Pharmacists Mutual Companies

New Drug Monograph

VerquvoTM (vericiguat)

By: Dr. Melissa Dempsey

Background: Approved January 20, 2021 Classification: Soluble guanylate cyclase stimulator Indication: FDA Approved – Heart failure with reduced ejection fraction (HFrEF) – specifically in patients with high risk of heart failure (HF) exacerbation who have recently been hospitalized or have needed intravenous (IV) diuretics.

Contraindications: Use of other soluble guanylate cyclase stimulators. Pregnancy – Category X due to embryo-fetal toxicity.

US Boxed Warning: Vericiguat is associated with embryo-fetal toxicity. Women of childbearing age should take a pregnancy test and be counseled on contraception before initiating this medication. A pregnancy test one month after discontinuation is also recommended.

Pharmacology: Variciguat works by stimulating soluble guanylate cyclase (sGC), which in turn helps to sensitize the patient to endogenous nitric oxide. Patients with HF have endothelial dysfunction, which in combination with oxidative stress and inflammation results in sGC insufficiency, leading to myocardial and vascular dysfunction. Variciguat fixes this process at the sGC step, resulting in cardioprotection.

Pharmacokinetics:

Absorption - Bioavailability is 93% when administered with a high-fat, high-calorie meal. It can be taken orally Distribution - Protein binding at 98% with a volume of distribution of 44L.

Metabolism - Glucuronidation occurs by UGT1A9. Less than 5% of metabolism is done by CYP enzymes.

Elimination - Patients with HF – t1/2 = 30 hours; Healthy patients – 1.6L/hr clearance; Inactive metabolites excreted in the urine = 53%; Unchanged drug excreted in the feces = 45%

Clinical Efficacy: In the SOCRATES-PRESERVED and SOCRATES-REDUCED phase-2 trials, two patient populations were evaluated on the safety and optimal dosing of vericiguat. SOCRATES-PRESERVED recruited 477 patients with HF with a preserved ejection fraction (HFpEF) and divided them into 5 arms: vericiguat 1.25mg, 2.5mg, 2.5mg titrated to 5mg, 2.5mg titrated to 10mg, and placebo. Endpoint analysis was done at baseline and week 12 on left arterial volume (LAV) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Data across the 2.5mg – 10mg treatment arms was pooled for primary analysis, revealing a non-statistically significant mean baseline decrease in LAV of -1.732mL compared to -3.361mL for placebo (p = 0.8156). Similar results were shown with log(NT-proBNP) data and a mean change of 0.038 for the treatment pooled arms compared to -0.098 for placebo (p = 0.8991). The Kansas City cardiomyopathy questionnaire (KCCQ) score that evaluated patient quality of life as a secondary endpoint improved 9.2 points after 12 weeks (p = 0.016) with vericiguant 10mg. In patients with HFrEF, SOCRATES-REDUCED recruited 456 patients and divided them into the same 5 treatment arms. After a follow up of 12 weeks, log(NT-proBNP) was evaluated as the primary endpoint. This study found similar results with no statistically significant difference of means for log(NT-proBNP) between pooled treatment arms and placebo (-0.122, p = 0.15). Higher doses of vericiguat displayed a greater reduction in NT-proBNP than lower doses: 10mg mean difference of -0.250, 2.5mg mean difference of -0.040, p < 0.02. Though not powered to detect a difference, rates of HF hospitalization were 17.4% in the placebo compared to 9.9% in the 5mg and 10mg treatment arms. A composite of cardiovascular death or HF hospitalization paralleled these results with a rate of 19.6% in the placebo group versus 12.1% in the 5mg vericiguat group and 11% in the 10mg vericiguat group. Rates of

any adverse effect were 77.2% for those in the placebo group and 70.3% for 1.25mg, 78.9% for 2.5mg, 73.6% for 5mg, and 71.4% for 10mg treatment groups. The most notable event was syncope, with 7 total patients in the treatment arms experiencing this compared to only 1 in the placebo group. Dosing was established at 10mg daily with these findings.

Another phase-2 trial, VITALITY-HFpEF, was a randomized, controlled trial that further evaluated quality of life measures seen in SOCRATES-PRESERVED. A total of 789 patients were treated with either vericiguat 10mg, 15mg, or placebo for a duration of 24 weeks. Endpoints evaluated included KCCQ physical limitation scores (PLS), adjusted to a 0-100 point scale, a 6-minute walking distance, as well as clinical outcomes of cardiovascular and non-cardiovascular death, hospitalizations for HF and non-HF reasons. Mean patient age was 72.7, with 59% being NYHA Class II and the remainder Class III. Mean follow up time was 149.5 days. No endpoints met statistical significance. The KCCQ PLS least-squares means after 24 weeks were 5.5 for 15mg vericiguat, 6.4 for 10mg vericiguat, and 6.9 for placebo.. Average distance increase for the 6-minute walk after 24 weeks was 16.8m for 15mg vericiguat, 26.2m for 10mg vericiguat, and 15.6m for placebo, with a least-squares mean difference between 15mg vericiguat and placebo of -5.5m.

