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 August 2014/GMCC_NP4 request 275741/expiry August 2015

SYMPTOMS & PROGRESSION RAAS inhibitors (ACEI, ARB, MRA) Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis of therapy β-blockers SNS Epinephrine Norepinephrine α1, β1, β2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Natriuretic peptide system HFrEF SYMPTOMS & PROGRESSION Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy NPRs NPs RAAS inhibitors (ACEI, ARB, MRA) RAAS Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Ang II AT1R Abbreviations 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=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system References 1. McMurray et al. Eur J Heart Fail. 2013;15:1062–73; 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;365–371; Schrier & Abraham N Engl J Med 2009;341:577–85 The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1 Benefits of β-blockers indicate that the SNS also plays a key role1 1. McMurray et al. Eur Heart J 2012;33:1787–847 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;365–371; Schrier & Abraham. N Engl J Med 2009;341:577–85;

Natriuretic peptides have potential beneficial actions in HF Release of ANP and BNP from heart and CNP in vasculature1 ANP/BNP2 Relaxation;  arterial stiffness4 CNP (endothelium)3  Sympathetic outflow2  Vasopressin2  Salt appetite and water intake2  Hypertrophy2,5–7  Fibroblast proliferation4,8,9  Na+/H2O loss2  Aldosterone2  Renin2 Abbreviations ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; HF=heart failure References Forssmann et al. Arch Histol Cytol 1989;52 Suppl:293–315 Levin et al. N Engl J Med 1998;339;321–8 Lumsden et al. Curr Pharm Des 2010;16:4080–8 Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9 Gardner et al. Hypertension 2007;49:419–26 Tokudome et al. Circulation 2008;117;2329–39 Horio et al. Endocrinology 2003;144:2279–84 D'Souza et al. Pharmacol Ther 2004;101:113–29 Cao & Gardner. Hypertension 1995;25:227–34 Vasodilation2,3,4  Systemic vascular resistance4  Pulmonary artery pressure4  Pulmonary capillary wedge pressure4  Right atrial pressure4 1. Forssmann et al. Arch Histol Cytol 1989;52 Suppl:293–315; 2. Levin et al. N Engl J Med 1998;339;321–8; 3. Lumsden et al. Curr Pharm Des 2010;16:4080–8; 4. Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9; 5. Gardner et al. Hypertension 2007;49:419–26; 6. Tokudome et al. Circulation 2008;117;2329–39; 7. Horio et al. Endocrinology 2003;144:2279–84; 8. D'Souza et al. Pharmacol Ther 2004 ;101:113–29; 9. Cao & Gardner. Hypertension 1995;25:227–34;

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 is a novel drug which delivers simultaneous neprilysin inhibition and AT1 receptor blockade1–3 LCZ696 is a salt complex that comprises the two active moieties:2,3 sacubitril (AHU377) – a pro-drug; further metabolized to the neprilysin inhibitor LBQ657, and valsartan – an AT1 receptor blocker in a 1:1 molar ratio 3D LCZ696 structure2 1. Bloch, Basile. J Clin Hypertens 2010;12:809–12; 2. Gu et al. J Clin Pharmacol 2010;50:401–14; 3. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9

LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks the AT1 receptor (via valsartan) Natriuretic and other vasoactive peptides* RAAS Angiotensinogen (liver secretion) – Neprilysin Sacubitril (AHU377; pro-drug) Ang I Inactive fragments LBQ657 (NEP inhibitor) OH O HN HO Valsartan N NH O OH – Ang II AT1 Receptor Vasorelaxation  Blood pressure  Sympathetic tone  Aldosterone levels  Fibrosis  Hypertrophy  Natriuresis/diuresis Enhancing Vasoconstriction  Blood pressure  Sympathetic tone  Aldosterone  Fibrosis  Hypertrophy Inhibiting Abbreviations 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 Following oral administration LCZ696 dissociates into the prodrug sacubitril (AHU377), which is further metabolized to LBQ657, and valsartan LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor. LCZ696 dissociates into the neprilysin inhibitor prodrug sacubitril (AHU377), which is subsequently converted to an active form (LBQ657) that inhibits neprilysin – the enzyme that degrades the biologically active natriuretic peptides – and the AT1 receptor blocker valsartan. Of note, the biologically inert NT-proBNP is not a substrate for LBQ657, and as such still represents a measure of cardiac wall stress even in the setting of neprilysin inhibition. Neprilysin also contributes to the breakdown of angiotensin, which provides the rationale for simultaneous inhibition of neprilysin and blockade of the renin-angiotensin-aldosterone system (RAAS). LCZ696 thus simultaneously inhibits the RAAS and augments the natriuretic peptide system, providing the potential for complementary benefits in heart failure. References Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42 Schrier & Abraham N Engl J Med 2009;341:577–85 Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9 Feng et al. Tetrahedron Letters 2012;53:275–6 *Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Schrier & Abraham N Engl J Med 2009;341:577–85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9; Feng et al. Tetrahedron Letters 2012;53:275–6

Study design

PARADIGM-HF: Study design Randomization n=8442 Double-blind Treatment period 2 Weeks 1–2 Weeks 2–4 Weeks Single-blind active run-in period LCZ696 200 mg BID‡ Enalapril 10 mg BID* LCZ696 100 mg BID† LCZ696 200 mg BID‡ Enalapril 10 mg BID§ PARADIGM-HF: study design The effect of LCZ696 on heart failure (HF) outcomes was assessed in the ‘Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure’ (PARADIGM-HF) study in patients with chronic HF (New York Heart Association [NYHA] II–IV) with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] ≤40%, lowered to ≤35% in a protocol amendment) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP) levels. Patients entered a single-blind run-in period where they received enalapril 10 mg twice daily (BID) for 2 weeks or, for those patients currently treated with angiotensin receptor blockers (ARBs) or lower doses of angiotensin-converting enzyme inhibitor (ACEIs), received enalapril 5 mg BID for 1–2 weeks followed by enalapril 10 mg BID. After receiving enalapril 10 mg for 2 weeks, patients received LCZ696 100 mg BID, which was up-titrated after 1–2 weeks to LCZ696 200 mg BID for 2–4 weeks. Patients who tolerated both enalapril 10 mg BID and LCZ696 200 mg BID for at least 2 weeks were then randomized to double-blind treatment with either LCZ696 200 mg BID or enalapril 10 mg BID in addition to optimal therapy for chronic HF. The primary outcome was CV death or HF hospitalization and was event driven (2,410 patients with primary events). The study was event-driven and was initially planned to complete when 2,410 patients achieved the primary composite endpoint of cardiovascular (CV) death or hospitalization for HF (expected to be approximately 34 months). Abbreviations ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; BID=twice daily; BNP=B-type natriuretic peptide; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal pro-B-type natriuretic peptide; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; TDD=total daily dose References McMurray et al. Eur J Heart Fail. 2013;15:106273.  McMurray et al. Eur J Heart Fail. 2014;16:81725.  Median of 27 months’ follow-up On top of standard HFrEF therapy (excluding ACEIs and ARBs) *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. McMurray et al. Eur J Heart Fail. 2013;15:1062–73; McMurray et al. Eur J Heart Fail. 2014;16:817–25; McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

