UNMET NEEDS IN THE MANAGEMENT OF HEART FAILURE

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1 UNMET NEEDS IN THE MANAGEMENT OF HEART FAILURE By Mohammed Sadaka, MD ALEXANDRIA UNIVERSITY 2 Presentation Title Presenter Name Date Subject Business Use Only 1

2 HF is a complex syndrome involving multiple organ systems and is associated with high re-hospitalization and mortality rates HF is a chronic progressive condition, punctuated by acute episodes Each acute event results in further organ damage; myocardial and renal damage occurring during such episodes may contribute to progressive left ventricular and/or renal dysfunction Increasing frequency of acute events with disease progression leads to high rates of hospitalization and increased risk of mortality Cardiac function and quality of life Chronic decline Hospitalizations for acute decompensation episodes Disease progression 3 1. Mihai Gheorghiade, Leonardo De Luca, Gregg C. Fonarow, et al. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol 2005;96:11 17; 2. Gheorghiade & Pang. Acute heart failure syndromes.j Am Coll Cardiol 2009;53: Heart failure Mortality statistics Mortality rates in heart failure are high even for patients compliant with the best available treatments 1 ~50 % DIE WITHIN 5 YEARS OF DIAGNOSIS 2 When heart failure symptoms are stabilised by current treatments, it may seem that patients are doing well, but the neurohormonal imbalance underlying heart failure is still silently occurring, resulting in disease progression. 1 The impact of heart failure on individuals is significant, and the worldwide prevalence is high 1. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA. 2004;292(3):

3 Evolution of heart failure therapy Only the first approval time for each therapeutic class is shown arecommended for AHF after stabilisation; brecommendation for treatment of hypertension in patients with symptomatic HF (NYHA functional class II-IV) and LV systolic dysfunction; ctolvaptan may be used to treat patients with resistant hyponatremia; deuropean Medical Agency has approved ivabradine for use in patients with a heart rate 75 bpm. May also be considered in patients with a contraindication to β-blockers. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin-receptor blocker; MRA: mineralocorticoid receptor antagonist; SNI: sinus node If channel inhibitor; VRA: vasopressin receptor antagonist Have current treatments fulfilled all gaps in Heart failure management? A. Yes B. No C. Not sure 6 3

4 Reduction in relative risk of mortality vs placebo Mortality in HFrEF remains high despite the introduction of new therapies that improve survival Survival rates in chronic HF have improved with the introduction of new therapies 1 ACEI* β-blocker* MRA* ARB* 16% (4.5% ARR; mean follow up of 41.4 months) SOLVD 1,2 34% (5.5% ARR; mean follow up of 1.3 years) CIBIS-II 3 30% (11.0% ARR; mean follow up of 24 months) RALES 4 17% (3.0% ARR; median follow up of 33.7 months) CHARM- Alternative 5 However, significant mortality remains ~50% of patients die within 5 years of diagnosis 6 8 *On top of standard therapy at the time of study (except in CHARM-Alternative where background ACEI therapy was excluded). Patient populations varied between trials and as such relative risk reductions cannot be directly compared. SOLVD (Studies of Left Ventricular Dysfunction), CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized Aldactone Evaluation Study) enrolled chronic HF patients with LVEF 35%. CHARM-Alternative (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) enroled chronic HF patients with LVEF 40% ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor blocker; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction; MRA=mineralocorticoid receptor antagonist 1. McMurray et al. Eur Heart J 2012;33: ; 2. SOLVD Investigators. N Engl J Med 1991;325: ; 3. Granger et al. Lancet 2003;362:772 6; 4. CIBIS-II Investigators. Lancet 1999;353:9 13; 5. Pitt et al. N Engl J Med 1999;341:709-17; 50; 6. Go et al. Circulation 2014;129:e28-e292; 7. Yancy et al. Circulation 2013;128:e ; 8. Levy et al. N Engl J Med 2002;347: PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF CHRONIC HF HAVE YET TO REALIZE THE POTENTIAL OF ENHANCING THE NATRIURETIC PEPTIDE SYSTEM 4

