Summary Basis of Decision for Verquvo

As described above, the clinical review of the New Drug Submission for Verquvo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

The pharmacokinetics and pharmacodynamics of vericiguat (the medicinal ingredient in Verquvo) were evaluated in Phase I and II studies. The clinical pharmacology program reviewed provided acceptable pharmacokinetic and pharmacodynamic data from healthy participants.

Verquvo was well tolerated at doses up to 10 mg daily in healthy males and females aged 20 to 86 years old. Vericiguat distributes through plasma and did not show clinically significant accumulation after daily doses for 14 days. Exposure was higher in participants with hepatic impairment and renal impairment compared to controls, likely due to slower clearance, but there was no efficacy or safety correlation (i.e., higher exposure did not lead to significantly lower blood pressure, higher heart rate, or more frequent adverse events). Time to maximal concentration was affected only by food intake. It is recommended that Verquvo be administered with food.

Vericiguat is metabolized predominantly by uridine 5'‑diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) 1A9 and 1A1 while cytochrome P450 (CYP) enzymes play a minor role (<5%). P‑glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters also contribute to the metabolic clearance of vericiguat.

Clinical drug‑drug interaction studies revealed no relevant effect on the pharmacokinetics of vericiguat when it was co‑administered with mefenamic acid (UGT1A9 inhibitor), ketoconazole (multi‑CYP and transporter inhibitor), rifampin (multi‑CYP, UGT1A1, UGT1A9 and P‑gp inducer), digoxin, warfarin, acetylsalicylic acid, sildenafil, or the combination of sacubitril/valsartan in healthy subjects. Physiologically-based pharmacokinetic simulations predicted no clinically relevant interaction between vericiguat and atazanavir (UGT1A1 inhibitor). Concomitant use of medications or substances that act on the nitric oxide‑soluble guanylyl cyclase‑cyclic guanosine monophosphate pathway may increase the risk of symptomatic hypotension due to potential pharmacodynamic interactions with Verquvo. Due to this potential pharmacodynamic interaction, the concomitant use of Verquvo with other soluble guanylate cyclase stimulators, phosphodiesterase‑5 inhibitors (including sildenafil), as well as long‑acting organic nitrates is not recommended.

In a dedicated QT study in 72 patients with stable coronary artery disease, administration of 10 mg of vericiguat at steady state did not prolong the QT/corrected QT (QTc) interval to a clinically relevant extent.

A population pharmacokinetic model was developed to characterize the pharmacokinetics of Verquvo in patients with heart failure with reduced ejection fraction (HFrEF) using data from the Phase II SOCRATES‑REDUCED and Phase III VICTORIA trials. Based on this population pharmacokinetic analysis, it was concluded that:

• age, sex, ethnicity, race, and baseline N-terminal pro‑B‑type natriuretic peptide (NT‑proBNP) did not have a significant impact on the pharmacokinetics of Verquvo. The analysis identified body weight as the only intrinsic factor with significant effect on both apparent clearance and apparent central volume of distribution. The covariate effects of body weight were small in magnitude and do not require a dose adjustment.

• no significant increase in Verquvo exposure was estimated for HFrEF patients with moderate or severe renal impairment not requiring dialysis.

• no significant effect on Verquvo exposure was anticipated when Verquvo was taken with drugs increasing gastric pH (e.g., proton pump inhibitors, H2‑receptor antagonists, antacids) in HFrEF patients. As it is recommended that Verquvo be given with food, no dose adjustment was deemed necessary when patients also take drugs that increase gastric pH.

• the proposed titration regimen (starting dose of Verquvo 2.5 mg orally once daily with food and a doubling of the dose approximately every two weeks to reach the target maintenance dose of 10 mg once daily, as tolerated by the patient) was acceptable and supported by exposure‑response analyses for clinical efficacy and safety using data from the Phase III VICTORIA trial.

For further details, please refer to the Verquvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Verquvo for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction following a recent heart failure decompensation event requiring hospitalization and/or intravenous diuretic therapy was evaluated in the randomized, double‑blind, placebo‑controlled, multicentre Phase III study, VICTORIA. In this study, the effect of Verquvo on cardiovascular outcomes was evaluated in patients with symptomatic chronic heart failure and ejection fraction less than 45% receiving either Verquvo up to 10 mg, orally, once daily, or placebo following worsening heart failure.

