Summary Basis of Decision for Entresto

Clinical Pharmacology

Entresto, a neprilysin inhibitor/angiotensin receptor blocker (ARB), is a fixed-dose combination of two active ingredients, sacubitril and valsartan. The beneficial effects of Entresto in patients with heart failure likely result from enhancement of protective endogenous systems such as the natriuretic peptide system and other vasoactive neprilysin substrates, and the simultaneous inhibition of organ injury driven by activation of the renin-angiotensin-aldosterone system.

Sacubitril is a New Active Substance (NAS). Oral administration of sacubitril results in inhibition of neprilysin (also known as neutral endopeptidase) following biotransformation of the pro-drug, sacubitril, into its active metabolite, LBQ657. Neprilysin is the key enzyme involved in the degradation of the natriuretic peptides, brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP). The inhibition of neprilysin results in enhancement of the physiologic effects of BNP and ANP. Natriuretic peptides exert their effects by activating membrane-bound guanylyl cyclase coupled receptors, resulting in increased concentrations of the second messenger, cyclic guanosine monophosphate (cGMP), which may lead to physiologically relevant effects, including vasodilation, natriuresis and diuresis, and inhibition of renin and aldosterone release.

Valsartan, an angiotensin II Type-1 (AT₁) receptor blocker, is a well-known active medicinal ingredient that has been available in Canada for almost twenty years for use in the treatment of hypertension and heart failure. Angiotensin receptor blockade is necessary with neprilysin inhibition to counteract the increased activity of angiotensin II, long thought to be detrimental to patients with heart failure. Angiotensin II and aldosterone are the principal effector hormones of the renin-angiotensin-aldosterone system, and are associated with vasoconstriction, renal sodium and fluid retention, resulting in increased blood pressure and blood volume, and activation of cellular growth, leading to proliferation of vascular and cardiac cells. These effects result in maladaptive remodeling of the heart.

Entresto must not be used in combination with an angiotensin-converting enzyme inhibitor (ACEi). Both angiotensin-converting enzyme (ACE) and neprilysin are important in the degradation of bradykinin, a widespread vasoactive peptide. Combined inhibition of both of these enzymes will result in substantial elevations of plasma bradykinin, leading to increased risk of angioedema, a potentially life-threatening adverse reaction. Similarly, Entresto should not be co-administered with any other drug formulation containing an angiotensin II receptor blocker (ARB), due to the angiotensin II receptor blocking activity of Entresto conferred by its valsartan moiety. Based on its demonstrated pharmacologic and therapeutic properties, Entresto must be substituted for either an ACEi or ARB. It is not to be "stacked", i.e., it must not be used simply as add-on treatment. Thus, initiation and up-titration of Entresto requires skill and experience in the treatment of the complex medical condition that is HFrEF. Further, as for all HFrEF therapies, the initiation of Entresto should begin at a low dose, followed by judicious up-titration, as directed in the Product Monograph. Careful patient selection and assessment of patient characteristics is required both before initiation and during use of Entresto to ensure optimal benefit-risk and the prevention of unwanted or unnecessary adverse reactions, such as hypotension or hyperkalemia.

Clinical pharmacological data consisted of reports on the human pharmacodynamic and pharmacokinetic studies, and the safety and tolerability of single and multiple oral doses of Entresto in appropriate populations, including healthy subjects, patients with heart failure, patients with hypertension, and special populations, such as elderly subjects, and subjects with renal or hepatic impairment. These data support the use of Entresto for the recommended indication.

Valsartan is a marketed product with an established pharmacology and safety profile. Angiotensin receptor blockers disrupt embryo-fetal development and are contraindicated during pregnancy.

