Principal results of the Prospective comparison of Angiotensin Receptor

neprilysin inhibitor with Angiotensin Receptor blocker MEasuring arterial sTiffness in the eldERly

(PARAMETER) Study

B. Williams,1 JR. Cockcroft,2 K. Kario,3 DH. Zappe,4 Q. Wang,5 W. Guo4 1University College London, London, UK, 2Cardiff University, Wales, UK, 3Jichi Medical School, Tochigi, Japan, 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 5Beijing Novartis Pharma Co. Ltd, Shanghai, China.

Clinical Trials Identifier: EUDract number 2012-002899-14; ClinicalTrials.gov NCT01692301

Study code: CLCZ696A2216

Protocol: Williams B. et al, BMJ Open, 2014

• Systolic hypertension and an increased pulse pressure (PP) are indicative of arterial ageing and large artery stiffening

• Systolic hypertension and an increased PP are also predictive of incident cardiovascular disease and heart failure - especially nocturnal hypertension

• Large artery stiffness also increases central aortic systolic pressure (CASP) and central aortic pulse pressure (CPP) relative to brachial blood pressure, which increases left ventricular loading conditions and this abnormal ventricular:vascular coupling contributes to the development of heart failure

• The purpose of the PARAMETER study was to assess both the short and long-term effects (12 and 52 weeks) of LCZ696, an angiotensin receptor neprilysin inhibitor, compared with olmesartan an angiotensin receptor blocker, on measures of central aortic hemodynamics and arterial stiffness in older patients with systolic hypertension and an increased PP

3

Background

Novel mechanism of action of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI)

NP system

Angiotensin receptor neprilysin inhibitor

(sacubitril/valsartan)

RAAS Inactive

fragments

Inactive fragments

Neprilysin

NPs Ang II AT1 receptor

Neprilysin – –

– Natriuresis/diuresis Sodium and

water retention Renin secretion

Vasodilation

Blood pressure

Hypertrophy

Fibrosis

Large artery stiffness

Sympathetic outflow

Vasoconstriction Blood pressure

Hypertrophy

Fibrosis

Sympathetic outflow

Vascular remodeling

NP, natriuretic peptides; RAAS, renin-angiotensin-aldosterone system

PARAMETER: Study design

Patient population:

454 patients aged ≥60 years

Elevated SBP (≥150 mmHg) & wide pulse pressure (>60 mmHg)

2–4 weeks

Olmesartan 40 mg qd

LCZ696 400 mg qd

12 weeks

Washout/

Placebo run-in

40 weeks

Add amlodipine (2.5-5 mg) ± HCTZ (6.25-25 mg) to reach

BP goal <140/90 mmHg

Multicenter, randomized, double-blind, active-controlled, 52-week study to evaluate

the safety and efficacy of an LCZ696 regimen on central aortic pressures and arterial

stiffness in elderly hypertensive patients

52 weeks

Primary outcome

*Patients initially randomized to LCZ696 200 mg qd or olmesartan 20 mg qd, followed by forced titration at Week 4 to double the initial dose

Forced titration at Week 4*

PARAMETER study objectives and analysis

6

Hypothesis: In older hypertensive patients with stiff arteries and an increased pulse pressure, LCZ696 will reduce central aortic systolic and pulse pressure more effectively than angiotensin receptor blockade

Primary End-Point: To demonstrate the superiority of LCZ696 400 mg daily, compared with olmesartan 40 mg daily, in reducing central aortic systolic pressure (CASP) after 12 weeks of treatment

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North America

1 country

11 sites

112 patients

South America

2 countries

5 sites

88 patients

Europe

6 countries

26 sites

194 patients

Asia

3 countries

6 sites

60 patients

PARAMETER: Executive committee & study allocation Executive Committee:

• Bryan Williams (UK) - Chair

• John Cockcroft (UK) - Member

• Kazuomi Kario (Japan) - Member

48 sites in 12 countries

Countries: USA, Columbia, Argentina, Spain, France, Germany,

Italy, Greece, Russia, Taiwan, Korea, Japan

Patient disposition

* Randomized N=454

LCZ696-based regimen N=229

Olmesartan-based regimen N=225

Completed 12 wk: 203(89%) 52 wk: 184 (80%)