In the phase-3, multi-center, international, randomized, placebo controlled, double-blind study, 5050 patients with worsening HFrEF were given either vericiguat or placebo for safety and efficacy evaluation. Patients in the study group were administered verticiguat 2.5mg by mouth daily and titrated up to 10mg, then evaluated at weeks 2 and 4, and every 4 months after that. Enrollment began September 2016 and concluded in December 2018, with 66% being enrolled within 3 months of their HF hospitalization. Inclusion criteria was as follows: adults aged 18 or older, New York Heart Association (NYHA) functional class II-IV, ejection fraction (EF) less than 45%, elevated BNP level within 30 days of randomization, evidence of worsening HF as defined by hospitalization within 3 months, hospitalization between 3 and 6 months, or the need for IV diuretics within 3 months of randomization. Exclusion criteria included systolic BP less than 100mmHg, or already taking a soluble guanylate cyclase stimulator, a PDE-5 inhibitor, or long-acting nitrates. The primary outcome for this study was a composite of death from CV causes or hospitalization for HF. The mean age for patients included in the study was 67.5 and 76% were male. The study included a variety of patients with diverse ethnic backgrounds including 23% Asian, 34% Eastern Europe, 17.5% Western Europe, 23.4% Asian-Pacific. Other baseline characteristics included a mean body mass index of 27.7, 58% with NYHA Class II, 40% with NYHA Class III, 85.8% had EF<40%. All patients were also continued on guideline-directed therapy with 60% being on triple therapy beta-blocker, mineralocorticoid antagonist and either an angiotensin converting enzyme inhibitor (ACEi), an angiotensin II receptor blocker (ARB), or an angiotensin receptor-neprilysin inhibitor (ARNI). Mean follow up time was 10.8 months. In the vericiguat arm, 35.5% of patients met the primary outcome, compared to 38.5% in the placebo group (hazard ratio (HR) 0.90, 95% CI 0.82-0.98, p = 0.02), with a number needed to treat of 33. Total hospitalizations for HF in the vericiguat were 38.3 events/100 patient years compared to 42.2 events/100 patient years in placebo HR 0.91, 95% CI 0.84-0.99, p = 0.02). Death from any cause was not statistically significant with a rate of 20.3% in the vericiguat group and 21.2% in placebo (HR 0.95, 95% CI 0.84-1.07, p = 0.38). Reduced HF hospitalization being statistically significant was likely driving the composite primary outcome.

Drug interactions: PDE-5 inhibitors – increased risk of hypotension – Risk X: avoid combination. PPIs, H2 blockers, antacids – decreased absorption of vericiguat Notably vericiguat is a substrate for P-glycoprotein (Pgp) & breast cancer resistance protein (BCRP), though no drug interactions have been documented. Adverse Effects: Hypotension (16%); Anemia (10%)

Pregnancy and Lactation: Do not use in pregnancy. Not recommended for breastfeeding.

Dosing: 2.5mg, 5mg, and 10mg tablets – target dose 10mg Take medications once daily, at the same time, with largest meal of the day. If a dose is missed, do not double up doses.

Storage: Store at room temperature (20-25 degrees Celsius). Temporary range between 15-30 degrees Celsius permitted.

Summary/Use in clinical practice: The treatment algorithm for HF patients is complex, covering many classes of medications. Patients with HFrEF seem to get the most benefit from the majority of medications, while patients with HFpEF are treated similarly without the same level of supporting data. Vericiguat still falls into this role, with its phase-3 trial data coming from the HFrEF patient population. With its once daily dosing, minimal side effects and a proven ability to reduce cardiovascular death or HF hospitalization, it can be another add-on therapy candidate for patients who are already on maximally tolerated guideline directed therapy. Its novel pathway targeting sGC may also prove to be of benefit, with opportunities for unique monitoring parameters as a gauge of patient health.

In a network meta-analysis comparing vericiguat with sacubitril/valsartan and sodium-glucose co-transporter-2 inhibitors based on their respective phase 2 and phase 3 trials, it was concluded that neither therapy is superior to the other for the prevention of cardiovascular death or HF hospitalization.7

The addition of vericiguat to therapy options that patients with HF can try in order to reduce morbidity and mortality allows for better therapy selection based on unique patient characteristics. The populations studied in the phase 3 trial had a higher morbidity and mortality risk (40% in NYHA Class III) than phase 2 studies with alternate therapies, opening a patient population that could see improved quality of life and reduced HF exacerbations leading to hospitalization. During the phase 3 trial, meeting the composite primary outcome resulted in a number needed to treat of 33. Additionally, vericiguat is a well-tolerated medication, making it a viable option for patients who are intolerant to other therapies in HF treatment. Caution should be used during titration for syncope events, or patients that are prone to falls or hypotension such as the geriatric population. It must also be considered whether an addon medication will increase pill burden for patients or be cost prohibitive. Reduced HF hospitalizations and possible quality of life improvement, demonstrated in phase-2 trials, though not statistically significant, could become clinically relevant as prescribing patterns increase. Bibliography: Armstrong PW, Lam CSP, Anstrom KJ, et al. Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The VITALITY-HFpEF Randomized Clinical Trial [published correction appears in JAMA. 2021 Feb 2;325(5):494]. JAMA. 2020;324(15):1512-1521.

Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020;382(20):1883-1893. doi:10.1056/NEJMoa1915928 Aimo Q, Pateras K, Stamatelopoulos K, et al. Relative efficacy of sacubitril-valsartan, vericiguat, and SGLT2 inhibitors in heart failure with reduced ejection fraction: a systematic review and network meta-analysis. Cardiovasc Drugs Ther. 2020. Gheorghiade M, Greene SJ, Butler J, et al. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial. JAMA. 2015;314(21):2251-2262.

Pieske B, Maggioni AP, Lam CSP, et al. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J. 2017;38(15):1119-1127.

Vericiguat. [package insert online]. Merck & Co., Inc. Whitehouse Station, NJ. Revised January 2021. https:// www.merckconnect.com/verquvo/coupons-samples. Accessed March 8, 2021.

Vericiguat. In: Lexicomp [database online]. Hudson, OH: Lexicomp, Inc. http://www.crlonline.com/lco/action/doc/retrieve/docid/ patch_f/7063084?cesid=2lp12c4osJO&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dvericiguat%26t%3Dname%26va%3Dvericiguat. Accessed March 8, 2021.