PARADIGM-HF: LCZ696 dose selection rationale AT1 receptor blockade LCZ696 200 mg BID delivers similar exposures to valsartan as Diovan® 160 mg BID, the dose recommended for treatment of HF and MI (based on Val-HeFT and VALIANT)13 Neprilysin (NEP) inhibition Biomarker analysis indicates that LCZ696 200 mg provides ~90% of its maximal NEP inhibition4,5 Both LCZ696 400 and 200 mg QD (but not 100 mg LCZ696) provided meaningful pharmacodynamic effect (BP lowering) attributable to NEP inhibtion5 BID dosing is considered essential to obtain 24-hour NEP inhibition1,6 BID dosing mitigates risk of post-dose hypotension (two smaller doses, compared to one larger once-daily dose, as used in the OVERTURE study with omapatrilat)1,6 Abbreviations NEP=neprilysin; MI=myocardial infarction; OVERTURE=Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events; QD=once daily; Val-HeFT=valsartan heart failure trial; VALIANT=valsartin in acute myocardial infarction; References McMurray et al. Eur J Heart Fail. 2013;15:1062–73 Valsartan Heart Failure Trial Investigators. N Engl J Med 2001;345:166775 Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003;349:18931906 Gu et al. J Clin Pharmacol 2010;50:401–14 Ruilope et al. Lancet 2010;375:12551266. Packer et al. Circulation 2002;106:920–6; 1. McMurray et al. Eur J Heart Fail. 2013;15:1062–732; 2. Valsartan Heart Failure Trial Investigators. N Engl J Med 2001;345:166775; 3. Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003;349:18931906; 4. Gu et al. J Clin Pharmacol 2010;50:401–14; 5. Ruilope et al. Lancet 2010;375:12551266; 6. Packer et al. Circulation 2002;106:920–6.

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) PARADIGM-HF: key inclusion and exclusion criteria For eligibility to be included in the study, patients were required to fulfil all of the following criteria: informed written consent prior to any assessment; male or female outpatient aged ≥18 years; a diagnosis of chronic HF (NYHA class II–IV and left ventricular ejection fraction [LVEF] ≤40% (lowered to ≤35% in a protocol amendment) plus either BNP ≥150 pg/mL (N-terminal proBNP [NT-proBNP] ≥600 pg/mL) or BNP ≥100 pg/mL (NT-proBNP ≥400 pg/ml) and a hospitalization for HF within the last 12 months; on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a stable dosage (equivalent to enalapril ≥10 mg/day) for ≥4 weeks; treated with a β-blocker at a stable dosage for ≥4 weeks, unless contraindicated or not tolerated; optimized dosing of background HF medications and use of aldosterone antagonists, where indicated. The PARADIGM-HF study excluded patients with any of the following: history of angioedema; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at screening or >35% decrease in eGFR between screening and end of enalapril run-in or screening and randomization; serum potassium >5.2 mmol/L at screening or >5.4 mmol/L at the end of the enalapril run-in or end of the LCZ696 run-in; requirement for treatment with both an ACEI and an ARB; symptomatic hypotension (systolic blood pressure [SBP] <100 mmHg at screening or SBP <95 mmHg at end of enalapril run-in or at randomization); current acute decompensated HF; history of severe pulmonary disease. Additional exclusion criteria are described in the study design publication.1 Abbreviations ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; BNP=B-type natriuretic peptide; eGFR=estimated glomerular filtration rate; HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal proBNP; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; SBP=systolic blood pressure References McMurray et al. Eur J Heart Fail. 2013;15:106273.  *The ejection fraction entry criteria was lowered to ≤35% in a protocol amendment #Dosage equivalent to enalapril ≥10 mg/day McMurray et al. Eur J Heart Fail. 2013;15:1062–73