Discontinuations

AEs 15 (6.6%)

Death 1 (0.4%)

Lack of efficacy 0

Protocol deviation 9 (3.9%)

Patient/guardian decision 16 (7.0%)

Other 4 (1.7%)

Completed 12 wk: 200 (89%) 52 wk: 183 (81%)

Discontinuations

AEs 12 (5.3%)

Death 2 (0.9%)

Lack of efficacy 5 (2.2%)

Protocol deviation 2 (0.9%)

Patient/Guardian decision 15 (6.7%)

Other 6 (2.6%)

Full Analysis Set = all randomized patients

-12.6

-6.4

-8.9

-4.0

-15

-10

-5

0

CASP - 12 week CPP - 12 week

∆ B

P (

mm

Hg)

LCZ696

Olmesartan

Primary and key secondary outcomes: Change from baseline in mean CASP and CPP at Week 12

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∆-2.4 mmHg (p=0.012)

∆-3.7 mmHg (p=0.01)

BP, blood pressure; CASP, central aortic systolic pressure; CPP, central pulse pressure

N=207

N=207

N=206

N=206

-13.7

-7.7

-9.9

-4.9

-15

-10

-5

0

SBP - 12 week PP - 12 week

∆ B

P (

mm

Hg)

LCZ696

Olmesartan

∆-3.8 mmHg (p=0.016)

Change in brachial SBP and PP at Week 12

10

∆-2.8 mmHg (p=0.013)

BP, blood pressure; PP, pulse pressure; SBP, systolic blood pressure

N=207

N=207

N=206

N=206

110

120

130

140

150

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

LCZ SBP OLM SBP LCZ cSBP OLM cSBP

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24-hour brachial and central aortic SBP at Week 12

SB

P (

mm

Hg

)

Night-time

Time (hours) : Post-dosing hours

cSBP, central systolic blood pressure; SBP, systolic blood pressure

Mean ∆ SBP: -4.1 mmHg, p<0.001 (-13.2 (LCZ696) vs. -9.1 (OLM) mmHg)

Mean ∆ cSBP: -3.35 mmHg, p<0.001 (-12.1 (LCZ696) vs. -8.7 (OLM) mmHg)

Brachial

Systolic BP

Central

Aortic

Systolic BP

Change from baseline in NT-proBNP and urinary cGMP at Week 12

-40

-30

-20

-10

0

12

% ∆

NT-p

roB

NP

%

∆ U

rin

ary

cG

MP

0

10

20

30

40

50

60

70 Baseline 93 87 pg/ml 460 441 nmol/L

NT-proBNP Urinary cGMP

34% (-41, -26%)

20% (-27, -12%)

59% (43, 78%)

0 (-9, 10%)

% change in geometric means from baseline, 95% CI NT-proBNP, N-terminal pro brain natriuretic peptide; cGMP, cyclic guanosine monophosphate

LCZ696 Olmesartan

N=196 N=200

N=197 N=201

# regimen, allowed add-on amlodipine/HCTZ for added BP control BP, blood pressure; bSBP, brachial systolic BP; bPP, brachial pulse pressure; CASP, central aortic systolic pressure; CPP, central pulse pressure

-16.2

-7.2

-14.7

-6.6

-25

-20

-15

-10

-5

0

CASP - 52 week CPP - 52 week

∆ C

en

tral

BP

(m

mH

g)

Central and brachial BP at Week 52

13

-17.7

-8.8

-16.1

-8.0

-25

-20

-15

-10

-5

0

bSBP - 52 week bPP - 52 week

∆ B

rach

ial B

P (

mm

Hg)

Brachial BP Central aortic BP

∆-1.5 mmHg (p=0.27)

∆-0.5 mmHg (p=0.6) ∆-0.8 mmHg

(p=0.48)

∆-1.6 mmHg (p=0.28)

LCZ696 Olmesartan

N=209

N=209

N=209

N=209

N=208

N=208

N=208

N=208

68

31

8

53

45

18

0

10

20

30

40

50

60

70

Monotherapy

%

Add-on antihypertensive therapies (Week 12-52)

Add-on therapy #

Amlodipine HCTZ

LCZ696 Olmesartan

N=229 N=229 N=229 N=225 N=225 N=225

# regimen, allowed add-on amlodipine/HCTZ for added BP control, Chi-square test showed statistically significant differences in use of add-on antihypertensive therapies between the 2 treatments, p=0.002.