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

Clinical Efficacy

The effectiveness of Entresto was primarily evaluated in the PARADIGM-HF trial, a Phase III, multinational, randomized, active-controlled, double-blind trial comparing Entresto (sacubitril/valsartan) to enalapril, on top of standard medical therapies for this condition. Enalapril is an ACEi that has long been used in the treatment of this condition. The trial included 8,442 adult patients with symptomatic chronic heart failure and reduced ejection fraction, i.e., left ventricular ejection fraction (LVEF) ≤40% with New York Heart Association (NYHA) functional Class II-IV (a classification of heart failure based on the severity of a patient's symptoms). The primary objective of PARADIGM-HF was to determine whether Entresto, a combination of sacubitril and valsartan, was superior to enalapril in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, in addition to other standard medical therapies.

The PARADIGM-HF trial had a rigorous screening process to ensure that patients who were to be randomized to treatment with Entresto or enalapril had HFrEF with a LVEF ≤40%, and did not have severe renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min], serum potassium >5.2 mmol/L, or systolic blood pressure (SBP) <100 mmHg, at baseline. Patients with a history of angioedema were excluded. Prior to study enrolment, patients were required to have a plasma BNP ≥150 pg/mL or N-terminal pro-BNP (NT-proBNP) ≥600 pg/mL, or, if they had been hospitalized for heart failure in the last 12 months, a BNP ≥100 pg/mL or a NT-proBNP ≥400 pg/mL. Patients had to have been on an ACEi or an ARB at a dose equivalent to at least 10 mg of enalapril daily for at least 4 weeks prior to screening, and on maximally tolerated doses of beta-blockers. Further, all patients were clinically stable prior to study entry.

The PARADIGM-HF trial contained two important sequential run-in phases prior to randomization to ensure that patients to be randomized to study drug (Entresto or enalapril) could tolerate the maximum dose of these drugs. This would allow for a direct comparison of the effectiveness of Entresto with enalapril, without interference due to differing rates of patient tolerability of deemed optimal dosing of these agents.

After discontinuing existing ACEi or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice daily for a median duration of 15 days, followed by one tablet of Entresto containing 48.6 mg sacubitril/51.4 mg valsartan taken twice daily, then increasing to one tablet of Entresto containing 97.2 mg sacubitril/102.8 mg valsartan taken twice daily, for a median duration of 29 days. Patients who successfully completed the sequential run-in periods were randomized to receive either one tablet of Entresto containing 97.2 mg sacubitril/102.8 mg valsartan [total number (n) = 4,209] twice-daily, or enalapril 10 mg (n = 4,233) twice daily, in a double-blind manner. The purpose of the run-in period was:

• to ensure that a minimal mean daily dose of enalapril (16.6 mg) could be achieved during the long-term follow-up period, i.e., during the randomization period. This was the mean daily dose of enalapril that demonstrated a mortality benefit compared to placebo in the classic SOLVD trial in patients with HFrEF. Achieving this dose of enalapril was deemed important to testing the hypothesis that Entresto is superior to guideline-recommended dosing of enalapril in reducing mortality and morbidity in HFrEF patients;
• to maximize the number of randomized patients able to tolerate the target dose of both Entresto and enalapril. It also served to minimize the number of early dropouts in the study after randomization;
• to assess the safety and tolerability of the target doses of enalapril (10 mg twice daily) and Entresto (twice daily) prior to randomization in the absence of prior Phase II safety experience with Entresto in HFrEF.

The population enrolled in the trial was 66% Caucasian, 18% Asian, and 5% Black, with a mean age of 64 years, of which 19% were ≥75 years, 7% were ≥80 years, and <1.5% were ≥85 years. In this trial, 78% of patients were male. At randomization, 70% were NYHA Class II, 24% NYHA Class III, and 0.7% NYHA Class IV. The mean LVEF was about 29% at baseline. The underlying cause of heart failure was coronary artery disease in 60% of patients. Baseline characteristics revealed that 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR of 30-60 mL/min/1.73 m², and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Essentially all patients were taking an ACEi or ARB at baseline. Some patients had an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) (15%).

