A multicenter, randomized, double-blind, parallel-group, active-controlled study to evaluate the...

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

August 2014/GMCC_NP4 request 275741/expiry August 2015

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Overactivation of the RAAS and SNS is detrimental in HFrEFand underpins the basis of therapy

SNS

RAAS

VasoconstrictionBlood pressure

Sympathetic toneAldosteroneHypertrophy

Fibrosis

Ang II AT1R

HFrEFSYMPTOMS &

PROGRESSION

EpinephrineNorepinephrine

α1, β1, β2

receptors

VasoconstrictionRAAS activity

VasopressinHeart rate

Contractility

RAAS inhibitors (ACEI, ARB, MRA)

β-blockers

Natriuretic peptidesystem

VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

NPRs NPs

1. McMurray et al. Eur Heart J 2012;33:1787–847Figure 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

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ANP/BNP2

Relaxation; arterial stiffness4

CNP(endothelium)3

Natriuretic peptides have potential beneficial actions in HF

Sympathetic outflow2

Vasopressin2

Salt appetite and water intake2

Na+/H2O loss2

Aldosterone2

Renin2

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;

Hypertrophy2,5–7

Fibroblast proliferation4,8,9

Release of ANP and BNP from heart and CNP in vasculature1

Vasodilation2,3,4

Systemic vascular resistance4

Pulmonary artery pressure4

Pulmonary capillary wedge pressure4

Right atrial pressure4

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LCZ696 is a first-in-classangiotensin 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 comprisesthe 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

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

3D LCZ696 structure2

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Vasorelaxation

Blood pressure

Sympathetic tone

Aldosterone levels

Fibrosis

Hypertrophy

Natriuresis/diuresis

Inactive fragments

Neprilysin

Natriuretic and othervasoactive peptides*

AT1 Receptor

Vasoconstriction

Blood pressure

Sympathetic tone

Aldosterone

Fibrosis

Hypertrophy

Angiotensinogen(liver secretion)

Ang I

Ang II

RAAS

––

*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

LCZ696

Sacubitril (AHU377; pro-drug)

InhibitingEnhancing

LBQ657(NEP inhibitor)

OH

OHN

O

HO

O

Valsartan

N

NHN

N

N

O

OH

O

LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks the AT1 receptor (via valsartan)

Study design

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Randomization

n=8442

PARADIGM-HF: Study design

*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.

2 Weeks 1–2 Weeks 2–4 Weeks

Single-blind activerun-in period

Double-blind Treatment period

On top of standard HFrEF therapy (excluding ACEIs and ARBs)

Median of 27 months’ follow-up

LCZ696 200 mg BID‡

LCZ696 100 mg BID†

Enalapril 10 mg BID*

Enalapril 10 mg BID§

LCZ696 200 mg BID‡

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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)13

PARADIGM-HF: LCZ696 dose selection rationale

1. McMurray et al. Eur J Heart Fail. 2013;15:1062–732; 2. Valsartan Heart Failure Trial Investigators. N Engl J Med 2001;345:166775; 3. Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003;349:18931906; 4. Gu et al. J Clin Pharmacol 2010;50:401–14;

5. Ruilope et al. Lancet 2010;375:12551266; 6. Packer et al. Circulation 2002;106:920–6.

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

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PARADIGM-HF: Key inclusion criteria

McMurray et al. Eur J Heart Fail. 2013;15:1062–73

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 HFrEFwithin 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

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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

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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

PARADIGM-HF: Primary objective

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

Rationale for endpoint selection

Primary outcome of CV death or HF hospitalization was chosen as the one thatbest reflects the major mortality and morbidity burden of HFrEF1,9

• ~80% of deaths in recent trials in patients with HFrEF are CV related24

• HF is associated with a high risk of hospitalization,5 representing the leading cause of hospitalization in patients aged ≥65 years58

The most commonly used primary endpoint in recent HF trials: CHARM-Added, SHIFT and EMPHASIS-HF1

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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

PARADIGM-HF: Secondary objectives


Patient population and baseline characteristics

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PARADIGM-HF: Patient disposition10,513 patients entered enalapril run-in phase

(median duration, 15 days; interquartile range [IQR], 14–21)

9419 entered LCZ696 run-in phase(median duration, 29 days; IQR, 26–35)

