Drug Monograph

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Drug Monograph Drug Name: Verquvo® (vericiguat) Tablet Drug Class: Heart Failure: Soluble Guanylate Cyclase Stimulators Prepared For: MO HealthNet Prepared By: Conduent

New Criteria Revision of Existing Criteria

Executive Summary

The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be made available on an open Purpose: access basis to prescribers, require a clinical edit or require prior authorization for use.

Verquvo is available as an oral tablet with 2.5 mg, 5 mg, or 10 mg of Dosage Forms: vericiguat.

Distributed by: Merck Sharp and Dohme Corporation, Whitehouse Station, NJ Manufacturer: 08889.

The efficacy of Verquvo was demonstrated in a randomized, parallel-group, placebo-controlled, double-blind, event-driven, multicenter pivotal phase 3 trial (n=5050). These patients were at high risk of hospitalization and cardiovascular death following a recent heart failure decompensation. Participants were randomized to receive either Verquvo once daily (titrated up to 10 mg) or placebo when given in combination with available heart Summary of failure therapies. The primary endpoint was a composite of time to first event Findings: 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 (hazard Ratio 0.90; 95% CI 0.82, 0.98; p=0.019). This reduction was driven by a reduction in heart failure hospitalizations but not cardiovascular death.

Status Clinical Edit PA Required Recommendation: Open Access PDL

Type of PA Appropriate Indications Non-Preferred Criteria: No PA Required Preferred

Purpose The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be considered a prior authorization drug, a clinical edit drug or an open access drug. While prescription expenditures are increasing at double-digit rates, payers are evaluating ways to control these costs by influencing prescriber behavior and guide appropriate medication usage. This review will assist in the achievement of qualitative and economic goals related to health care resource utilization. Restricting the use of certain medications can reduce costs by requiring documentation of appropriate indications for use, and where appropriate, encourage the use of less expensive agents within a drug class.

Introduction (1,2,3) Heart failure (HF) is considered a global issue affecting 26 million people worldwide and 5.7 million people in the United States. It is anticipated that by 2030 the number of HF patients in the U.S. will increase to 8 million. The condition is characterized by the reduced ability of the heart to pump and/or fill with blood and carries high risk for morbidity and mortality. The prevalence of HF is rising because of an aging population and improvements in treatment. This will result in further increases in hospitalization rates. The American College of Cardiology/American Heart Association (ACC/AHA) classifies HF into three categories based on left ventricular ejection fraction (LVEF): HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), and HF with mid-range ejection fraction (HFmrEF). HFrEF occurs when the LVEF is 40% or less and is accompanied by progressive LV dilatation, adverse cardiac remodeling, and coronary artery disease. Patients with chronic HF (even those already being treated with first line agents such as angiotensin converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], angiotensin-neprilysin inhibitors [ARNIs], beta-blockers [BB], and mineralocorticoid receptor antagonists [MRAs]) that have required hospitalization for decompensation or required IV diuretics to treat congestion have substantially worsened prognosis and outcomes. Verquvo is the second drug approved by the FDA in the novel class of soluble guanylate cyclase (sGC) stimulator and is indicated for use in these high risk patients. Key differences between Verquvo and Adempas® (riociguat) are that Adempas is indicated to treat pulmonary hypertension and has a much shorter half-life requiring three times-a- day dosing.

Dosage Form (4) Verquvo is available as an oral tablet in 2.5 mg, 5 mg, and 10 mg of vericiguat.

Manufacturer (4) Distributed by: Merck Sharp and Dohme Corporation, Whitehouse Station, NJ 08889.

Indication(s) (4) Verquvo is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic HF and ejection fraction less than 45%. Clinical Efficacy (4,5,6) (mechanism of action/pharmacology, comparative efficacy) Verquvo is a soluble guanylate cyclase (sGC) stimulator. Soluble guanylate cyclase is an enzyme in the cardiopulmonary system and an intracellular receptor for nitric oxide (NO). NO, produced in endothelial cells in response to physiologic stimuli, diffuses to vascular or cardiac muscle cells

2021 Conduent Business Services, LLC All Rights Reserved / Page 2 where it stimulates sGC to catalyze the synthesis of cyclic guanosine monophosphate (cGMP). Production of cGMP plays an important role in the regulation of vascular tone, cardiac contractility, and cardiac remodeling. Reductions in NO bioavailability lead to decreased sGC activity and a subsequent reduction in cGMP synthesis. Both impaired NO synthesis and decreased sGC activity are seen in heart failure, which may contribute to myocardial and vascular dysfunction. Reductions in cGMP may contribute to the progression of heart failure with reduced ejection fraction through negative effects on the heart, kidneys and vessels. Thus, through direct sGC stimulation, in a manner that is independent of and synergistic with NO, Verquvo increases intracellular cGMP levels, leading to smooth muscle relaxation and vasodilation.