Patients were eligible to participate in the VICTORIA study if they had 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 (HFH) within 6 months before randomization or use of outpatient intravenous diuretics for heart failure within 3 months before randomization. Patients were also required to have elevated levels of natriuretic peptides (NT‑proBNP ≥1,000 pg/mL or B-type natriuretic peptide [BNP] ≥300 pg/mL in sinus rhythm or NT‑proBNP ≥1,600 pg/mL or BNP ≥500 pg/mL in atrial fibrillation). Patients were excluded if they had systolic blood pressure <100 mmHg or symptomatic hypotension, or if they were taking long‑acting nitrates or nitric oxide donors, phosphodiesterase‑5 inhibitors, or soluble guanylate cyclase stimulators. Patients received standard of care therapy for heart failure prior to and during the study.

The VICTORIA study included 5,050 patients from 42 countries who were randomized to receive Verquvo (number of patients [n] = 2,526) or placebo treatment (n = 2,524). Patients were treated up to the target maintenance dose of Verquvo 10 mg once daily or matching placebo, if tolerated. For patients treated with Verquvo, therapy was initiated at 2.5 mg once daily and was then increased in approximately 2‑week intervals to 5 mg once daily and then 10 mg once daily, based on maintaining a minimum systolic blood pressure. After approximately 1 year, 90% of patients in both the Verquvo and placebo arms were treated with the 10 mg target dose.

Overall, the treatment groups were similar with regard to baseline demographics and disease characteristics and were representative of an adult population with advanced symptomatic chronic heart failure. The trial population was 64% Caucasian, 22% Asian, and 5% Black. Regional representation was approximately 11% for North America. The mean age was 67 years and 76% of patients were male. At randomization, 59% of patients were NYHA Class II, 40% were NYHA Class III, and 1% were NYHA Class IV. The mean ejection fraction (EF) was 29% with approximately half of all patients having an EF <30% and 14% of patients having an EF between 40% and 45%. At randomization, the median NT-proBNP and estimated glomerular filtration rate (eGFR) levels were 2,816.0 pg/mL and 58.4 mL/min/1.73 m², respectively. The mean time from initial HFrEF diagnosis to randomization was 4.8 years.

Sixty‑seven percent of the patients in VICTORIA were enrolled within 3 months of an HFH index event; 17% were enrolled within 3 to 6 months of HFH, and 16% were enrolled within 3 months of outpatient treatment with intravenous diuretics for worsening heart failure. At baseline, more than 99% of patients were receiving treatment with other heart failure therapies; 93% of patients were on a beta blocker, 73% of patients were on an angiotensin‑converting enzyme inhibitor or angiotensin receptor blockers, 70% of patients were on a mineralocorticoid receptor antagonist, 15% of patients were on an angiotensin receptor/neprilysin inhibitor, 28% of patients had an implantable cardioverter‑defibrillator, and 15% had a biventricular pacemaker.

Efficacy results

There was a statistically significant improvement in the primary composite endpoint of the time to first event of HFH or cardiovascular death in patients administered Verquvo compared to placebo 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 with Verquvo compared with placebo. This translates to a number needed to treat of 24 patients per year to prevent one primary composite outcome event, which is comparable to results from recent landmark HFrEF drug trials. The treatment effect for the primary endpoint was mainly driven by a reduction in HFHs, though cardiovascular death also contributed to the treatment effect.

Verquvo demonstrated a statistically significant improvement in the secondary endpoint of time to first HFH (HR 0.90 [95% CI: 0.81, 1.00], p = 0.048), while there was only a trend towards a reduction in the secondary endpoint of cardiovascular deaths (HR 0.93 [95% CI: 0.81, 1.06], p = 0.269). There was no statistically significant improvement in all‑cause mortality (HR 0.95 [95% CI: 0.84, 1.07], p = 0.377). For health‑related quality of life measures, changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) measures from baseline to Week 32 were similar in patients treated with Verquvo compared with placebo. Overall, this large multicentre study demonstrated sufficient evidence to support the efficacy of Verquvo in the target population.

