Katelyn Yamartino, PharmD

Heart failure with reduced ejection fraction (HFrEF) is characterized by dyspnea or exertional limitation and occurs when the left ventricular ejection fraction (LVEF) is 40% or less.

 Treatment for patients with HFrEF includes a diuretic, a beta blocker, and either an angiotensin receptor-neprilysin inhibitor, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Ivabridine, hydralazine/ isosorbide, and sodium-glucose cotransporter 2 inhibitors have also been shown to provide additional benefit in patients with persistent symptoms. On January 20, 2021, the FDA approved vericiguat (Verquvo; Merck) for use in adults with symptomatic HF and an ejection fraction less than 45% to reduce the risk of cardiovascular death and HF hospitalization following a hospitalization for HF or need for outpatient intravenous diuretics.

 HF is characterized by myocardial and vascular dysfunction, which may be due to impaired synthesis of nitric oxide (NO) and decreased activity of soluble guanylate cyclase (sGC).

 Vericiguat stimulates sGC, an enzyme that, when it binds to NO, catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP). The increased intracellular levels of cGMP lead to smooth muscle relaxation and vasodilation.

The efficacy and safety of vericiguat are based on the results of the VICTORIA trial.4 This was a phase 3, randomized, double-blind, placebo-controlled trial that randomized 5050 patients with chronic HF (New York Heart Association (NYHA class II-IV)) and an ejection fraction less than 45% to receive either vericiguat 10 mg daily (n = 2526) or placebo (n = 2524), in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for HF and occurred in 35.5% of patients in the vericiguat group and 38.5% of patients in the placebo group. The secondary end points were cardiovascular death and HF hospitalization. Cardiovascular death occurred in 12.9% and 13.9% of patients given vericiguat and placebo, respectively. HF hospitalization was reported at 25.9% and 29.1% of patients in the vericiguat and placebo group, respectively. The study investigators concluded based on the efficacy data from this study, that vericiguat reduced the incidence of death from cardiovascular causes or hospitalizations for HF compared with placebo.

The prescribing information for vericiguat contains a warning for embryo-fetal toxicity and is contraindicated in pregnant females.

 Females of reproductive potential must use effective forms of contraception during treatment and for 1 month after stopping the treatment to prevent pregnancy. Vericiguat is also contraindicated in patients taking other sGC stimulators and is not recommended to be used in patients also taking phosphodiesterase-5 inhibitors due to the potential for hypotension. The most common adverse events seen in the VICTORIA trial were hypotension (16% vs 15% in the vericiguat and placebo group, respectively) and anemia (10% vs 7% in the vericiguat and placebo group, respectively).

Vericiguat is available as 2.5, 5, and 10 mg tablets.

 The initial dose is 2.5 mg orally once daily with food. The dose may be doubled about every 2 weeks until the target maintenance dose of 10 mg once daily is achieved, as tolerated by the patient. The tablets may be crushed and mixed with water immediately before administration in patients who are unable to swallow whole tablets. Vericiguat does not need to be dose-adjusted in patients with an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 min2 or with mild or moderate hepatic impairment. Vericiguat has not been studied in patients with an eGFR < 15 mL/min/1.73m2, patients on dialysis, or patients with severe hepatic impairment (eg, Child-Pugh C). If a dose is missed, the patient should take the dose as soon as the patient remembers on the same day of the missed dose. Patients should not take 2 doses on the same day.

Katelyn Yamartino, PharmD, is a PGY-1 pharmacy resident at UConn John Dempsey Hospital at UConn Health, Farmington, Connecticut.

Kevin W. Chamberlin, PharmD, FASCP, is university director of pharmacy residency programs at UConn Health.

Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart failure with reduced ejection fraction: a review. JAMA. 2020;324(5):488-504. Published correction appears in JAMA. 2020;324(20):2107. doi:10.1001/jama.2020.10262

Merck Announces U.S. FDA Approval of VERQUVO® (vericiguat). News release. Merck. January 20, 2021. Accessed February 3, 2021. https://www.merck.com/news/merck-announces-u-s-fda-approval-of-verquvo-vericiguat/

Verquovo. Prescribing Information. Merck; 2021. Accessed February 3, 2021. https://www.merck.com/product/usa/pi_circulars/v/verquvo/verquvo_pi.pdf

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


Articles

A new drug review for vericiguat, indicated for heart failure, reports efficacy and safety data. 

Vericiguat (Verquvo) for Heart Failure With Reduced Ejection Fraction 

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by inflammatory lesions that primarily affect the optic nerve and spinal cord. NMOSD attacks can lead to permanent vision impairment and paralysis, along with pain, fatigue, sensory loss, and bladder dysfunction.