Pharmacokinetics: Absorption Bioavailability=93% Metabolism Glucuronidation via UGT1A9 and UGT1A1 Excretion Urine (53%), Feces (45%) Half-life 30 hours

Clinical Trials Experience STUDY 1 DESIGN Randomized, parallel-group, placebo-controlled, double-blind, event- (VICTORIA, driven, multicenter pivotal phase 3 trial (n=5,050) NCT 02861534) INCLUSION  History of chronic HF on standard therapy before qualifying HF CRITERIA decompensation  Previous HF hospitalization within 6 months prior to randomization or IV diuretic treatment for HF (without hospitalization) within 3 months  Brain natriuretic peptide (BNP) levels: sinus rhythm ≥300 pg/ml; atrial fibrillation ≥500 pg/ml and N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels; sinus rhythm ≥1000 pg/ml; atrial fibrillation ≥1600 pg/ml within 30 days prior to randomization  Left ventricular ejection fraction (LVEF) of <45% assessed within 12 months prior to randomization by any method  If female, is not of reproductive potential or agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug EXCLUSION  Clinically unstable at the time of randomization as defined by CRITERIA either the administration of any IV treatment within 24 hours prior to randomization, and/or systolic blood pressure (SBP) <100 mmHg or symptomatic hypotension  Current of anticipated use of long-acting nitrates or nitric oxide (NO) donors including isosorbide dinitrate, isosorbide 5- mononitrate, pentaerythritol tetranitrate, nicorandil or transdermal nitroglycerin (NTG) patch, and molsidomine  Current of anticipated use of phosphodiesterase type 5 (PDE5) inhibitors such as verdenafil, tadalafil, and sildenafil  Current use or anticipated use of a sGC stimulator such as riociguat  Known allergy of sensitivity to any sGC stimulator  Awaiting heart transplantation, receiving continuous IV infusion of an inotrope, or has/anticipates receiving an implanted ventricular

device  Primary valvular heart disease requiring surgery or intervention, or is within 3 months after valvular surgery intervention  Hypertrophic obstructive cardiomyopathy  Acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy  Post-heart transplant cardiomyopathy  Tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia  Acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction (NSTEMI), or ST elevation myocardial infarction (STEMI) or coronary revascularization (coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) within 60 days, or indication for coronary revascularization at the time of randomization  Symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 days  Complex congenital heart disease  Active endocarditis or constrictive pericarditis  Estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m2 or chronic dialysis  Severe hepatic insufficiency such as with hepatic encephalopathy  Malignancy or other non-cardiac condition limiting life expectancy to <3 years  Require continuous home oxygen for severe pulmonary disease  Current alcohol and/or drug abuse  Participated in another interventional clinical study and treatment with another investigational product ≤30 days prior to randomization or plans to participate in any other trial/investigation during the duration of this study  Mental or legal incapacitation and is unable to provide informed consent  Immediate family member who is involved with this study  Interstitial Lung Disease  Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during the course of the study TREATMENT Patients were randomized to receive Verquvo 10 mg or matching REGIMEN 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 1 year, 90% of patients in both treatment groups were treated with the 10 mg target dose. RESULTS The primary endpoint was a composite of time to first event of CV death or hospitalization for heart failure with the median follow-up for the primary endpoint being 11 months.

Verquvo Placebo Treatment Comparison (N=2,526) (N=2,526) n Event n Event Hazard p- ARR§ (%) rate:% of (%) rate:% of Ratio value‡ patients patients (95% CI)† per year* per year* Primary Endpoint Composite of cardiovascular 897 972 0.90 33.6 37.8 0.019 4.2 death or HF (35.5) (38.5) (0.82, 0.98) hospitalization¶ Secondary Endpoints Cardiovascular 414 12.9 441 0.93 13.9 death (16.4) (17.5) (0.81, 1.06) Heart failure 691 747 0.90 25.9 29.1 hospitalization (27.4) (29.6) (0.81, 1.00) *Total patients with an event per 100 patient years at risk. †Hazard ratio (Verquvo over Placebo) and confidence interval from a Cox proportional hazards model. ‡From the log-rank test. §Absolute risk reduction, calculated as difference (Placebo-Verquvo) in event rate per 100 patient years. ¶For patients with multiple events, only the first event contributing to the composite endpoint is counted. N=Number of patients in intent-to-treat (ITT) population; n=number of patients with an event.