5 Decline in Systolic Function leads to Activation of Three Major Neurohormonal Systems Sympathetic nervous system 2 Natriuretic peptide system 1,2,3 NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine Renin angiotensin aldosterone system 2 Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Ang=angiotensin; AT 1R=angiotensin II type 1 receptor; HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system 1. Ellis r. Levin m.d., David g. Gardner, m.d.,and willisk. Samson, ph.d. Natriuretic peptides The New England Journal of Medicine 1998;339: Surakit Nathisuwan, Pharm.D., and Robert L. Talbert, Pharm.D., FCCP A review of vasopeptidase inhibitors: A new modality in the treatment of hypertension and chronic heart failure Pharmacotherapy 2002;22(1): Clinton D. Kemp, John V. Conte The pathophysiology of heart failure Cardiovascular Pathology 21 (2012) Evolution of pharmacologic approaches in HF: Neprilysin inhibition as a new therapeutic strategy in patients with HF1 NP system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Neprilysin inhibitors INACTIVE FRAGMENTS HF SYMPTOMS & PROGRESSION SNS Epinephrine Norepinephrine RAAS Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis β-blockers RAAS inhibitors (ACEI, ARB, MRA) NEP inhibitors: natriuretic and other vasoactive peptides enhancement ACEI=angiotensin-converting-enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT1 = angiotensin II type 1; HF=heart failure; MRA=mineralocorticoid receptor antagonist; NEP=neprilysin; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=reninangiotensin-aldosterone system; SNS=sympathetic nervous system 1. McMurray et al. Eur J Heart Fail. 2013;15: ; Figure references: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012; ; Schrier & Abraham N Engl J Med 2009;341:

6 Natriuretic peptides have potential beneficial actions in HF Release of ANP and BNP from heart and CNP in vasculature 1 Sympathetic outflow 1 Vasopressin 1 Salt appetite and water intake 1 CNP (endothelium) 2 ANP/BNP 1 Relaxation; arterial stiffness 2 Hypertrophy 1,4,5,6 Fibroblast proliferation 3 Na + /H 2 O loss 1 Aldosterone 1 Renin 1 Vasodilation 1,2,3 Systemic vascular resistance 3 Pulmonary artery pressure 3 Pulmonary capillary wedge pressure 3 Right atrial pressure 3 1. Levin,Gardner,samsonet.Natriuretic peptides. N Engl J Med 1998;339;321 8; 2. Lumsden,khambata,Hobbs C-type natriuretic peptide (CNP): cardiovasular roles and potential as therapeutic target.. Curr Pharm Des 2010;16:4080 8; ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; 11 CNP=C-type natriuretic peptide; HF=heart failure; H 20=water; NA=sodium 3. Langenickel & Dole. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure Drug Discovery Today: Ther Strateg 2012;9:e131 9; 4. Gardner,chen,glenn,Grigsby Molecular Biology of the Natriuretic Peptide System Implications for Physiology and Hypertension. Hypertension 2007;49:419 26; 5. Tokudome,kishimoto,Horio.et al.regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart. Circulation 2008;117; ; 6. Horio,nishkimi,yoshihara et al. Inhibitory Regulation of Hypertrophy by Endogenous Atrial Natriuretic Peptide in Cultured Cardiac Myocytes.Hypertension 2000;35:19 24; Have there been treatment approaches to utilize the potential of enhancing the NP system? A. Yes B. No C. Not sure 12 6

7 New Modalities in the treatment of Heart Failure patients 1981 Discovery of ANP 2002 Omapatrilat (NEPi+ACEI)* OVERTURE study LCZ696 (ARNI) PARADIGM-HF study s 1990s 2000s 2010s Approved HF agents Digitalis Diuretics Vasodilators Inotropes (dobutamine) MRA (spironolactone) ACEIs (captopril; enalapril) *Development terminated 3 ACEIs (lisinopril) β-blockers(bisoprolol) ACEIs (ramipril) ARBs (candesartan; valsartan) β-blockers (metoprolol) MRA (eplerenone) H-ISDN (hydralazine and isosorbide dinitrate) I f channel inhibitor (ivabradine) Since the discovery of ANP in 1981, numerous agents have been adopted into clinical practice for treatment of chronic HF 1,2 Despite the known potential beneficial effects of the natriuretic peptide system, 3 enhancing this system is not exploited by any currently approved chronic HF agents ACEI=angiotensin-converting-enzyme inhibitor; ANP=atrial natriuretic peptide;; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; HF=heart failure; MRA=mineralocorticoid receptor. de Bold et al. Life Sci 1981;28:89 94; 2.McMurray et al. Eur Heart J 2012;33: ; 3. Langenickel & Dole. Drug Discov antagonist; NEPI=neprilysin inhibitor; NP=natriuretic peptide; OVERTURE=Omapatrilat Versus Enalapril Today: Ther Strateg ;9:e131 9; 4. Packer et al. Circulation 2002;106:920 6; 5. McMurray et al. Eur J Heart Fail. Randomized Trial of Utility in Reducing Events; PARADIGM-HF= Prospective comparison of ARNI with ACEI to 2014;16: See notes for drug timeline references Determine Impact on Global Mortality and morbidity in Heart Failure 13 NOT ALL PHARMACOLOGICAL APPROACHES TO ENHANCE NP SYSTEM WERE SUCCESSFUL 7