The patient population of the PARADIGM-HF trial is reflective of the general population of HFrEF patients, and was generally well treated with guideline-recommended standard of care, but still remained at high, or relatively high, risk for cardiovascular mortality and morbidity. Key demographic and disease characteristics were well balanced between treatments.

About 10% of patients enrolled in the PARADIGM-HF trial did not complete the enalapril run-in phase, and another 10% did not complete the Entresto run-in phase, mostly due to intolerable adverse events. Thus, the key issue for deliberation during the review of this submission was the generalizability of the reported post-randomization results to the HFrEF patient population at large. Especially careful consideration to appropriate patient selection criteria and to the advice to be given to prescribers to initiate and then titrate Entresto in an optimal fashion was undertaken during the review of this submission, and was captured in the final Entresto Product Monograph.

In the Entresto group, 76% of patients remained on the target dose of one tablet of 97.2 mg sacubitril/102.8 mg valsartan taken twice daily at the end of the study, with a reported mean daily dose of 182.2 mg sacubitril and 192.8 mg valsartan. In the enalapril group, 75% of patients remained on the target dose of 10 mg twice daily at the end of the study, with a reported mean daily dose of 18.9 mg.

The composite endpoint of time-to-first-occurrence of cardiovascular death or heart failure hospitalization was defined as the primary endpoint in PARADIGM-HF; however, the study was specifically powered for the cardiovascular mortality benefit in order to provide compelling evidence of the benefit of Entresto compared to the current standard of care for this condition. The results of the PARADIGM-HF trial demonstrated superiority of Entresto over enalapril, when enalapril was used at a dose consistent with guideline-recommended dosing.

Entresto reduced the risk of the primary, pre-specified endpoint of cardiovascular death by 20% [Hazard Ratio (HR) 0.80, 1-sided p = 0.00004)] and heart failure hospitalization by 21% (HR 0.79, 1-sided p = 0.00004), and to a greater extent than a standard dose of enalapril in patients with HFrEF. The magnitude of the risk reduction of Entresto over enalapril was statistically significant and clinically meaningful even though Entresto was compared against enalapril given at a dose shown to reduce mortality when compared with placebo. These benefits in improved clinical outcomes occurred in patients receiving other guideline-directed therapies for HFrEF (except for ACEi or ARB) at patient-optimized doses, as well as treatment for other cardiovascular conditions, such as hypertension, dyslipidemia, coronary artery disease, valvular disease, et cetera, that included statins and anti-platelet agents. This risk reduction was generally observed consistently across subgroups including: age, gender, race, geography, ejection fraction, renal function, history of diabetes or hypertension, and presence of atrial fibrillation. The benefit of Entresto was seen early and was sustained for the entire study duration.

Entresto also reduced the risk of all-cause death by 16% when compared to enalapril (HR 0.84, 1-sided p = 0.0005), a secondary endpoint in the study. The treatment difference was sustained during the entire duration of study. The reduction in all-cause mortality was mainly driven by the risk reduction of cardiovascular death, which accounted for 81% of all-cause death in this study. Furthermore, Entresto reduced the risk of sudden death (45% of all cardiovascular deaths) by 20% (HR 0.80, p = 0.008), and reduced the risk of the composite of sudden death or resuscitated sudden death by 22% (HR 0.78, p = 0.003). Entresto also reduced the risk of pump failure (26% of all cardiovascular deaths) by 21% (HR 0.79, p = 0.03).

The duration of the PARADIGM-HF trial was initially planned as 44 months to show the required clinical outcome benefit over standard therapy; however, following an interim assessment of the effectiveness of Entresto, the trial was terminated early, with a median follow-up of 27 months, due to overwhelming efficacy demonstrated in favour of Entresto over enalapril.

In the PARADIGM-HF trial, the final vital status was known for all but 20 (0.24%) patients (11 in the Entresto group, and 9 in the enalapril group).