Verquvo was superior to placebo in reducing the risk of CV death or heart failure hospitalization based on a time-to-event analysis. Secondary endpoints: Verquvo was superior to placebo in reducing the risk of total (first and recurrent) events of HF hospitalization (Hazard Ratio 0.91; 95% CI 0.84, 0.99) and the first occurrence of either all-cause mortality or HF hospitalization (Hazard Ration 0.90; 95% CI 0.83, 0.98).

SAFETY Discussed in the Adverse Effects section below.

Contraindications (5,6)  Patients with concomitant use of other sGC stimulators  Pregnancy

Warnings and Precautions (5,6)  Embryo-Fetal Toxicity: Verquvo may cause fetal harm when administered to a pregnant woman. Obtain a pregnancy test before the start of treatment. Advise females of reproductive potential to use effective contraception during treatment with Verquvo and for at least one month after the final dose.

Adverse Effects (5,6)

Most common, ≥ 5% Verquvo Placebo (n =2,519) % (n=2,515) % Hypotension 16 15 Anemia 10 7

Drug Interactions (5,6)  PDE-5 Inhibitors: Concomitant use is not recommended due to risk of hypotension

Dosage and Administration (5,6) Initial dose is 2.5 mg orally once daily with food. The dose should then be doubled approximately every 2 weeks as tolerated to the target maintenance dose of 10 mg orally once daily. Cost

Generic Name Brand Name Manufacturer Dose Cost**/ Month Vericiguat Verquvo Merck Sharp Adult maintenance: $582.90 and Dohme 10 mg once daily Sacubitril/valsartan Entresto Novartis Adult maintenance: $582.60 24 mg sacubitirl/26 mg valsartan twice daily Dapagliflozin Farxiga AstraZeneca 10mg once daily $532.84 Eplerenone Inspra Pfizer, various 25 mg once daily $41.97 Riociguat Adempas Bayer 1 mg three times $11,615.40 HealthCare daily ** Wholesale Acquisition Cost Conclusion Verquvo is a sGC stimulator indicated to reduce the risk of cardiovascular death and HF hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic HF and ejection fraction less than 45%. The efficacy of Verquvo was demonstrated in a randomized, parallel-group, placebo-controlled, double-blind, event- driven, multicenter pivotal phase 3 trial. Participants were randomized to receive either Verquvo once daily or placebo when given in combination with available heart failure therapies. 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 CV death or heart failure hospitalization based on a time-to-event analysis (hazard Ratio 0.90; 95% CI 0.82, 0.98; p=0.019). Although the size of the relative effect was modest compared with other therapies for HFrEF, the participants in the VICTORIA trail were considered to be a higher risk population compared to the participants in other recent HF trials. Based on this absolute risk reduction, the number needed to treat (NNT) with Verquvo for 1 year to prevent a primary outcome is approximately 24 patients, while the NNT with both Farxiga and Entresto is 21 patients. However Verquvo’s once-daily dosing, cleaner side effect profile, and lack of monitoring requirements (i.e., electrolytes, renal function) are all potential advantages it has over these two competitors. The most common adverse events are hypotension and anemia.

Recommendation The MO Healthnet Division recommends creating a new clinical edit for this medication.

References 1) Verquvo [new drug review]. IPD Analytics. Available at: https://secure.ipdanalytics.com/User/Pharma/RxStrategy/Search?q=Verquvo. Accessed February 4, 2021. 2) Yancy, C, Jessup, M, Bozkurt, B, et al. 2021 ACC/AHA/HFSA Focused Update of the 2017

ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017 Aug;70(6):776-803. 3) Maddox, T, Januzzi, J, Allen, L, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. Epublished January 11, 2021. DOI:10.1016/j.jacc.2020.11.022. 4) Pieske B, Patel MJ, Westerhout CM, et al. Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. Eur J Heart Fail. 2019 Dec;21(12):1596-1604. doi: 10.1002/ejhf.1664. Epub 2019 Dec 9. PMID: 31820546. 5) Verquvo [package insert]. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; January 2021. 6) Clinical Pharmacology [drug reference database]. Available at: https://www.clinicalkey.com/pharmacology/. Accessed February 4, 2021.

Prepared by: April Ash, PharmD. Date: February 4, 2021