8 15 WHAT ABOUT OTHER TREATMENT MODALITIES? 8

9 LCZ696 is a first-in-class angiotensin receptor neprilysininhibitor (ARNI) LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) ARNI=angiotensin receptor neprilysin inhibitor; AT 1 =angiotensin II type 1 LCZ696 is a novel drug which delivers simultaneous neprilysin inhibition and AT 1 receptor blockade 1 3 LCZ696 is a salt complex that comprises the two active components: 2,3 sacubitril (AHU377) a pro-drug; further metabolized to the neprilysin inhibitor LBQ657, and valsartan an AT 1 receptor blocker in a 1:1 molar ratio 3D LCZ696 structure 2 1. Michael J Bloch, Jan N Basile Combination angiotensin receptor blocker-neutral endopeptidase inhibitor provides additive blood pressure reduction over angiotensin receptor blocker alone,j Clin Hypertens 2010;12: Jessie Gu, PhD, Adele Noe, PhD, Priya Chandra, PhD, et al Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual-Acting Angiotensin Receptor Neprilysin Inhibitor (ARNi),J Clin Pharmacol 2010;50: Langenickel & Dole. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discov Today: Ther Strateg 2012;9:e LCZ696 MECHANISM OF ACTION 9

10 LCZ696 simultaneously inhibits neprilysin (via LBQ657) and blocks AT 1 receptors (via valsartan) 1-4 ANP, BNP, CNP, other vasoactive peptides* LCZ696 Sacubitril (AHU377; pro-drug) RAAS Angiotensinogen (liver secretion) Ang I Inactive fragments LBQ657 (NEP inhibitor) Valsartan Ang II Enhancing Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis *Neprilysin substrates listed in order of relative affinity for neprilysin: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP Ang=angiotensin; ANP=atrial natriuretic peptide; AT1=angiotensin II type 1; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; NEP=neprilysin; RAAS=renin-angiotensin-aldosterone system 19 O HO HN O OH O O N N N N O OH NH AT 1 receptor Inhibiting Vasoconstriction Blood pressure Sympathetic tone Aldosterone Fibrosis Hypertrophy 1. Ellis R Levin, David G Gardener, Willis K Samson, Natriuretic Peptides N Engl J Med 1998;339: Surakit Nathisuwan, Pharm.D., and Robert L. Talbert, Pharm.D., FCCP A Review of Vasopeptidase Inhibitors: A New Modality in the Treatment of Hypertension and Chronic Heart Failure Pharmacotherapy 2002;22: Robert W Schrier & William T. Abraham Hormones and Hemodynamics in Heart Failure. N Engl J Med 2009;341: Langenickel & Dole. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure.drug Discov Today: Ther Strateg 2012;9:e131 9 PARADIGM-HF STUDY PROSPECTIVE COMPARISON OF ARNI WITH ACEI TO DETERMINE IMPACT ON GLOBAL MORTALITY AND MORBIDITY IN HEART FAILURE A multicenter, randomized, double-blind, parallel-group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared with enalapril on morbidity and mortality in patients with chronic HF and reduced ejection fraction PARADIGM-HF Study Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure 10

11 PARADIGM-HF: Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure PARADIGM-HF: Is the first study to test the effect of LCZ696 on morbidity and mortality in patients with HFrEF primarily evaluates whether simultaneous angiotensin receptor neprilysin inhibition with LCZ696 compared with enalapril, in addition to conventional HF treatment delays time to first occurrence of either CV death or HF hospitalization in patients with stable NYHA FC II IV HF and reduced ejection fraction (LVEF 40%*) Determined the place of the ARNI LCZ696 as an alternative to an ACEI (enalapril) in patients with chronic systolic HFrEF May change the approach to neurohormonal modulation in HFrEF *The ejection fraction entry criteria was lowered to 35% in a protocol amendment. ACEI=angiotensin-converting enzyme inhibitor; ARNI=angiotensin receptor neprilysin inhibitor; CV=cardiovascular; FC=functional class; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction; NYHA= New York 22 Heart Presentation Association Title Presenter Name Date Subject Business Use Only McMurray.packer.Desai et al. Dual angiotension receptor neprylisin inhibition as ana alternative to angiotension converting enzyme inhibition in patients with chronic systolic heart failure rationale for design of the prospective comparison of ARNI and ACEI to determine impact on global mortality and morbidity in heart failure trial(paradigm).eur J Heart Fail 2013;15: Paradigm study is comparing LCZ696 to... A. Placebo B. Enalapril 10 mg bid C. Not sure ARNI=angiotensin receptor neprilysin inhibitor; AT 1 =angiotensin II type 1 11