Supportive Studies

Supportive efficacy data was also submitted from the Phase II TITRATION trial, a safety and tolerability trial that compared two titration regimens of Entresto in patients with HFrEF. TITRATION was a multicentre, randomized, double-blind, parallel group, Phase II study conducted in 538 clinically stable HFrEF outpatients or hospitalized patients, of whom 498 were randomized. The purpose of the study was to provide data on initiating and up-titrating Entresto in patients who were ACEi/ARB naïve, or who were taking various doses of ACEi/ARB. The study population consisted of patients of both genders who were ≥18 years of age and who were diagnosed with HFrEF NYHA Class II-IV, LVEF ≤35%.

The primary objective of this 12-week study was to characterise the safety and tolerability of initiating and up-titrating Entresto in HFrEF patients based on reported adverse events (AEs) and laboratory assessments, including hypotension, renal dysfunction, and hyperkalemia, while using either a 3-week or a 6-week up-titration regimen to achieve the target dose of 97.2 mg sacubitril/102.8 mg valsartan twice daily. In this study, all patients received a dose of 24.3 mg sacubitril/25.7 mg valsartan taken twice daily for one week in a run-in phase, prior to randomization to either the so-called, condensed, or conservative up-titration regimens for Entresto.

The results of this 12-week study of HFrEF patients largely representative of this heart failure patient population demonstrated that Entresto was generally well tolerated following either a condensed or conservative up-titration regimen to achieve the target dose of 97.2 mg sacubitril/102.8 mg valsartan taken twice daily. Patients who were ACEi/ARB naïve or who were taking lower pre-study doses of ACEi/ARB, were better able to achieve and maintain the target dose of Entresto 97.2 mg sacubitril/102.8 mg valsartan twice daily if they were up-titrated more gradually.

Indication

During the original filing of this New Drug Submission (NDS), the sponsor proposed the following indication:

Entresto is for the treatment of heart failure (NYHA Class II-IV) in patients with systolic dysfunction (reduced ejection fraction). Entresto has been shown to reduce the rate of cardiovascular death and heart failure hospitalization, as well as all-cause mortality, compared to enalapril.

Health Canada recommended the following narrowed indication:

Entresto (sacubitril/valsartan) is indicated for the treatment of heart failure with reduced ejection fraction (HFrEF) of NYHA Class II or III, to reduce the incidence of cardiovascular death and heart failure hospitalization.

Entresto should be administered in combination with other heart failure therapies, in place of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB).

Entresto should be initiated, and up-titration conducted, by a physician experienced in the treatment of heart failure.

This indication has been deemed by Health Canada to appropriately reflect the patient population studied in the pivotal Entresto trial, while allowing for its use in clinical settings leading to favourable, clinically-relevant benefit-risk, when used as directed in the Entresto Product Monograph.

About 99.3% of HFrEF patients studied in the pivotal registration trial were assessed as being in NYHA functional Class II or III at study entry. Accordingly, Entresto is not indicated for initiation in patients in NYHA Class IV.

Entresto has only been studied when its initiation occurred as a switch from previous renin-angiotensin system (RAS) blockade, i.e., ACEi or ARB, in addition to other standard treatments of HFrEF, including loop diuretics, beta-blockers, and/or mineralocorticoid receptor antagonists (MRA).

Heart failure with reduced ejection fraction is a complex medical condition. Initiation and up-titration of Entresto requires skill in the treatment of heart failure by the prescribing physician. Careful patient selection is required.

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

Clinical Safety

The Entresto safety database comprises approximately 15,000 patients with heart failure or hypertension, who have been exposed to Entresto at daily doses of up to 400 mg, for treatment durations of up to 51 months. The key safety evaluation focused on patients with HFrEF from the pivotal Phase III trial, PARADIGM-HF (described in the Clinical Efficacy section), comparing the safety profile of Entresto to that of enalapril, when used in addition to other standard cardiovascular therapies. Additional safety data are presented from PARAMOUNT-HF, a Phase II study comparing 97.2 mg sacubitril/102.8 mg valsartan taken twice daily to valsartan 160 mg twice daily with respect to changes in NT-proBNP and several other pharmacodynamic markers in heart failure with preserved ejection fraction (HFpEF) patients. Supportive safety data were also submitted from the TITRATION study (described in the Clinical Efficacy section), a Phase II safety and tolerability study comparing two Entresto up-titration regimens in patients with HFrEF.