PARADIGM-HF: Key exclusion criteria History of angioedema eGFR <30 mL/min/1.73 m2 at screening, end of enalapril run-in or randomization, or a >35% decrease in eGFR between screening and end of enalapril run-in or between screening and randomization Serum potassium >5.2 mmol/L at screening OR >5.4 mmol/L at the end of the enalapril run-in or end of the LCZ696 run-in Requirement for treatment with both ACEI and ARBs Symptomatic hypotension, SBP <100 mmHg at screening, OR SBP <95 mmHg at end of enalapril run-in or at randomization Current acute decompensated HF History of severe pulmonary disease Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other major CV surgery, PCI, or carotid angioplasty within the 3 months prior to screening PARADIGM-HF: key inclusion and exclusion criteria For eligibility to be included in the study, patients were required to fulfil all of the following criteria: informed written consent prior to any assessment; male or female outpatient aged ≥18 years; a diagnosis of chronic HF (NYHA class II–IV and left ventricular ejection fraction [LVEF] ≤40% (lowered to ≤35% in a protocol amendment) plus either BNP ≥150 pg/mL (N-terminal proBNP [NT-proBNP] ≥600 pg/mL) or BNP ≥100 pg/mL (NT-proBNP ≥400 pg/ml) and a hospitalization for HF within the last 12 months; on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a stable dosage (equivalent to enalapril ≥10 mg/day) for ≥4 weeks; treated with a β-blocker at a stable dosage for ≥4 weeks, unless contraindicated or not tolerated; optimized dosing of background HF medications and use of aldosterone antagonists, where indicated. The PARADIGM-HF study excluded patients with any of the following: history of angioedema; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at screening or >35% decrease in eGFR between screening and end of enalapril run-in or screening and randomization; serum potassium >5.2 mmol/L at screening or >5.4 mmol/L at the end of the enalapril run-in or end of the LCZ696 run-in; requirement for treatment with both an ACEI and an ARB; symptomatic hypotension (systolic blood pressure [SBP] <100 mmHg at screening or SBP <95 mmHg at end of enalapril run-in or at randomization); current acute decompensated HF; history of severe pulmonary disease. Additional exclusion criteria are described in the study design publication.1 Abbreviations ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; BNP=B-type natriuretic peptide; eGFR=estimated glomerular filtration rate; HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal proBNP; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PCI=percutaneous coronary intervention; SBP=systolic blood pressure References McMurray et al. Eur J Heart Fail. 2013;15:106273.  McMurray et al. Eur J Heart Fail. 2013;15:1062–73

PARADIGM-HF: Primary objective To evaluate the effect of LCZ696 200 mg BID compared with enalapril 10 mg BID, in addition to conventional HFrEF treatment, in delaying time to first occurrence of either CV death or HF hospitalization1 Rationale for endpoint selection Primary outcome of CV death or HF hospitalization was chosen as the one that best reflects the major mortality and morbidity burden of HFrEF1,9 ~80% of deaths in recent trials in patients with HFrEF are CV related24 HF is associated with a high risk of hospitalization,5 representing the leading cause of hospitalization in patients aged ≥65 years58 The most commonly used primary endpoint in recent HF trials: CHARM-Added, SHIFT and EMPHASIS-HF1 Abbreviations CV=cardiovascular; HF=heart failure; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Reference McMurray et al. Eur J Heart Fail. 2013;15:106273. McMurray et al. Lancet 2003;362:767–77 Swedberg et al. Lancet 2010;376:875–88 Zannad et al. N Engl J Med 2011;364:11–2 Cowie et al. Improving care for patients with acute heart failure. Oxford Health policy Forum 2014 Hunt et al. J Am Coll Cardiol 2009;53:e1–90 Yancy et al. Circulation 2013;128:e240–327 Rodriguez-Artalejo et al. Rev Esp Cardiol 2004;57:163–70 Dunlay et al. Circ Cardiovasc Qual Outcomes 2011;4:68–75; 1. McMurray et al. Eur J Heart Fail. 2013;15:1062–73 ; 2.McMurray et al. Lancet 2003;362:767–77; 3. Swedberg et al. Lancet 2010;376:875–88; 4. Zannad et al. N Engl J Med 2011;364:11–2; 5. Cowie et al. Improving care for patients with acute heart failure. Oxford Health policy Forum 2014; 6.Hunt et al. J Am Coll Cardiol 2009;53:e1–90; 7.Yancy et al. Circulation 2013;128:e240–327; 8.Rodriguez-Artalejo et al. Rev Esp Cardiol 2004;57:163–70; 9.Dunlay et al. Circ Cardiovasc Qual Outcomes 2011;4:68–75

PARADIGM-HF: Secondary objectives To assess whether LCZ696 was superior to enalapril in: Improving quality of life (assessed by KCCQ score) Delaying time to all-cause mortality Delaying time to new-onset atrial fibrillation Delaying time to decline of renal function as defined by: 50% decline in eGFR from baseline, or >30 mL/min/1.73 m2 decline in eGFR relative to baseline and to a value of <60 mL/min/1.73 m2 (indicating the development of moderate renal dysfunction), or development of end-stage renal disease Abbreviations ACEI=angiotensin-converting enzyme inhibitor; ARNI=angiotensin receptor neprilysin inhibitor; BNP=B-type natriuretic peptide; CV=cardiovascular; eGFR=estimated glomerular filtration rate; EQ-5D=EuroQol; HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire; NYHA=New York Heart Association; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Reference McMurray et al. Eur J Heart Fail. 2013;15:106273. McMurray et al. Eur J Heart Fail. 2013;15:1062–73