Change from baseline in PWV at Week 12 and 52

-0.7

-0.89

-0.55

-0.75

-1.0

-0.8

-0.5

-0.3

0.0

PWV - 12 weeks PWV - 52 weeks

∆ b

ase

line

in P

WV

, m/s

ec

15

p=0.38

p=0.47

10.20 10.27 10.22 10.18 m/sec Baseline

LCZ696 Olmesartan

N=187 N=189 N=173 N=166

Key Safety Parameters

LCZ696 N=229 n (%)

Olmesartan N=225 n (%)

Deaths 1 (0.4) 2 (0.9)

SAEs 16 (7.0) 13 (5.8)

Discontinuations due to AEs 16 (7.0) 14 (6.2)

Drug-related AE discontinuations 6 (2.6) 5 (2.2)

SAE discontinuations 6 (2.6) 6 ( 2.7)

Any AEs 132 (57.6) 121 (53.8)

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AEs, adverse events; SAEs, Serious AEs

Summary

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In older patients with systolic hypertension and an increased pulse pressure, indicative of arterial stiffening:

• The PARAMETER study met its primary and key secondary objectives by demonstrating superior efficacy of LCZ696 400 mg/day, compared to olmesartan 40 mg/day, in lowering both CASP and CPP after 12-weeks monotherapy

• LCZ696 also lowered 24-hour ambulatory SBP compared to olmesartan after 12-week monotherapy, with more significant BP reduction observed during the night-time period

• There was no difference between the two regimens in central and brachial BP profiles at Week 52 due to the allowance of add-on antihypertensive therapy; however, a higher percentage of patients in the olmesartan group requiring add-on amlodipine and/or HCTZ

Conclusions

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• PARAMETER is the first randomized study demonstrating the ability of LCZ696 to reduce central BP and PP, more effectively than an ARB, in high-risk older patients with systolic hypertension and an increased pulse pressure

• These results suggest that LCZ696 provides beneficial effects on central aortic hemodynamics and function, that could provide a therapeutic advantage beyond those observed with RAS blockade alone

Acknowledgements

N. America (US) • H. Resnick

• G. Sack

• T.R. Smith

• M.E. Trevino

• A.L. Phillips

• D.H. Sugimoto

• J.I. Fidelholtz

• S.C. Gorton

• V.E. Miller, A. Salahudeen, V. Garcia-Fragoso

• J. Mersey • J.L. Izzo

S. America • C.R. Majul (AG) • O.R. Montana (AG) • D. Piskorz (AG) • M. Urina (CO)

• A. Cadena (CO)

Europe

• R.E. Schmieder (DE)

• J. Scholze (DE)

• L. Sans (ES)

• J. Olivan (ES)

• C. Calvo (ES)

• J.M. Pascual (ES)

• P. Gomez (ES)

• L. Ruilope, J. Segura (ES)

• J.L. Zamorano (ES)

• A. de la Sierra (ES)

• S. Narejos (ES)

• L.P. Fernandez (ES)

• G. Chironi (FR)

• K. Tsioufis (GR)

• A. Spanos (GR)

• M. Doumas (GR)

• S. Taddei (IT)

• M. Destro (IT)

• L. Mos (IT)

• Z.D. Kobalava (RU)

• S.Y. Martsevich (RU)

• L.I. Pavlova (RU)

• E.I. Barnova (RU)

• A.O. Konrady (RU)

• T.V. Treshkur (RU)

• M.E. Mozheiko (RU)

Asia

• S. Hoshide (JP)

• H. Lee (KR)

• S. Ihm (KR)

• K-C. Chang (TW)

• C-H. Chen (TW)

• B-H. Tzeng (TW)

We would like to thank the patients, the clinic staff and all of the

investigators listed below, who contributed to this study