The total Entresto exposure across the three Phase II-III heart failure studies, including the run-in periods, was 10,106 patients. For hypertension, the safety database consisted of 3,874 patients who received Entresto. This safety exposure represents an extensive safety experience in heart failure with a substantial duration of exposure, supported by hypertension experience, which ensures a comprehensive and rigorous assessment of the safety of Entresto. Given the number of patients exposed to Entresto treatment in the double-blind portion of PARADIGM-HF Study (n = 4,203), there is a reasonable possibility that rare serious events (i.e., those occurring with an incidence of 1/1,000), may have been detected, helping to characterize the safety profile of Entresto in heart failure.

PARADIGM-HF Trial

During the trial, the Entresto and enalapril treatment groups had a similar duration of exposure in the post-randomization phase. The median duration of follow-up was 27 months, with a maximum exposure of 51 months. A large majority of patients were on the target dose of 97.2 mg sacubitril/102.8 mg valsartan taken twice daily or on the target dose of enalapril 10 mg twice daily throughout the double-blind period. The exposure duration to Entresto in the run-in phase of the trial was longer than that for enalapril, as per study design. In the run-in phase, the median duration of exposure to Entresto was 29 days, as compared to 15 days for enalapril. The longer exposure in the Entresto run-in was taken into consideration when assessing safety information from the run-in period.

Some patients did not complete the sequential enalapril (10.5%) and Entresto (10.4%) run-in periods, including patients who did not meet the protocol-specified continuation safety criteria. Adverse events (AEs) were the most common reason for permanent discontinuation of study medication, with overall, 5.6% and 5.9% of patients discontinuing study medication due to AEs during the enalapril and the Entresto run-in periods, respectively. The most common AEs that led to discontinuation during both run-in periods were hypotension, hyperkalemia, and renal dysfunction.

Run-in Period

In total, 22.5% of patients in the enalapril run-in period experienced AEs. The majority of reported AEs were mild or moderate, with 2.0% of enalapril run-in patients reporting a severe adverse event (SAE). The most commonly reported AEs during the enalapril run-in period were cough (2.8%), hyperkalemia (2.7%), renal impairment (2.2%), and hypotension (2.0%). These AEs led to discontinuation of study treatment in 0.5%, 1.7%, 1.6%, and 1.4% of enalapril run-in patients, respectively. By comparison, 28.7% of patients in the Entresto run-in period experienced an AE. The majority of reported AEs were also mild or moderate with 2.5% of Entresto run-in patients reporting a SAE. The most commonly reported AEs during the Entresto run-in period were hypotension (3.1%), hyperkalemia (2.8%), and renal impairment (2.3%). These AEs led to discontinuation of study treatment in 1.7%, 1.2% and 1.2% of Entresto run-in patients, respectively. It should be noted, that in these run-in phases, the median duration of exposure was almost twice as long for Entresto treatment, compared to enalapril, and that their order, in that the enalapril run-in phase preceded the Entresto treatment phase in all cases, should be expected to influence reported rates of AEs, SAEs, and study discontinuations in each of these study run-in periods.

Serious adverse events were reported in 2.6% of the enalapril run-in patients, the most common of which were SAEs involving cardiac disorders, which occurred in 1.4% of patients. For the Entresto run-in patients, SAEs were reported in 3.5% of patients, the most common of which were SAEs involving cardiac disorders, which occurred in 1.8% of patients. Serious adverse events of hypotension, renal and urinary disorders, and hyperkalemia occurred in <0.1% of both enalapril and Entresto run-in patients.

