Verquvo vericiguat 5 mg Tablet, Film Coated, 14-count — NDC 0006-5029-06 (Billing 00006-5029-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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), 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.

12.2Pharmacodynamics The mean reduction in systolic blood pressure was approximately 1 to 2 mm Hg greater in patients who received VERQUVO compared with placebo. VERQUVO demonstrated a dose-dependent reduction in NT-proBNP, a biomarker in heart failure, at 12 weeks compared to placebo when added to standard of care. The estimated reduction from baseline NT-proBNP at week 32 was greater in patients who received VERQUVO compared with placebo [see Clinical Studies (14) ] .

Cardiac Electrophysiology There was no evidence of proarrhythmic risk in an in vitro assessment of vericiguat or its major N-glucuronide metabolite. No inhibition of cardiac ion channels (hERG, hNav1.5, or hKvLQT1/mink) was observed at substantial multiples of their unbound C max values at the recommended target dose of 10 mg. The integrated risk assessment of nonclinical and clinical data supports that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation.

Drug Interaction Studies No clinically significant differences on bleeding time or platelet aggregation were observed when a single dose of vericiguat 15 mg was used concomitantly with 500 mg of aspirin. No clinically significant differences in prothrombin time or the activities of Factors II, VII, and X were observed when multiple doses of VERQUVO 10 mg once daily were used concomitantly with a single dose of warfarin 25 mg. No clinically significant differences on seated blood pressure (BP) were observed when multiple doses of VERQUVO 2.5 mg were used concomitantly with sacubitril/valsartan in healthy subjects.

No clinically significant differences on seated BP were observed when multiple doses of VERQUVO 10 mg were used concomitantly with short- and long-acting nitrates (nitroglycerin spray and isosorbide mononitrate [ISMN] modified release 60 mg) in patients with coronary artery disease. In patients with heart failure, concomitant use with short-acting nitrates was well tolerated, but there is limited experience with long-acting nitrates. Concomitant use of VERQUVO 10 mg with single doses of sildenafil (25, 50, or 100 mg) was associated with additional seated BP reduction of up to 5.4 mm Hg (systolic/diastolic BP, MAP), compared to administration of VERQUVO alone.

There is limited experience with concomitant use of VERQUVO and PDE-5 inhibitors in patients with heart failure.

12.3Pharmacokinetics Vericiguat steady-state mean (coefficient of variation %) C max is 350 mcg/L (29%) and AUC is 6,680 mcg•h/L (33.9%) following administration of VERQUVO 10 mg in patients with heart failure. Vericiguat pharmacokinetics increases in a slightly less than dose-proportional manner. Vericiguat accumulates in plasma up to 155-171% and reaches steady-state after approximately 6 days.

Absorption The absolute bioavailability of vericiguat is 93% when taken with food. Results were comparable when VERQUVO was administered orally as a whole tablet or as a crushed tablet in water. Effect of Food Administration of VERQUVO 10 mg with a high-fat, high-calorie meal increases T max from about 1 hour (fasted) to about 4 hours (fed), reduces PK variability, and increases vericiguat AUC by 44% and C max by 41% compared with administration in the fasted state.

Simila… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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), 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.

12.3Pharmacokinetics Vericiguat steady-state mean (coefficient of variation %) C max is 350 mcg/L (29%) and AUC is 6,680 mcg•h/L (33.9%) following administration of VERQUVO 10 mg in patients with heart failure. Vericiguat pharmacokinetics increases in a slightly less than dose-proportional manner. Vericiguat accumulates in plasma up to 155-171% and reaches steady-state after approximately 6 days.

Absorption The absolute bioavailability of vericiguat is 93% when taken with food. Results were comparable when VERQUVO was administered orally as a whole tablet or as a crushed tablet in water. Effect of Food Administration of VERQUVO 10 mg with a high-fat, high-calorie meal increases T max from about 1 hour (fasted) to about 4 hours (fed), reduces PK variability, and increases vericiguat AUC by 44% and C max by 41% compared with administration in the fasted state.

Similar results were obtained when VERQUVO was administered with a low-fat, low-calorie meal when compared to administration with a high-fat, high-calorie meal. Distribution The mean steady-state volume of distribution of vericiguat is approximately 44 L in healthy subjects. Protein binding (primarily to serum albumin) of vericiguat is about 98%.

