Date: 2014-11-17
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the American Heart Association Scientific Sessions 2014
Company: Novartis (Switzerland)
Product: LCZ696
Action
mechanism: LCZ696 is an ARNI (Angiotensin Receptor Neprilysin Inhibitor). This twice a day pill for heart failure acts in multiple ways on the neurohormonal systems of the heart, blocking receptors exerting harmful effects while simultaneously promoting protective mechanisms. It is thought to reduce the strain on the failing heart, promoting the ability of the heart muscle to recover.
Disease: chronic heart failure with reduced ejection fraction (HF-REF)
Therapeutic area: Cardiovascular diseases
Country: Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, China, Columbia, Czech Republic, Denmark, Dominican republic, Ecuador, Estonia, Finland, France, Germany, Hong Kong, Hungary, Iceland, India, Israel, Italy, Republic of Korea, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Panama, Peru, Philippines, Poland, Portugal, Romania, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Taiwan, Turkey, UK, Venezuela
Trial
details: PARADIGM-HF is a randomized, double-blind, Phase III outcome study evaluating the efficacy and safety profile of LCZ696 versus enalapril (a widely used ACE inhibitor) in 8,442 patients with heart failure with reduced ejection fraction (HF-REF). It was specifically designed to see if LCZ696 could increase survival by at least 15% over and above what can be achieved with enalapril in addition to current best treatment in HF-REF patients. The primary outcome is a composite of time to first occurrence of either cardiovascular death or heart failure hospitalization, and is the largest heart failure study ever done. It was initiated in December 2009 and in March 2014 the Data Monitoring Committee confirmed those given LCZ696 were significantly less likely to die from CV causes, leading to the trial being stopped early. (NCT01035255)
Latest
news: * On November 17, 2014, Novartis announced that new data on LCZ696, for patients with heart failure with reduced ejection fraction (HFrEF) show it has the potential to change the course of the disease for patients. In August 2014 Novartis presented topline results from the landmark PARADIGM-HF study showing LCZ696 was superior to ACE inhibitor enalapril on key endpoints, including significantly reducing the risk of CV death or heart failure hospitalization (see below). The new analyses being presented for the first time at the American Heart Association Scientific Sessions 2014, with a paper being simultaneously published in Circulation, show that versus enalapril, LCZ696 significantly: -reduced the risk of dying suddenly by 20% - in HFrEF patients 45% of CV deaths and 36% of all cause deaths are sudden - reduced first and subsequent HFrEF hospitalizations by 21% and 23% respectively - reduced hospitalizations for a cardiovascular reason or for any reason both by 16% - reduced the need for more intense treatment at home by 16% - reduced emergency room visits because of rapid symptom worsening by 30%. When hospitalized, LCZ696 and enalapril patients remained under care for approximately the same time, but those on LCZ696 had 18% fewer stays in intensive care and were 31% less likely to need IV drugs to help their heart pump. Patients' reports of how well they felt and doctors' assessments of disease severity were also significantly better with LCZ696 than enalapril. 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. Novartis plans to complete the file for marketing authorization with the US FDA by the end of 2014 and in the European Union in early 2015. (Packer M, McMurray JJV, Desai AS, et al. Angiotensin-Neprilysin Inhibition and Clinical Progression in Surviving Patients with Heart Failure. Circulation. 2014) * On August 30, 2014, at the European Society of Cardiology congress and published simultaneously in the New England Journal of Medicine, Novartis revealed that LCZ696, was superior to ACE-inhibitor enalapril on key endpoints in the largest heart failure study ever done. In PARADIGM-HF patients with heart failure with reduced ejection fraction (HF-REF) who were given LCZ696 were more likely to be alive and less likely to have been hospitalized for sudden deterioration of their heart failure than those given ACE-inhibitor enalapril. The magnitude of benefit with LCZ696 against enalapril in HF-REF patients was highly statistically significant and clinically important. In the study, the benefit of LCZ696 was seen early, was sustained and was consistent across subgroups. LCZ696 reduced the risk of death from cardiovascular causes by 20% (p=0.00004). It also reduced heart failure hospitalizations by 21% (p=0.00004) and risk of all-cause mortality by 16% (p=0.0005). Overall there was a 20% risk reduction on the primary endpoint, a composite measure of CV death or heart failure hospitalization (p=0.0000002). Analysis of the safety data from PARADIGM-HF showed side effects were manageable in the study[1]. 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 and non-serious angioedema but less renal impairment, hyperkalemia and cough than the enalapril group. Novartis plans to file the application for marketing authorization with the US FDA by the end of 2014 and in the EU in early 2015. * On August 11, 2014, Novartis announced that new data revealing the reduction in cardiovascular (CV) deaths with LCZ696 in patients with heart failure with reduced ejection fraction (HF-REF) will be presented at the European Society of Cardiology (ESC) Congress 2014, on Sunday August 31st at 08.30 CET (2:30AM EDT). The study met the primary endpoint showing LCZ696 reduced heart failure hospitalizations along with CV deaths. The 8,442 patient study, PARADIGM-HF, was specifically designed to see if LCZ696 could increase survival over and above what can be achieved with ACE-inhibitor enalapril in addition to current best treatment in HF-REF patients1. In March 2014 the Data Monitoring Committee overseeing the study confirmed those given LCZ696 were significantly less likely to die from CV causes, leading to the trial being closed early. * On March 31, 2014, Novartis has announced that the Data Monitoring Committee (DMC) unanimously recommended early closure of the PARADIGM-HF study, indicating patients with chronic heart failure with reduced ejection fraction (HF-REF) who received LCZ696 lived longer without being hospitalized for heart failure than those who received standard care with ACE-inhibitor enalapril. Based on the compelling efficacy and primary endpoint having been met, the trial will now close early. This follows two previous interim analyses that showed the safety profile of LCZ696 was acceptable. The results of PARADIGM-HF will be submitted to a major medical conference for presentation and Novartis will now initiate discussions with global health authorities regarding approval for marketing.