Post-Randomization Phase

The most commonly reported AEs, reported by ≥5% of patients in any treatment group, were hypotension, cardiac failure, hyperkalemia, renal impairment, cough, dizziness, atrial fibrillation, pneumonia, peripheral edema, dyspnea, and bronchitis.

Hypotension is often observed in heart failure patients, as many of their medications have blood pressure lowering effects. Entresto also has a blood pressure lowering effect, based on its ARB and neprilysin inhibition properties. Hypotension was reported more frequently as an AE in the Entresto group compared to the enalapril group, at 17.6% versus (vs.) 11.9%, respectively; however, the incidence of hypotension as an SAE was similar between Entresto (1.4%) vs. enalapril (1.6%). The incidence of hypotension as an AE leading to treatment discontinuation was low and comparable between the two groups: Entresto (0.6%) vs. enalapril (0.5%).

Dizziness was more frequently reported with Entresto (6.3%) compared with enalapril (4.9%).

Hyperkalemia was less frequently reported in the Entresto group (11.6%) compared to enalapril (14.0%).

The incidence of hypokalemia was higher with Entresto (3.3%) when compared to the enalapril group (2.5%). This higher incidence of hypokalemia with Entresto is consistent with the lower incidence of hyperkalemia with Entresto. This may be a result of natriuretic and diuretic effects of Entresto.

Cough was less frequently reported in the Entresto group (8.8%) compared to the enalapril group (12.6%).

The incidence of renal failure was lower in the Entresto group (2.7%) compared to the enalapril group (3.4%). The incidence of acute renal failure was similar between the two groups, reported as 2.3% for Entresto vs. 2.2% for enalapril.

Overall, the incidence of SAEs during the double-blind period was numerically lower in the Entresto group (46.1%) compared to the enalapril group (50.7%). The most common SAE was cardiac failure, occurring in 14.0% in the Entresto group and 15.4% in the enalapril group. Serious adverse events of hypotension occurred at 1.4% for Entresto and 1.6% for enalapril. Numerically, with the exception of dizziness, all other SAEs were lower in the Entresto group, including syncope, pneumonia, renal failure, and renal impairment.

Overall Analysis of Safety

Adequate safety characterization of Entresto has been carried out for its use in the HFrEF patient population. The most common adverse drug reactions observed were hypotension and hyperkalemia. The incidence of hypotension was more frequent with Entresto than with the comparator, enalapril, although the incidence of serious hypotension was not markedly increased. Hypotension events did not result in more SAEs, and the incidence of study drug discontinuations with Entresto was comparable relative to enalapril. Hypotension was generally manageable with dose reduction or temporary interruption of treatment. The incidence of hyperkalemia was not more frequent than observed with enalapril, a drug that is known to increase this adverse event. Angioedema occurred more frequently with Entresto, but most of these cases were not life-threatening. Angioedema occurred more commonly in black patients than non-black patients treated with Entresto. If angioedema occurs, Entresto should be immediately discontinued, and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Entresto must not be re-administered.

Entresto must not be administered with an ACEi due to the risk of angioedema. Treatment with Entresto must not be initiated until at least 36 hours have elapsed following discontinuation of ACEi therapy. If treatment with Entresto is stopped, ACEi therapy must not be initiated until 36 hours after the last dose of Entresto.

Entresto should not be co-administered with any other drug formulation containing an ARB, due to the angiotensin II receptor blocking activity of Entresto by its valsartan moiety.

Caution is required while co-administering Entresto with direct renin inhibitors such as aliskiren. In general, such use is not recommended, since this combination has not been adequately studied. Entresto must not be administered with aliskiren in patients with Type 2 diabetes or having significantly impaired renal function.

The following warning has been included in a Serious Warnings and Precautions box in the Product Monograph for Entresto: When used in pregnancy, angiotensin receptor (AT₁) blockers (ARB) can cause injury or even death of the developing fetus. When pregnancy is detected, Entresto should be discontinued as soon as possible. Appropriate warnings and precautions are in place in the approved Entresto Product Monograph to address the identified safety concerns.

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