh class C). ¹

If the patient is unable to swallow whole tablets, the tablets can be crushed and mixed with water immediately before administration. ¹

PRODUCT AVAILABILITY AND STORAGE: In July 2020, the FDA classified the vericiguat New Drug Application as a priority review. The Prescription Drug User Fee Act date was set for January 20, 2021. ¹⁹ Vericiguat was approved by the FDA on January 19, 2021. ²⁰

Vericiguat is available as 2.5, 5, and 10 mg tablets. The 2.5 and 5 mg tablets are available in 14- and 30-count bottles, while the 10 mg tablets are available in 30- and 90-count bottles. All 3 dose strengths are also available in cartons containing 10 blister cards of 10 tablets. ¹

The vericiguat tablets should be stored at 20°C to 25°C (68°F-77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). ¹

Drug Safety/REMS: No REMS is required for vericiguat. ¹

CONCLUSION: Vericiguat, a new sGC stimulator, is approved to reduce the risk of cardiovascular death and HF hospitalization following a hospitalization for HF or need for outpatient IV diuretics in adults with symptomatic chronic HF and ejection fraction less than 45%. Vericiguat is not a substitute for previously approved HF drugs, but is added to the existing guideline-based background therapy; addition of vericiguat was well tolerated in a clinical trial. The most common adverse reactions associated with vericiguat included hypotension, symptomatic hypotension, anemia, and dizziness. There are no comparison studies with other adjunctive therapies (eg, sacubitril/valsartan, dapagliflozin).