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New data from PARADIGM-HF study for heart failure drug LCZ696 released

New data from , the largest-ever study showed that LCZ696 has the potential to change the course of the disease for patients with HFrEF.[1,2] LCZ696 is an ARNI (Angiotensin Receptor Neprilysin Inhibitor) and has a unique mode of action, which is thought to reduce stress and damage on the and has been shown to cut deaths and hospitalisations by 20% compared to the gold standard ACE inhibitor, enalapril.[3]

The new data being presented for the first time at the AHA Scientific Sessions 2014 in Chicago, with a paper being simultaneously published in Circulation, show that versus enalapril, LCZ696 significantly:

  • Cut the risk of sudden death by 20% (p=0.008)[2]
  • Cut first heart failure hospitalisation by 21% (537 vs 658; p<0.001) and all heart failure hospitalisations by 23% (851 vs 1079; P<0.001) respectively[1,2]
  • Cut hospitalisations for any reason and for any CV reason by 16% (any reason 3564 vs. 4053; P<0.0001, CV reason 2216 vs. 2537; P<0.001)[1]
  • Cut the need for intensification of heart failure treatment by 16% (520 vs 604; P=0.003)[1]
  • Cut A&E visits for heart failure by 30% (151 vs. 208; P=0.017)[1]

Patients reporting how well they felt and doctors’ assessments of the disease severity were significantly better with LCZ696 than enalapril.[1] Additionally, LCZ696 patients had 18% (771 vs 880; P=0.017) fewer stays in intensive care and were 31% (161 vs 229; P<0.001) less likely to need intravenous drugs to help their heart pump compared to those taking enalapril.[1]

“LCZ696 works in a new way to the treatments that have been the mainstay of heart failure management for over two decades. LCZ696 acts to enhance the protective neurohormonal systems of the heart (Natriuretic peptide [NP] system), while also reducing the detrimental effects of the harmful Renin- Angiotensin-Aldosterone System (RAAS). This appears to slow progression of the disease, meaning fewer deaths and hospitalisations and also a better quality of life for patients” says Professor Iain Squire, lead UK trialist for the PARADIGM-HF study.

Analysis of cardiac biomarkers (NTpro-BNP and troponin), substances that indicate the progression of cardiac disease and risk, showed levels were consistently lower with LCZ696 than enalapril, reflecting reduced heart stress and subsequent damage.[1,2]

LCZ696, a twice-daily oral medicine, acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful Renin- Angiotensin-Aldosterone System (RAAS). Currently available medicines for HFrEF only block the harmful effects and mortality remains very high, with up to 60% of patients dying within five years of a diagnosis of heart failure.[6,7]

Novartis plans to complete the file for marketing authorisation with the US FDA by the end of 2014 and in the European Union in early 2015.

Analysis of the safety data from PARADIGM-HF showed that fewer patients on LCZ696 discontinued study medication for any adverse event compared to those on enalapril (10.7% vs 12.3%, respectively, p=0.03). The LCZ696 group had more hypotension although this did not lead to greater discontinuation of therapy. The LCZ696 group had less renal impairment, hyperkalaemia and cough than the enalapril group. There was no statistically significant difference in angioedema between the two groups.[3]

About the PARADIGM-HF study

PARADIGM-HF is a randomised, double-blind, Phase III study that evaluated the efficacy and safety profile of LCZ696 versus enalapril (a widely studied ACE inhibitor) in 8,442 patients with HFrEF.[3] The baseline characteristics showed the patients enrolled were typical HFrEF patients with NYHA Class II-IV heart failure.[8] PARADIGM-HF was specifically designed to see if LCZ696 could decrease CV mortality by at least 15% vs. enalapril.[6] Patients received LCZ696 or enalapril in addition to a current best treatment regimen. The primary endpoint was a composite of time to first occurrence of either CV death or heart failure hospitalisation, and it is the largest heart failure study ever done.[6,8]

Secondary endpoints were a change in the clinical summary score for heart failure symptoms and physical limitations (as assessed by Kansas City Cardiomyopathy Questionnaire) at eight months; time to all-cause mortality; time to new onset atrial fibrillation; and time to occurrence of renal dysfunction.[6] PARADIGM-HF was initiated in December 2009, and in March 2014, the Data Monitoring Committee (DMC) confirmed that patients given LCZ696 were significantly less likely to die from CV causes, leading to the trial being stopped early.[9] The DMC also confirmed the primary endpoint had been met.

About LCZ696 in heart failure

LCZ696 is an ARNI (Angiotensin Receptor Neprilysin Inhibitor) and has a unique mode of action, which is thought to reduce the strain on the failing heart.[6,10] It harnesses the body’s natural defences against heart failure, simultaneously acting to enhance the levels of natriuretic and other endogenous vasoactive peptides, while also inhibiting the Renin- Angiotensin-Aldosterone System (RAAS).

Heart failure is a debilitating and life-threatening disease in which the heart cannot pump enough blood around the body. Symptoms such as breathlessness, fatigue and fluid retention can appear slowly and worsen over time, significantly impacting quality of life.11

Heart failure presents a growing health-economic burden globally, and consumes almost 2% of the National Health Service (NHS) budget in the UK, which equates to approximately £1.9 billion.[12-15]

Source

Heart failure has a poor prognosis with around 60% of patients dying within five years of diagnosis[4,5]

LCZ696 keeps patients alive longer and in better health than current gold standard ACE inhibitor (enalapril) – in heart failure with reduced ejection fraction (HFrEF)

1 Packer M, et al. Angiotensin-Neprilysin Inhibition and Clinical Progression in Surviving Patients with Heart Failure. Circulation. 2014

2 McMurray JJV. The Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor (ARNI) With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM- HF) Trial. Abstract: American Heart Association Scientific Sessions 2014

3 McMurray JJV et al. Angiotensin-Neprilysin Inhibition versus enalapril in heart failure, N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077

4 Sutherland K. Bridging the quality gap: heart failure. 2010. Available from: http://www.health.org.uk/public/cms/75/76/313/583/Bridging%20the%20quality%20gap%20Heart %20Failure.pdf?realName=cXqFcz.pdf

5 NICE. Clinical Guideline. Chronic heart failure. Available online at http://guidance.nice.org.uk/CG108

6 McMurray JJ, 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;15:1062-73. doi:10.1093/eurjhf/hft052

7 Go A, et al. Heart Disease and Stroke Statistics?2014 Update: A Report From the American Heart Association. Circulation. 2014;4(129):e28-e292

8 McMurray JJ, 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;16:817-825

9 Novartis press release ‘PARADIGM-HF trial of Novartis’ LCZ696 for chronic heart failure stopped early based on strength of interim results’ issued on March 31, 2014

10 Langenickel TH and Dole WP. Angiotensin Receptor-Neprilysin Inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discovery Today: Therapeutic Strategies. 2012;9(4):e131-e139. doi: 10.1016/j.ddstr.2013.11.002

11 Fauci A and Longo D. Disorders of the Heart. Harrison’s ‘Principles of Internal Medicine. 17th ed. 2008;4:1442-55

12 Zannad F, et al. Heart failure burden and therapy, Europace 2009; 11; v1-v9

13 Neumann et al. Heart failure: the commonest reason for hospitalization in Germany-medical and economic perspectives. Dtsch Arztebl Int. 2009;106:269-75

14 Stewart et al. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail. 2002;4:361371

15 Berry et al. Economics of chronic heart failure. Eur J Heart Fail. 2001;3:283291

Source: Novartis