12 PARADIGM-HF: study design 1-3 Single-blind active run-in period Randomization n=8442 Double-blind Treatment period LCZ mg BID Enalapril 10 mg BID* LCZ mg BID LCZ mg BID Enalapril 10 mg BID # 2 Weeks 1 2 Weeks 2 4 Weeks *Enalapril 5 mg BID (10 mg TDD) for 1 2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated with ARBs or with a low dose of ACEI; 200 mg TDD; 400 mg TDD; # 20 mg TDD. ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; BID=twice daily; HFrEF=heart failure with reduced ejection fraction; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; TDD=total daily dose Median of 27 months follow-up On top of standard HFrEF therapy (excluding ACEIs and ARBs) 1.McMurray.packer.Desai et al. Dual angiotension receptor neprylisin inhibition as ana alternative to angiotension converting enzyme inhibition in patients with chronic systolic heart failure rationale for design of the prospective comparison of ARNI ans ACEI to determine impact on global mortality and morbidity in heart failure trial(paradigm).eur J Heart Fail 2013;15: McMurray.Packer.Desai.et al. Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF Eur J Heart Fail 2014;16: McMurray.packer.Desai.et al. Angiotension neprylsin inhibition versus enalpril in heart failure.n Engl J Med 2014;371: PARADIGM-HF: Key Inclusion Criteria Chronic HF NYHA FC II IV with LVEF 40%* BNP (or NT-proBNP) levels as follows: 150 (or 600 pg/ml), or 100 (or 400 pg/ml) and a hospitalization for HFrEF within the last 12 months 4 weeks stable treatment with an ACEI or an ARB, and a β-blocker Aldosterone antagonist should be considered for all patients (with treatment with a stable dose for 4 weeks, if given) *The ejection fraction entry criteria was lowered to 35% in a protocol amendment; Dosage equivalent to enalapril 10 mg/day. ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; BNP=B-type natriuretic peptide; FC=functional class; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction; NT-proBNP=N-terminal pro-b-type natriuretic peptide; NYHA=New York Heart Association; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure McMurray JJ, Packer M, Desai AS et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF).Eur J Heart Fail 2013;15:

13 Cumulative proportion of patients with primary end point (%) RESULTS Results Overall 20% reduction in risk of CV death or unplanned HF hospitalization HR: 0.80 (95% CI 0.73, 0.87) p= Enalapril 1,117 (n=4,212) % LCZ696 (n=4,187) At risk Enalapril: LCZ696: 1-sided p value shown ,080 1,260 CI=confidence interval; CV=cardiovascular; 27 HR=hazard ratio Days after randomization 4,212 3,883 3,579 2,922 2,123 1, ,187 3,922 3,663 3,018 2,257 1, McMurray et al. N Engl J Med 2014;371: ; Novartis Data on File: PARADIGM-HF Clinical Study Report 13

14 Cumulative proportion of patients who died from any cause (%) Cumulative proportion of patients who died from CV causes (%) Cumulative proportion of patients who were hospitalized for HF (%) Results Overall 20% reduction in risk of CV death alone and 21% reduction in risk of UHHF alone 40 HR: 0.80 (95% CI 0.71, 0.89) p= HR: 0.79 (95% CI 0.71, 0.89) p= Enalapril (n=4,212) % 20 Enalapril (n=4,212) % 10 LCZ696 (n=4,187) 10 LCZ696 (n=4,187) ,080 1, ,080 1,260 Days after randomization Days after randomization 1-sided p value shown UHHF=unplanned hospitalization for heart failure 28 McMurray et al. N Engl J Med 2014;371: ; Novartis Data on File: PARADIGM-HF Clinical Study Report Results Overall 16% reduction in risk of all-cause death 40 HR: 0.84 (95% CI 0.76, 0.93) p= Enalapril (n=4,212) LCZ696 (n=4,187) % ,080 1,260 Days after randomization 29 1-sided p value shown McMurray et al. N Engl J Med 2014;371: ; Novartis Data on File: PARADIGM-HF Clinical Study Report 14