Patient population and baseline characteristics

PARADIGM-HF: Patient disposition 10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14–21) 1102 discontinued study: 591 (5.6%) had adverse event 66 (0.6%) had abnormal laboratory or other test result 171 (1.6%) withdrew consent 138 (1.3%) had protocol deviation, administrative problem or were lost to follow-up 49 (0.5%) died 87 (0.8%) had other reasons 9419 entered LCZ696 run-in phase (median duration, 29 days; IQR, 26–35) 977 discontinued study: 547 (5.8%) had adverse event 58 (0.6%) had abnormal laboratory or other test result 100 (1.1%) withdrew consent 146 (1.6%) had protocol deviation, had administrative problem, or were lost to follow-up 47 (0.5%) died 79 (0.8%) had other reasons 8442 underwent randomization 43 were excluded: 6 did not undergo valid randomization 37 were from four sites prematurely closed because of major Good Clinical Practice violations 4187 were assigned to receive LCZ696 4176 had known final vital status 11 had unknown final vital status 4212 were assigned to receive enalapril 4203 had known final vital status 9 had unknown final vital status McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

PARADIGM-HF: Summary of baseline characteristics LCZ696 (n=4187) Enalapril (n=4212) Age, years 63.8 ± 11.5 63.8 ± 11.3 Women, n (%) 879 (21.0) 953 (22.6) Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1) LV ejection fraction, % 29.6 ± 6.1 29.4 ± 6.3 NYHA functional class, n (%) II III 2998 (71.6) 969 (23.1) 2921 (69.3) 1049 (24.9) SBP, mmHg 122 ± 15 121 ± 15 Heart rate, beats/min 72 ± 12 73 ± 12 NT pro-BNP, pg/mL (IQR) 1631 (885–3154) 1594 (886–3305) BNP, pg/mL (IQR) 255 (155–474) 251 (153–465) History of diabetes, n (%) 1451 (34.7) 1456 (34.6) Treatments at randomization, n (%) Diuretics 3363 (80.3) 3375 (80.1) Digitalis 1223 (29.2) 1316 (31.2) β-blockers 3899 (93.1) 3912 (92.9 Mineralocorticoid antagonists 2271 (54.2) 2400 (57.0) ICD 623 (14.9) 620 (14.7) CRT 292 (7.0) 282 (6.7) *mean ± standard deviation, unless stated McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Results