Elimination The half-life of vericiguat is 30 hours in patients with heart failure. Clearance in healthy subjects is

1.6L/h. Metabolism Vericiguat primarily undergoes glucuronidation by UGT1A9 and to a lesser extent, by UGT1A1 to form an inactive N-glucuronide metabolite. CYP-mediated metabolism is a minor clearance pathway (<5%).

Excretion Following oral administration of radiolabeled vericiguat to healthy subjects, approximately 53% of the dose was excreted in urine (primarily as inactive metabolite) and 45% in feces (primarily as unchanged drug). Specific Populations Renal Impairment In patients with heart failure with mild, moderate, and severe renal impairment not requiring dialysis, the mean exposure (AUC) of vericiguat was increased by 5%, 13%, and 20% respectively, compared to patients with normal renal function. These differences in exposure are not considered clinically relevant.

The pharmacokinetics of vericiguat have not been studied in patients with eGFR <15 mL/min/1.73m 2 at treatment initiation or on dialysis [see Use in Specific Populations (8.6) ] . In a dedicated clinical pharmacology study, otherwise healthy participants with mild, moderate, and severe renal impairment, had 8%, 73%, and 143% respectively, higher mean vericiguat exposure (unbound AUC normalized for body weight) after a single dose compared to healthy controls. The apparent discrepancy of the effect of renal impairment on vericiguat exposure between the dedicated clinical pharmacology study and the analysis in patients with heart failure may be attributed to differences in study design and size.

Hepatic Impairment No clinically relevant increases in exposure (unbound AUC normalized for body weight) were observed for individuals with mild and moderate hepatic impairment (Child Pugh A-B). Mean vericiguat exposures were 21% and 47% higher, respectively, compared to individuals with normal hepatic function. The pharmacokinetics of vericiguat have not been studied in patients with severe hepatic impairment (e.g., Child-Pugh C) [see Use in Specific Populations (8.7) ] .

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. Effects of specific populations on the pharmacokinetics of vericiguat are shown in Figure 1 . Figure 1: Pharmacokinetics of Vericiguat in Specific Populations Drug Interaction Studies Clinical Studies Effects of Other Drugs on the Pharmacokinetics of Vericiguat Vericiguat is less soluble at neutral than at acidic pH.

Pre- and co-treatment with drugs that increase gastric pH, such as proton pump inhibitors or antacids, decrease vericiguat exposure (AUC) by about 30% following fasted admini… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The mean reduction in systolic blood pressure was approximately 1 to 2 mm Hg greater in patients who received VERQUVO compared with placebo. VERQUVO demonstrated a dose-dependent reduction in NT-proBNP, a biomarker in heart failure, at 12 weeks compared to placebo when added to standard of care. The estimated reduction from baseline NT-proBNP at week 32 was greater in patients who received VERQUVO compared with placebo [see Clinical Studies (14) ] .

Cardiac Electrophysiology There was no evidence of proarrhythmic risk in an in vitro assessment of vericiguat or its major N-glucuronide metabolite. No inhibition of cardiac ion channels (hERG, hNav1.5, or hKvLQT1/mink) was observed at substantial multiples of their unbound C max values at the recommended target dose of 10 mg. The integrated risk assessment of nonclinical and clinical data supports that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation.

Drug Interaction Studies No clinically significant differences on bleeding time or platelet aggregation were observed when a single dose of vericiguat 15 mg was used concomitantly with 500 mg of aspirin. No clinically significant differences in prothrombin time or the activities of Factors II, VII, and X were observed when multiple doses of VERQUVO 10 mg once daily were used concomitantly with a single dose of warfarin 25 mg. No clinically significant differences on seated blood pressure (BP) were observed when multiple doses of VERQUVO 2.5 mg were used concomitantly with sacubitril/valsartan in healthy subjects.

No clinically significant differences on seated BP were observed when multiple doses of VERQUVO 10 mg were used concomitantly with short- and long-acting nitrates (nitroglycerin spray and isosorbide mononitrate [ISMN] modified release 60 mg) in patients with coronary artery disease. In patients with heart failure, concomitant use with short-acting nitrates was well tolerated, but there is limited experience with long-acting nitrates. Concomitant use of VERQUVO 10 mg with single doses of sildenafil (25, 50, or 100 mg) was associated with additional seated BP reduction of up to 5.4 mm Hg (systolic/diastolic BP, MAP), compared to administration of VERQUVO alone.