 Recently, eculizumab and inebilizumab were approved by the FDA for the treatment of NMOSD in adults in 2019 and 2020, respectively. Prior to their approval, no medications were approved to treat this disease. On August 14, 2020, the FDA approved satralizumab-mwge (Enspryng; Genentech) for the treatment of NMOSD in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. The exact mechanism of satralizumab in NMOSD is unknown, but it involves the inhibition of interleukin-6 (IL-6) mediated signaling, which is thought to play a key role in NMOSD pathogenesis.

Two multicenter, double-blind, placebo-controlled trials were conducted in two 96-week clinical studies to determine the safety and efficacy of satralizumab in NMOSD. The SAkuraStar trial (NCT02073279) included 95 patients, of which 64 were anti-AQP4 positive. Patients were randomized 2:1 to receive either satralizumab (N = 41) or placebo (N= 23) subcutaneously at weeks 0, 2, 4, and once every 4 weeks after. Study results showed that treatment with satralizumab reduced the number of NMOSD relapses by 74% in patients who were anti-AQP4 positive compared with placebo. In the satralizumab group, 82.9% and 76.5% of patients were relapse free at 48 and 96 weeks, respectively.

The SAkuraSky trial (NCT02028884) randomized anti-AQP4 positive patients to receive satralizumab plus immunosuppressive therapy (IST) with corticosteroids, azathioprine, or mycophenolate mofetil (N = 26) or placebo plus IST (N = 26) at weeks 0, 2, 4, and once every 4 weeks after. Satralizumab reduced the number of relapses by 78% compared with placebo. 91.1% of patients in the satralizumab arm were relapse free at both 48 and 96 weeks.4There was no evidence of a benefit in anti–AQP4 negative patients in either trial.

The prescribing information for satralizumab includes a warning for increased risk of infections, specifically potential reactivation of hepatitis B and tuberculosis. Therefore, satralizumab is contraindicated in patients with an active hepatitis B infection, or active or untreated latent tuberculosis. Satralizumab also has been shown to increase liver enzymes, decrease neutrophil counts, and increase the risk for hypersensitivity reactions. Health care providers should screen patients for hepatitis B virus, tuberculosis, and liver transaminases prior to the first dose and assess for active infection prior to every use.

 The most common adverse effects seen in the SAkuraStar and SAkuraSky trials include rash, arthralgia, nasopharyngitis, headache, upper respiratory tract infections, gastritis, joint pain, extremity pain, fatigue, and nausea.

 Live attenuated or live vaccines are not recommended during treatment and should be administered at least 4 weeks prior to initiating therapy.

Satralizumab is intended for self-administration and dispensed as a 1 mL single-dose prefilled syringe. Initial dosing is 120 mg given subcutaneously every other week for a total of 3 injections. This is followed by maintenance doses of 120 mg once every 4 weeks. Prior to use, patients or caregivers should remove the prefilled syringe from the refrigerator and allow the syringe to sit at room temperature outside of the carton for 30 minutes. The solution should be clear and colorless to slightly yellow. Patients should inject the full amount of the syringe into the abdomen or thigh, and they should rotate injection sites with each administration.

If a dose of satralizumab is missed for any reason other than increases in liver enzymes and it has been less than 8 weeks since the last dose, administer a dose as soon as possible and continue the dosing schedule from there. If it has been 8 to 12 weeks since the last dose, administer 120 mg at 0 and 2 weeks, followed by 120 mg every 4 weeks. If it has been 12 weeks or longer, administer 120 mg at 0, 2, and 4 weeks, followed by 120 mg every 4 weeks.

1. FDA approves Genentech’s Enspryng for neuromyelitis optica spectrum disorder. News release. Genentech; August 14, 2020. Accessed October 6, 2020. https://www.gene.com/media/press-releases/14873/2020-08-14/fda-approves-genentechs-enspryng-for-neu

2. Enspryng. Package insert. Genentech Inc; 2020. Accessed August 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761149s000lbl.pdf

3. Traboulsee A, Greenberg BM, Bennett JL, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomized, double-blind, multicentre, placebo-controlled phase 3 trial. 

. 2020;19(5):402-412. doi:10.1016/S1474-4422(20)30078-8

4. Yamamura T, Kleiter I, Fujihara K, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. 

. 2019;381(22):2114-2124. doi:10.1056/NEJMoa1901747

An overview of the use of satralizumab-mwge (Enspryng; Genentech) in neuromyelitis optica spectrum disorder (NMOSD).