PARADIGM-HF trial of Novartis’ LCZ696 for chronic heart failure closes early based on strength of interim results

• Data Monitoring Committee (DMC) unanimously recommends early closure confirming combined primary endpoint met – LCZ696 delayed cardiovascular death and reduced heart failure hospitalizations vs. enalapril

• PARADIGM-HF is the largest ever trial of a heart failure treatment, robustly designed to assess LCZ696 in patients with chronic heart failure with reduced ejection fraction^1,2
• Over 20 million people across the US and EU live with chronic heart failure, facing a high risk of death and poor quality of life, despite currently available medicines^3,4,5

Novartis announced today 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. 

“Novartis recognizes the huge global need for treatments that extend and improve the lives of people with heart failure and we believe LCZ696’s unique mechanism of action could be transformative,” said Tim Wright, Global Head of Development, Novartis Pharmaceuticals. “This result is a demonstration of our commitment to developing innovative medicines that have an impact on the most important outcomes like cardiovascular mortality.”

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.

“The results of PARADIGM-HF are truly impressive” said Dr. Milton Packer, Professor and Chair for the Department of Clinical Sciences at University of Texas Southwestern Medical Center, Texas, USA and one of the two Principal Investigators. “The finding that treatment with LCZ696 was superior to currently recommended doses of enalapril has profound implications for the care of patients with chronic heart failure. We now have compelling evidence that supports LCZ696 as a new cornerstone in the management of chronic heart failure.”

LCZ696, a twice a day pill for heart failure, is a first in class medicine that acts in multiple ways on the neurohormonal systems of the heart, blocking receptors exerting harmful effects while simultaneously promoting protective mechanisms^2,6,7. Known as an ARNI (Angiotensin Receptor Neprilysin Inhibitor) LCZ696 is thought to reduce the strain on the failing heart, promoting the ability of the heart muscle to recover^2,7.

LCZ696 is the second treatment being developed by Novartis for patients with heart failure, along with RLX030 (serelaxin) for acute heart failure⁸.

References

1.  Clincaltrials.gov, NCT01035255 last accessed online 19 March 2014
2. McMurray JJ, Packer M, Desai AS, 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;15,1062-1073 (doi:10.1093/eurjhf/hft052)
3. Zannad F. et al, Heart failure burden and therapy, Europace 2009, 11; v1-v9.
4. Gheorghiade M, Pang P, Acute heart failure syndromes, Journal of the American College of Cardiology 2009; 53 (7):557-73
5. Harrison’s ‘Principles of Internal Medicine’, Seventeenth Edition pages 1442 – 1455
6. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010;50:401-14.
7. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387-95.