There is limited experience with concomitant use of VERQUVO and PDE-5 inhibitors in patients with heart failure.

14 CLINICAL STUDIES VICTORIA VICTORIA was a randomized, parallel-group, placebo-controlled, double-blind, event-driven, multi-center trial comparing VERQUVO and 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 6 months before randomization or use of outpatient IV diuretics for heart failure within 3 months before randomization.

Patients were randomized to receive VERQUVO 10 mg or matching placebo. VERQUVO was initiated at 2.5 mg once daily and increased at approximately 2 week intervals to 5 mg once daily and the target dose of 10 mg once daily, as tolerated. Placebo doses were similarly adjusted.

After approximately 1 year, 90% of patients in both treatment groups were treated with the 10 mg target dose. The primary endpoint was a composite of time to first event of CV death or hospitalization for heart failure. The median follow-up for the primary endpoint was 11 months.

The population was 64% Caucasian, 22% Asian, and 5% Black. The mean age was 67 years and 76% were male. At randomization, 59% of patients were NYHA Class II, 40% were NYHA Class III, and 1% were NYHA Class IV.

The mean left ventricular ejection fraction (EF) was 29%. Approximately half of all patients had an EF <30%, and 14% had an EF between 40% and 45%. The most frequently reported medical history conditions other than heart failure included hypertension (79%), coronary artery disease (58%), hyperlipidemia (57%), diabetes mellitus (47%), atrial fibrillation (45%) and myocardial infarction (42%).

At randomization, the mean eGFR was 62 mL/min/1.73 m 2 ; the majority of patients (88%) had an eGFR >30 mL/min/1.73 m 2 . Sixty-seven percent of the patients were enrolled within 3 months of a HF-hospitalization index event; 17% were enrolled within 3 to 6 months of HF hospitalization, and 16% were enrolled within 3 months of outpatient treatment with IV diuretics for worsening HF. The median NT-proBNP level was 2800 pg/mL at randomization.

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

At baseline, 6% of patients were on ivabradine and 3% of patients were on a sodium glucose co-transporter 2 (SGLT2) inhibitor. In VICTORIA, VERQUVO was superior to placebo in reducing the risk of CV death or heart failure hospitalization 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% annualized absolute risk reduction (ARR) with VERQUVO compared with placebo.

The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization (see Table 2 ). Table 2: Treatment Effect for the Primary Composite Endpoint and the Secondary Endpoints of Cardiovascular Death and Heart Failure Hospitalization VERQUVO N=2,526 Placebo N=2,524 Treatment Comparison n (%) Event rate: % of patients per year Total patients with an event per 100 patient years at risk. n (%) Event rate: % of patients per year Hazard Ratio (95% CI) Hazard ratio (VERQUVO over Placebo) and confidence interval from a Cox proportional hazards model. p-value From the log-rank test.

ARR Absolute risk reduction, calculated as difference (Placebo-VERQUVO) in event rate… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats. Vericiguat did not show a carcinogenic effect in mice dosed up to 150 mg/kg/day (males) or up to 250 mg/kg/day (females). These doses were associated with exposures 41 times (males) or 78 (females) times the human exposure (total AUC) at the MRHD of 10 mg/day.

In the carcinogenicity study in rats, no vericiguat-related tumor or hyperplastic findings were observed at doses up to 20 mg/kg/day, at exposures of 16 (males) and 21 times (females) the human exposure at the MRHD. Mutagenesis Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay and the in vivo rat and mouse micronucleus assay. Impairment of Fertility There were no effects on fertility, mating performance or early embryonic development when vericiguat was administered to rats at up to 32 times the human exposure (total AUC) at the MRHD.

13.2Animal Toxicology and/or Pharmacology In growing rats, reversible effects on bone formation were observed, consisting of hypertrophy of growth plate and hyperostosis and remodeling of metaphyseal and diaphyseal bone. These effects were not observed after chronic administration of vericiguat at up to 22X (adult male rats), 25X (adult female rats), and 2.4X (adult dogs) the human exposure (total AUC) at the MRHD [see Use in Specific Populations (8.4) ] .