The treatment effect for the primary and key secondary endpoints was generally consistent across subgroups regardless of baseline characteristics, with one exception. Among patients within the highest quartile (Q4) of the prespecified subgroup of baseline serum NT-proBNP level, the estimated hazard ratio for cardiovascular death was 1.16 (95% CI: 0.95, 1.43) and for first HFH was 1.19; (95% CI: 0.9, 1.44). The sponsor provided supportive evidence demonstrating that a favourable treatment effect was still observed in Q4 NT‑proBNP patients who were adequately stabilized prior to Verquvo use (sufficient stabilization period and diuretic use). The results of a non‑prespecified subgroup analysis showed patients with markedly elevated baseline NT‑proBNP levels (>3,000 pg/ml) who did not have an implantable cardioverter defibrillator or biventricular pacemaker (32% VICTORIA population) had a more pronounced risk of cardiovascular death; the estimated HR for cardiovascular death in this subgroup was 1.38; (95% CI: 1.11, 1.70).

Due to uncertainties regarding differential treatment effects observed in markedly elevated NT‑proBNP patient subgroups, particularly the more pronounced increased risk of cardiovascular death in patients that did not have a cardiac device, a Notice of Deficiency (NOD) was issued by Health Canada to the sponsor on November 23, 2021.

Upon the review of the response from the sponsor, the totality of evidence supports that the increased risk of cardiovascular deaths in patients with markedly elevated NT‑proBNP levels who did not have a cardiac device was attributable to an epiphenomenon in a highly fragile subgroup of advanced heart failure patients. No evidence for a proarrhythmic effect of Verquvo was observed. The different treatment effects of Verquvo in the patient subgroups were likely due to underlying clinical instability, resulting in a heterogeneous treatment effect post‑randomization. Post‑hoc data, particularly from a non‑prespecified subgroup associated with cardiovascular death should be interpreted with caution.

Although some uncertainty remains, appropriate risk mitigation measures were added to the Verquvo Product Monograph for all markedly elevated NT‑proBNP patient subgroups (e.g., warnings and statements promoting adequate clinical stabilization by an experienced healthcare professional prior to Verquvo use, particularly in patients with markedly elevated NT‑proBNP levels) as well as pharmacovigilance activities included in the Risk Management Plan.

Indication

The New Drug Submission for Verquvo was filed by the sponsor with the following indication:

Verquvo (vericiguat) is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following a worsening HF event, in adults with symptomatic chronic HF and ejection fraction less than 45%, in combination with other HF therapies.

To support safe and effective use of the product, Health Canada approved the following indication:

Verquvo (vericiguat) is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent heart failure decompensation event requiring hospitalization and/or intravenous diuretic therapy. Verquvo should be used in combination with standard of care therapy for heart failure.

Verquvo should be initiated under the supervision of a healthcare professional who is experienced in the management of heart failure.

For more information, refer to the Verquvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Verquvo in patients with symptomatic chronic heart failure with reduced ejection fraction (HFrEF) was evaluated in the Phase III VICTORIA trial previously described in the Clinical Efficacy section. The VICTORIA trial included 2,519 patients treated with Verquvo and 2,515 patients treated with a matching placebo. The mean duration of Verquvo exposure was one year, and the maximum duration was 2.6 years. Vital status was obtained for 99.9% of patients after the end of study notification.

Overall, serious adverse events occurred in 32.8% of patients receiving Verquvo and in 34.8% of patients receiving placebo. The most frequently reported adverse reaction leading to discontinuation of treatment was hypotension, which led to study medication discontinuation in 1.9% of patients in the Verquvo group and 1.3% of patients in the placebo group. Permanent discontinuation due to adverse reactions occurred in 7.0% of patients receiving Verquvo and in 6.4% of patients receiving placebo.

The most commonly reported adverse reactions (5% or more of patients receiving Verquvo and with a higher frequency in Verquvo‑treated patients) were hypotension (16.4% Verquvo‑treated patients versus [vs.] 14.9% placebo‑treated patients), anemia (9.6% Verquvo vs. 7.4% placebo) and dizziness (6.7% Verquvo vs. 6.0% placebo). Each of these adverse reactions are considered to be associated with the mechanism of action of the drug and have been previously reported with other soluble guanylate cyclase stimulators. Additional imbalances in adverse reactions reported in 1% or more of patients receiving Verquvo and with a higher frequency in Verquvo‑treated patients were syncope (4.0% Verquvo vs. 3.5% placebo), nausea (3.8% Verquvo vs. 2.7% placebo), headache (3.4% Verquvo vs. 2.4% placebo), dyspepsia (2.7% Verquvo vs. 1.1% placebo), vomiting (2.2% Verquvo vs. 1.8% placebo), gastroesophageal reflux disease (1.7% Verquvo vs. 0.7% placebo), and iron deficiency anemia (1.1% Verquvo vs. 0.8% placebo). A greater proportion of hematocrit decrease (3.9% Verquvo vs. 2.2% placebo) and hemoglobin decrease (5.0% Verquvo vs. 3.2% placebo) was observed in patients receiving Verquvo treatment compared to placebo.