8442 underwent randomization

4187 were assigned to receive LCZ6964176 had known final vital status11 had unknown final vital status

4212 were assigned to receive enalapril4203 had known final vital status9 had unknown final vital status

1102 discontinued study:591 (5.6%) had adverse event66 (0.6%) had abnormal

laboratory or other test result171 (1.6%) withdrew consent138 (1.3%) had protocol

deviation, administrative problem or were lost to

follow-up49 (0.5%) died87 (0.8%) had other reasons977 discontinued study:547 (5.8%) had adverse event58 (0.6%) had abnormal

laboratory or other test result100 (1.1%) withdrew consent146 (1.6%) had protocol

deviation, had administrativeproblem, or were lost to

follow-up47 (0.5%) died79 (0.8%) had other reasons43 were excluded:6 did not undergo valid

randomization37 were from four sites

prematurely closed becauseof major Good Clinical

Practice violations

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

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Characteristic*LCZ696 (n=4187)

Enalapril (n=4212)

Age, years 63.8 ± 11.5 63.8 ± 11.3Women, 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 ± 15Heart rate, beats/min 72 ± 12 73 ± 12NT 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 (92.9Mineralocorticoid antagonists 2271 (54.2) 2400 (57.0)ICD 623 (14.9) 620 (14.7)CRT 292 (7.0) 282 (6.7)

PARADIGM-HF: Summary of baseline characteristics

*mean ± standard deviation, unless statedMcMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Results

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Primary endpoint:

Death from CV causes or first hospitalization for HF


Hazard ratio = 0.80 (95% CI: 0.73–0.87)p<0.001

Days since randomizationNo at riskLCZ696 4187 3922 3663 3018 2257 1544 896 249Enalapril 4212 3883 3579 2922 2123 1488 853 236

Cum

ulat

ive

prob

abili

ty

1.0

0.6

0.4

0.2

00 180 360 540 720 900 1080 1260

Enalapril

LCZ696

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Components of primary endpoint:

Death from CV causes


Hazard ratio = 0.80 (95% CI: 0.71–0.89)p<0.001


Cum

ulat

ive

prob

abili

ty

1.0

0.6

0.4

0.2

00 180 360 540 720 900 1080 1260

Enalapril

LCZ696

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Components of primary endpoint:

First hospitalization for HF


Hazard ratio = 0.79 (95% CI: 0.71–0.89)p<0.001


Cum

ulat

ive

prob

abili

ty

1.0

0.6

0.4

0.2

00 180 360 540 720 900 1080 1260

Enalapril

LCZ696

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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) <0.001

First hospitalization for worsening of HF

537 (12.8) 658 (15.6) 0.79 (0.71–0.89) <0.001

Primary outcome


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

*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

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OutcomeLCZ696(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

Secondary outcomes


*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

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Death from any cause


Hazard ratio = 0.84 (95% CI: 0.76–0.93)p<0.001


Enalapril

LCZ696

Cum

ulat

ive

prob

abili

ty

1.0

0.6

0.4

0.2

00 180 360 540 720 900 1080 1260

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Systolic blood pressure during run-in and after randomization

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

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

140

120

100

80

60

SB

P (

mm

Hg)

–11w 4m 8m 1yr 2yrs 3yrs

Time

Ran

dom

izat

ion

Enalapril

LCZ696

Mean difference (LCZ696–enalapril):–2.70 (–3.07, –2.34) (mmHg)p-value: <0.001

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Prospectively defined safety events


• 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)

Event, n (%)LCZ696(n=4187)

Enalapril(n=4212) p-value‡

HypotensionSymptomatic 588 (14.0) 388 (9.2) <0.001Symptomatic 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) 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) 0.007

Cough 474 (11.3) 601 (14.3) <0.001Angioedema (adjudicated by a blinded expert committee)

No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19Catecholamines or glucocorticoids without hospitalization

6 (0.1) 4 (0.1) 0.52

Hospitalized without airway compromise 3 (0.1) 1 (<0.1) 0.31Airway compromise 0 0 ---

For further information please contact:

Sander de GrootMedical Scientific Liaison Heart Failure+31 6 5024 [email protected]

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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

Summary of results – efficacy


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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

Summary of results – safety


A multicenter, randomized, double-blind, parallel-group, active-controlled study to evaluate the...

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