15 Total number of events In patients who were alive, LCZ696 was also superior to enalapril in reducing 4,500 4,000 3,500 LCZ696 (n=4,187) Enalapril (n=4,212) RR=0.84 p< ,000 2,500 RR=0.84 p< ,000 1,500 1, HR=0.84 p=0.003 RR=0.70 p=0.017 RR=0.82 p=0.005 RR=0.77 p< Intensification of outpatient HF therapy Total ED visits for HF All of this while enalapril had: i. fewer survivors, and ii. greater intensification of therapy Total stays in intensive care Total hospitalizations for HF Total hospitalizations for CV reasons Total hospitalizations for any reason 30 ED=emergency department; RR=relative risk Packer et al. Circulation 2014;131:54-61 SECONDARY ANALYSIS: CLINICAL PROGRESSION Packer et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with HFrEF Circulation 2015;131:

16 Proportion of patients (%) EMERGENCY DEPARTMENT VISITS AND HOSPITALIZATIONS Lower proportion of HFrEF patients on LCZ696 were treated in the emergency department for worsening of HF (discharge without hospitalization) 4 HR 0.66 (95% CI: ) p= % 3 2.4% p= % LCZ696 (N=4,187) Enalapril (N=4,212) 2 1.9% 1 0 p=0.003 p= % 0.4% n=102 n=102 n=150 n=78 n=78 n=111 n=111 n=15 n=27 n=15 n=15 n=27 n=27 n=9 n=9n=12 n=12 n=12 Total number of patients visiting the emergency department once and multiple times Number of emergency department visits without hospitalization CI=confidence interval; HF=heart failure; HR=hazard 33ratio Packer M, McMurray JJ, Desai AS et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure Circulation 2015;131:

17 Kaplan-Meier estimate of cumulative rate Proportion of patients (%) Treatment with LCZ696 resulted in a lower likelihood of multiple hospitalizations for HF 16 HR 0.79 (95% CI: ) p< % LCZ696 (N=4,187) Enalapril (N=4,212) % p< % 8.8% 29% fewer HFrEF patients were hospitalized more than once for HF with LCZ696 than with enalapril (n=170 and n=240, respectively; p=0.001) 8 6 p< n=537 n=658 Total number of patients hospitalized for HF once and multiple times 3.4% 2.6% p<0.001 p< % 0.8% 1.0% 0.6% n=367 n=418 n=110 n=143 n=33 n=53 n=27 n= Number of admissions for HF CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; HR=hazard 34 ratio Packer M, McMurray JJ, Desai AS et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure Circulation 2015;131:54 61 The reduction in HF hospitalization with LCZ696 was evident within the first 30 days after randomization 1.5 Enalapril (N=4,212) LCZ696 (N=4,187) 1.0 HR 0.60 (95% CI: ) p= Days after randomization Number of patients at risk LCZ696 4,187 4,174 4,153 4,140 Enalapril 4,212 4,192 4,166 4,143 Shown is the Kaplan-Meier estimate of the cumulative probability of a first hospitalization for HF during the first 30 days after randomization. The 35analysis at 30 days was prespecified and also represented the earliest time point at which the difference between the LCZ696 and enalapril groups was statistically significant. CI=confidence interval; HF=heart failure; HR=hazard ratio Packer M, McMurray JJ, Desai AS et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure Circulation 2015;131:

18 Proportion of HFrEF patients with worsening HF leading to intensification of outpatient therapy* (%) Lower proportion of patients treated with LCZ696 required intensification of outpatient HF therapy* (defined as treatment failure) HR 0.84 (95% CI: ) p= % 14.3% n=520 n=604 LCZ696 (N=4,187) Enalapril (N=4,212) Addition of a new drug for treatment of HF, intravenous therapy or increase in daily dose of diuretic; for >1 month, prospectively defined as a treatment failure. CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection 36 fraction; HR=hazard ratio Packer M, McMurray JJ, Desai AS et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure Circulation 2015;131:54 61 PARADIGM-HF: POST-HOC ANALYSIS Effects on quality of life (AHA congress, Orlando, FL, Nov2015) 18