Use in pregnancy and in pediatric patients including use during breastfeeding is uncertain due to lack of data. Use in patients with severe hepatic impairment and end stage kidney failure (<15 mL/min/1.73 m²) is also uncertain as these populations were excluded from clinical studies. The concomitant use of Verquvo with drugs that act on the nitric oxide pathway, such as other soluble guanylate cyclase stimulators, phosphodiesterase‑5 inhibitors, or long‑acting organic nitrates have not been studied in patients with heart failure and remain uncertain. Long‑term safety is also uncertain.

In summary, the efficacy and safety profile of Verquvo is considered acceptable for the target population to be treated. In order to ensure that this benefit continues to outweigh any risk after authorization, potential safety issues of interest will be monitored post‑market in periodic safety reports. Appropriate cautionary statements, such as additional patient monitoring, dosage adjustments/interruptions and factual description of the findings and efficacy and safety concerns are included in the approved Verquvo Product Monograph. These measures are added to guide health professionals and patients on the safe and efficacious use of Verquvo.

For more information, refer to the Verquvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

As described above, the review of the non-clinical component of the New Drug Submission for Verquvo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The non-clinical program for Verquvo included primary pharmacodynamics, secondary pharmacodynamics, safety pharmacology, pharmacokinetic, general toxicology, carcinogenicity, reproductive and developmental toxicology and phototoxicity studies. Toxicology studies were conducted in mice, rats, rabbits, and dogs using the oral route of administration, and were compliant with Good Laboratory Practice principles and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines.

Repeat‑dose toxicity studies in rats revealed prominent myocardial vasculature and hypertrophy of adrenal glands without additional degenerative or pathological findings at exposure margins 11 and 2‑times the human exposure (AUC total) at the maximal human recommended dose (MHRD) of 10 mg/day, respectively. The effects observed in the repeat‑dose toxicity studies were mainly due to either the exaggerated pharmacodynamic activities of vericiguat (the medicinal ingredient in Verquvo) or secondary adaptive responses.

Carcinogenicity studies in mice and rats revealed an absence of carcinogenic effect with margins of exposure of ≥5.7‑times the human exposure (AUC total) at MHRD in rats and ≥41‑times in mice. Non-statistical numerical increases in benign pheochromocytomas and Leydig cell tumors (in males) were observed at exposures 20 times the human exposure (AUC total) at MHRD. No carcinogenicity risk for humans at clinical doses was identified.

Reproductive and developmental toxicity studies revealed exaggerated pharmacodynamic‑mediated maternal and embryo‑fetal toxicity. In rabbits, an increase in late spontaneous abortion was observed at maternally toxic doses ≥3.7‑times human exposure (AUC total) at MHRD. In the pre‑ and post‑natal development study in rats, maternally administered vericiguat caused a reduction in pup body weight and consequently slight delayed sexual maturation at maternally toxic doses ≥7.3 times of MHRD, in terms of body surface area. In rats, vericiguat and/or its metabolites crossed the placenta and was shown to be excreted in milk. Although, the relevance of these findings in humans is unclear, Verquvo is not recommended for use during pregnancy and breastfeeding. 

In rapidly growing adolescent rats, reversible bone effects consisting of hypertrophy of growth plate and hyperostosis and remodeling of metaphyseal and diaphyseal bone were observed at doses ≥22 times the human exposure (AUC total) at MHRD.

The main findings of the non‑clinical program support the safe use of the drug and contribute to the understanding of the toxicological profile which is included in Verquvo Product Monograph.

For more information, refer to the Verquvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

As described above, the review of the quality component of the New Drug Submission for Verquvo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Verquvo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

All sites involved in the production, packaging, labelling, and importation are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.