Disclosure of Relationships

Transcription

1 Disclosure of Relationships Over the past 12 months Dr Ruilope has served as Consultant and Speakers Bureau member of Astra-Zeneca, Bayer, Daiichi-Sankyo, Menarini, Novartis, Otsuka, Pfizer, Relypsa, Servier and Takeda

2 Neprilysin (NEP) is responsible for natriuretic peptide degradation Metabolism of ANP and other peptide hormones by NEP ProEndothelin Endothelin Degradation NPR-C ANP NEP NPR-A Guanylate cyclase Ang II Bradykinin Adrenomedullin GMP cgmp Diuresis Natriuresis Vasodilation Antiproliferative/ antihypertrophic Ferro et al. Circulation 1998;97:

3 Structure and Known Functions of the Natriuretic Peptide Receptors (NPRs) Source: Gardner, D. G. et al. Hypertension 2007;49:

4 Dual NEP / ACE inhibitors

5 Omapatrilat (vasopeptidase inhibitor): dual ACE-NEP inhibition Omapatrilat ACE Neprilysin Aminopeptidase (APP)

6 Introduction Dual-acting compounds that augment the activity of natriuretic peptides while inhibiting RAAS activity may offer benefits for the treatment of cardiovascular disease LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that provides neprilysin (NEP) inhibition and blockade of the AT1 receptor

7 Dual angiotensin receptor blockade and NEP inhibition Counter-regulatory systems Natriuretic peptides Angiotensin II X NEP Inactive fragments Dual NEP/RAAS blockade LCZ696 RAAS X AT 1 receptor Vasodilation blood pressure sympathetic tone aldosterone levels fibrosis hypertrophy Natriuresis/Diuresis Symptoms / disease progression Vasoconstriction blood pressure sympathetic tone aldosterone fibrosis hypertrophy Neurohormonal balance Schrier, et al. N Engl J Med 1999;341:577 85; Levin et al. N Engl J Med 1998;339:321 8;

8 Mechanism of LCZ696 acting on the RAAS and natriuretic peptide systems Waeber and Feihl. Lancet, 2010

9 8-h time-weighted average [ANPir] (% baseline) 24-h time-weighted average MAP (mm Hg) LCZ696 dose-dependently enhances ANP levels and reduces BP Rats infused with ANP* dtgr hypertensive rat model LCZ696 dose (mg/kg) Vehicle Vehicle LCZ696 dose (mg/kg) *Conscious Sprague-Dawley rats infused with ANP (450 ng/kg/min; n=4 per treatment group) dtgr = double transgenic rats over-expressing renin and angiotensinogen (n=6 per treatment group) Gu et al. J Clin Pharmacol 2010;50:

10 Change from baseline (n-fold) Change from baseline (n-fold) Effects of LCZ696 on biomarkers of NEP inhibition and AT1 receptor blockade Healthy volunteers received once-daily oral LCZ696 50, 200, 600 or 900 mg or placebo for 14 days cgmp measured as a biomarker of NEP inhibition and Ang II as a measure of AT1 receptor blockade Placebo LCZ mg LCZ mg LCZ mg LCZ mg cgmp Ang II * * * * * * * * * 10 * * * * * * * * * * * * * * Time (h) Time (h) *p < 0.05 vs placebo, n=8/group Values are n-fold change from baseline (logarithmic scale) at the post-dose time points indicated Ang, angiotensin; AT1, angiotensin II type 1; cgmp, cyclic guanosine monophosphate; NEP, neprilysin Gu et al. J Clin Pharmacol 2010;50:401 14

11 LCZ696 in mild-to-moderate hypertension A randomized, double-blind, placebo-controlled, active-comparator study in 1,328 patients with mild-to-moderate hypertension Double-blind randomized treatment period LCZ mg QD Unmasked run-in period LCZ mg QD LCZ mg/400 mg QD* Washout period Placebo run-in period Valsartan 80 mg QD Valsartan 160 mg QD Valsartan 160 mg/320 mg QD* AHU mg QD Placebo 2 weeks 2 weeks 8 weeks *1 week on lower dose followed by 7 weeks on higher dose; Mean sitting DBP of mmhg after antihypertensive washout, or mmhg for untreated patients Ruilope et al. Lancet 2010;375:

12 Change in placebo-subtracted BP from baseline to week 8 (mmhg) LCZ696 in mild-to-moderate hypertension: Complementary effects of NEP inhibition and AT1 receptor blockade 0 SBP reduction (placebo-subtracted) DBP reduction (placebo-subtracted) AHU LCZ Val LCZ Val LCZ Val AHU LCZ Val LCZ Val LCZ Val mg p= p= p= p= p= Placebo effect = 7.72 mmhg p< AHU=AHU377; LCZ=LCZ696; Val=valsartan Placebo effect = 6.78 mmhg Ruilope et al. Lancet 2010;375:

13 Change in placebo-subtracted BP from baseline to week 8 (mmhg) LCZ696 in mild-to-moderate hypertension: 24-hr mean ambulatory SBP (placebo subtracted) 0 AHU 200 Valsartan 80 mg LCZ mg Valsartan LCZ mg 200 mg Valsartan 320 mg LCZ mg p=0.059 vs pbo p = p = p <.0001 Placebo effect = -2.9 mmhg n = 48 to 61/group

14 Change from baseline in mean sitting pulse pressure (mmhg) LCZ696 in mild-to-moderate hypertension: Dose-related reductions in mean sitting pulse pressure 0 1 LCZ mg Valsartan 80 mg LCZ mg Valsartan 160 mg LCZ mg Valsartan 320 mg n=154 n=163 n=168 n=163 n=170 n= p=0.68 p= p=0.003 Placebo effect = 0.94 mmhg Ruilope et al. Lancet 2010;375:

15 LCZ696 in mild-to-moderate hypertension Compared with RAAS inhibition with valsartan alone, LCZ696: Provided complementary pharmacological effects (additional BP reduction) in patients with hypertension Well tolerated at all doses No increased risk of angioedema was observed Ruilope et al. Lancet 2010;375:

16 Heart failure: a state of neurohumoral imbalance Vasoconstrictor/ anti-natriuretic /pro-mitotic Mediators Vasodilator/ natriuretic/ anti-mitotic mediators ACEi and ARBs Beta-blockers Aldosterone antagonists Navigant Consulting Inc. Confidential

17 A paradigm shift... from neuro-humoral inhibition to neuro-humoral modulation? Vasodilator/ natriuretic/ anti-mitotic mediators ACEi and ARBs Beta-blockers Aldosterone antagonists Natriuretic peptides Vasoconstrictor/ anti-natriuretic /pro-mitotic Mediators Navigant Consulting Inc. Confidential

18 PARADIGM-HF: Study Design Double-blind randomized treatment Single-blind run-in LCZ mg bid Enalapril 10 mg bid LCZ mg bid LCZ mg bid N = 7,980 patients Testing tolerability to target doses of enalapril and LCZ696 Enalapril 10 mg bid On top of standard heart failure therapy (excluding ACEIs and ARBs) 2 weeks 1 2 weeks 2 4 weeks ~ 21 to 43 months (event-driven) Enalapril 5 mg bid for 1 2 weeks followed by enalapril 10 mg bid as an optional starting run-in dose for those pts who are treated with ARBs or with low dose of ACEI Primary outcome: CV death or heart failure hospitalization (event driven: 2,410 patients with primary events) Clinicaltrials.gov; Accessed July

19 PARADIGM-HF: key efficacy outcomes Primary outcome measure: Time to first occurrence of either CV mortality or HF hospitalization Secondary outcomes measures: HF symptoms and physical limitations measured by the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) All-cause mortality Renal progression assessed by first occurrence of 50% decline in egfr, >30 ml/min/1.73m 2, or reaching end-stage renal disease Clinicaltrials.gov; 19

20 PARAMOUNT: Phase 2 study in HF-PEF Prospective comparison of ARNI with ARB on examination Of heart failure with preserved ejection fraction LCZ mg BID LCZ mg BID LCZ mg BID Placebo run-in Discontinue ACEI or ARB therapy one day prior to randomization Valsartan 40 mg BID Valsartan 80 mg BID Valsartan 160 mg BID Prior ACEi/ARB use discontinued 2 weeks Primary endpoint Secondary endpoints Population 1 2 wks 1 2 wks 10 weeks Reduction in NT-proBNP Echocardiographic parameters of diastolic function, cardiac filling pressures and structure QoL KCCQ Patient global symptom assessment/nyha class Biomarkers (BNP, ANP, cgmp, aldosterone, collagen/fibrosis biomarkers) Renal function Arterial stiffness (substudy) 6 month extension Approximately 300 patients with CHF (NYHA II-IV), LVEF 45%, baseline NT-proBNP >400 pg/ml, symptoms of HF, diuretic therapy required Clinicaltrials.gov;

21 LCZ696: potential new treatment paradigm Angiotensin Receptor Neprilysin Inhibitor (ARNI) Potential for added neurohormonal modulation potentiation of natriuretic peptides Proven neurohormonal RAAS blockade antagonism of angiotensin II Potential for treatment in heart failure and other cardiovascular disorders in which vasoconstriction, volume overload and neurohormonal activation play a role