Primary endpoint: Death from CV causes or first hospitalization for HF 1.0 0.6 0.4 0.2 180 360 540 720 900 1080 1260 Enalapril LCZ696 Hazard ratio = 0.80 (95% CI: 0.73–0.87) p<0.001 Cumulative probability Days since randomization No at risk LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236 McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Components of primary endpoint: Death from CV causes 1.0 0.6 0.4 0.2 180 360 540 720 900 1080 1260 Enalapril LCZ696 Hazard ratio = 0.80 (95% CI: 0.71–0.89) p<0.001 Cumulative probability Days since randomization No at risk LCZ696 4187 4056 3891 3282 2478 1716 1005 280 Enalapril 4212 4051 3860 3231 2410 1726 994 279 McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Components of primary endpoint: First hospitalization for HF 1.0 0.6 0.4 0.2 180 360 540 720 900 1080 1260 Enalapril LCZ696 Hazard ratio = 0.79 (95% CI: 0.71–0.89) p<0.001 Cumulative probability Days since randomization No at risk LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236 McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Primary outcome Outcome, n % LCZ696 (n=4187) Enalapril (n=4212) Hazard ratio* (95% CI) p-value‡ Primary composite outcome Death from CV causes or first hospitalization for worsening of HF 914 (21.8) 1117 (26.5) 0.80 (0.73–0.87) <0.001 Death from CV causes 558 (13.3) 693 (16.5) 0.80 (0.71–0.89) First hospitalization for worsening of HF 537 (12.8) 658 (15.6) 0.79 (0.71–0.89) *Calculated with the use of stratified cox proportional-hazard models ‡Two-sided p-values calculated by means of a stratified log-rank test without adjustment for multiple comparisons The difference in favor of LCZ696 was seen early in the trial and at each interim analysis Over the duration of the trial, the numbers of patients who would need to have been treated (NNT) to prevent: one primary event was 21 patients, and one death from CV causes was 32 patients McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Secondary outcomes Outcome LCZ696 (n=4187) Enalapril (n=4212) Hazard ratio* or difference (95% CI) p-value‡ Death from any cause, n (%) 711 (17.0) 835 19.8) 0.84 (0.76–0.93) <0.001 Change in KCCQ clinical summary score† at 8 months, mean ± SD -2.99 ± 0.36 -4.63 ± 0.36 1.64 (0.63–2.65) 0.001 New onset atrial fibrillation¶, n (%) 84 (3.1) 83 (3.1) 0.97 (0.72–1.31) 0.83 Decline in renal function§, n (%) 94 (2.2) 108 (2.6) 0.86 (0.65–1.13) 0.28 *Calculated with the use of stratified cox proportional-hazard models ‡Two-sided p-values calculated by means of a stratified log-rank test without adjustment for multiple comparisons †KCCQ scores range from 0 to 100 – higher scores indicate fewer symptoms and physical limitations associated with HF ¶2670 patients in the LCZ696 and 2638 in the enalapril group who did not have atrial fibrillation at randomization were evaluated §Defined as: (a) ≥ 50% decline in eGFR from randomization; (b) > 30 mL/min/1.73 m2 decline in eGFR from randomization or to a value of <60 ml/min/1.73 m2, or (c) progression to end-stage renal disease McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Death from any cause 1.0 0.6 0.4 0.2 180 360 540 720 900 1080 1260 Enalapril LCZ696 Hazard ratio = 0.84 (95% CI: 0.76–0.93) p<0.001 Cumulative probability Days since randomization No at risk LCZ696 4187 4056 3891 3282 2478 1716 1005 280 Enalapril 4212 4051 3860 3231 2410 1726 994 279 McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Systolic blood pressure during run-in and after randomization 140 Compared with the randomization level, the mean SBP at 8 months was 3.2 ± 0.4 mmHg lower in the LCZ696 group than in the enalapril group (p<0.001) When modeled as a time-dependent covariate, the difference in BP was not a determinant of the incremental benefits of LCZ696 120 SBP (mmHg) 100 Enalapril LCZ696 80 Randomization Mean difference (LCZ696–enalapril): –2.70 (–3.07, –2.34) (mmHg) p-value: <0.001 60 –11w 4m 8m 1yr 2yrs 3yrs Time McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077. (Supplementary appendix)

Prospectively defined safety events Event, n (%) LCZ696 (n=4187) Enalapril (n=4212) p-value‡ Hypotension Symptomatic 588 (14.0) 388 (9.2) <0.001 Symptomatic with SBP <90 mmHg 112 (2.7) 59 (1.4) Elevated serum creatinine ≥2.5 mg/dL 139 (3.3) 188 (4.5) 0.007 ≥3.0 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) 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) McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

For further information please contact: Sander de Groot Medical Scientific Liaison Heart Failure +31 6 5024 8516 sander.de_groot@novartis.com

Summary of results – efficacy Primary outcome 20% reduction in CV death or HF hospitalization with LCZ696 compared with enalapril 20% reduction in CV mortality 21% reduction in HF hospitalization Secondary outcomes 16% reduction in all-cause mortality with LCZ696 vs enalapril LCZ696 superior to enalapril in reducing symptoms and physical limitations of HF (indicated by KCCQ score) No significant difference in incidence of new onset atrial fibrillation between treatment groups No significant difference in protocol-defined decline in renal function between treatment groups McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

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 McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.