19 Change in KCCQ scores at 8 months Health-Related Quality of Life - Kansas City Cardiomyopathy Questionnaire Health-related quality of life (HRQL) is a key target of therapy in the management of patients with CHF KCCQ: directly completed by the patient (patient-based); supplements NYHA Functional class (provider-based) HF Pathology oxygenation to tissues Signs & Symptoms Fatigue Weakness Dyspnea Impacts Decreased Physical abilities Worsening symptoms Social needs and self-help PRO Kansas City Cardiomyopathy Questionnaire Concept Physical Function Symptom domains Self efficacy/ social limitation HRQL= health-related quality of life; KCCQ= Kansas city cardiomyopathy questionnaire; CHF= chronic heart failure; NYHA= New York Heart Association Lewis E, et al. Circulation. 2015;132:A Between-treatment Analysis of Change* in KCCQ Summary Scores and all KCCQ Domains at 8 Months *Adjusted for baseline score and treatment **LSM differences range from favoring LCZ696 with p-values range from 0.05 to <0.001 KCCQ Kansas City Cardiomyopathy Questionnaire, LSM Least squares mean, OS- Overall summary, CS-clinical summary Lewis E, et al. Circulation. 2015;132:A

20 Patients who discontinued study drug (%) Prospectively defined safety events Event, n (%) LCZ696 (n=4,187) Enalapril (n=4,212) p value Hypotension Symptomatic 588 (14.0) 388 (9.2) <0.001 Symptomatic with SBP <90 mmhg 112 (2.7) 59 (1.4) <0.001 Elevated serum creatinine 2.5 mg/dl 139 (3.3) 188 (4.5) mg/dl 63 (1.5) 83 (2.0) 0.10 Elevated serum potassium >5.5 mmol/l 674 (16.1) 727 (17.3) 0.15 >6.0 mmol/l 181 (4.3) 236 (5.6) Cough 474 (11.3) 601 (14.3) <0.001 Angioedema (adjudicated by a blinded expert committee) No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19 Catecholamines or glucocorticoids without hospitalization 6 (0.1) 4 (0.1) 0.52 Hospitalized without airway compromise 3 (0.1) 1 (<0.1) 0.31 Airway compromise Fewer patients in the LCZ696 group than in the enalapril group stopped their study medication because of an AE (10.7 vs 12.3%, p=0.03) AE=adverse event; SBP=systolic blood pressure McMurray JJ, Packer M, Desai AS et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371: Adverse events leading to permanent study drug discontinuation Fewer patients in the LCZ696 group than in the enalapril group discontinued study drug due to an adverse event (10.7 vs 12.3%; p=0.03) 15 p= LCZ696 (n=4,187) Enalapril (n=4,212) 5 0 Any adverse event p=0.38 p= p= Hypotension Renal impairment Hyperkalemia McMurray JJ, Packer M, Desai AS et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:

21 Summary of results safety The superiority of LCZ696 over enalapril was not accompanied by important safety concerns Fewer patients stopped their study medication because of an adverse event in the LCZ696 group than in the enalapril group There was no increase in the rate of discontinuation due to possible hypotension-related adverse effects, despite a higher rate of symptomatic hypotension in the LCZ696 group Fewer patients in the LCZ696 group developed renal impairment, hyperkalemia or cough than in the enalapril group The LCZ696 group had a higher proportion of patients with non-serious angioedema, but LCZ696 was not associated with an increase in serious angioedema 46 McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371: Conclusions from the PARADIGM-HF results publication angiotensin receptor neprilysin inhibition with LCZ696 was superior to ACE inhibition alone in reducing the risks of death and of hospitalization for HF The magnitude of the beneficial effect of LCZ696, as compared with enalapril, on CV mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo. This robust finding provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the RAS alone in patients with chronic HF. results are applicable to a broad spectrum of patients with HF, including those who are currently taking an ACE inhibitor or ARB or who are likely to be able to take such an agent without having unacceptable side effects. ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; CV=cardiovascular; HF=heart failure; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and 47 morbidity in Heart Failure; RAS=renin-angiotensin system McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:

22 Commentary from the accompanying NEJM editorial PARADIGM-HF may well represent a new threshold of hope for patients with HF Now, a novel drug, LCZ696, a dual inhibitor of angiotensin II receptor and neprilysin, may prove to be the first disruptive agent to the heartfailure treatment algorithm, which has remained essentially unchanged for a decade The beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy HF=heart failure; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart 48 Failure Jessup M. Neprilysin inhibition--a novel therapy for heart failuren Engl J Med 2014;371: THANK YOU 22

Sacubitril/Valsartan in HFrEF for All Protagonist View George Honos MD FRCPC FCCS FACC

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