Novartis' investigational heart failure medicine LCZ696 cut cardiovascular deaths by 20% vs. ACE-inhibitor in PARADIGM-HF trial

• LCZ696 mortality benefit exceeded what was achieved with enalapril, an ACE-inhibitor, when replacing  enalapril combined with current treatment regimen for HF-REF¹
• Study showed significantly more HF-REF patients on LCZ696 regimen were alive and had fewer hospitalizations than those given enalapril regimen¹
• Heart failure affects more than 600,000 Canadians¹⁸ and is responsible for 9 per cent of all deaths in Canada¹⁹ representing an equal prevalence of death from breast, colorectal, prostate and pancreatic cancer combined²².

DORVAL, QC, Aug. 30, 2014 /CNW/ - Today at the European Society of Cardiology congress and published simultaneously in the New England Journal of Medicine, Novartis Pharmaceuticals Canada Inc. revealed, in the largest heart failure study to date,^1,5 that its investigational heart failure medicine, LCZ696, was superior to the ACE-inhibitor enalapril on key endpoints. In PARADIGM-HF, patients with heart failure and reduced ejection fraction (HF-REF) who were given LCZ696 were more likely to remain alive and have less re-hospitalization for heart failure than those given the ACE-inhibitor enalapril¹. Patients received LCZ696 or enalapril combined with the current best treatment regimen for heart failure treatment. The safety and efficacy of LCZ696 is still under investigation and market authorization has not yet been obtained in Canada.

"The results of the PARADIGM study showed a reduction in hospitalizations for heart failure, a reduction in cardiovascular mortality and a reduction in total mortality when added to optimal therapy. It also improved the quality of life of patients in the trial," said cardiologist Dr. Jean-Lucien Rouleau of the Montreal Heart Institute, a member of the PARADIGM-HF executive committee and a co-author of the study article. "These results are important given that one in every five or six of the Canadian population, over the age of 40 will experience heart failure. The PARADIGM-HF results are promising and may have a major impact in the way we manage heart failure in the future."

The PARADIGM-HF results showed that the investigational treatment LCZ696, when added to current optimal care and compared to adding the ACE-inhibitor enalapril to optimal care: ¹

• reduced the risk of death from cardiovascular causes by 20% (p=0.00004)
• reduced heart failure hospitalizations by 21% (p=0.00004)
• reduced the 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)¹.

"Given the increasing prevalence, the high hospitalization rate and mortality in heart failure, there is a great need for new treatment alternatives in Canada and around the world'' said Dr. Jean Godin, Chief Scientific Officer and Vice-President, Clinical and Regulatory Affairs of Novartis Pharmaceuticals Canada Inc. "These results show the importance of pursuing research and development efforts to further improve the health outcomes of patients affected by this condition."

About LCZ696 in heart failure
LCZ696, a twice-a-day tablet being investigated for heart failure, has a unique mode of action which is thought to reduce the strain on the failing heart^5,6,7. It acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the RAAS system^5,7.

Analysis of the safety data from PARADIGM-HF showed side effects were manageable in the study¹. 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 pursue filings for marketing authorizations in different jurisdictions around the world starting late in 2014 and continuing in 2015.

About the PARADIGM-HF study
PARADIGM-HF was a randomized, double-blind, phase III study evaluating the efficacy and safety profile of LCZ696 versus enalapril (a widely studied ACE inhibitor) in 8,442 patients with HF-REF^5,12. The baseline characteristics showed that the patients enrolled were typical HF-REF patients with NYHA Class II-IV heart failure. PARADIGM-HF was specifically designed to see if LCZ696 could decrease CV mortality by at least 15% vs. enalapril⁵. Patients received LCZ696 or enalapril in addition to the current best treatment regimen. The primary endpoint was a composite of time to first occurrence of either cardiovascular death or heart failure hospitalization, and was the largest heart failure study done to date⁵.

Secondary endpoints included change in the clinical summary score for heart failure symptoms and physical limitations (as assessed by Kansas City Cardiomyopathy Questionnaire) at 8 months; time to all-cause mortality; time to new onset atrial fibrillation; and time to occurrence of renal dysfunction⁵. 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 early¹³. The DMC also confirmed the primary endpoint had been met.

About heart failure in Canada
Heart failure is a debilitating and potentially 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^3,14. More than 600,000 Canadians have heart failure¹⁸ and it is responsible for 9 per cent of all deaths in Canada¹⁹ which is almost equal to the number of deaths from breast, colorectal, prostate and pancreatic cancer combined.²² It is the second leading cause of hospitalization in Canada for patients over 65²⁰ and resulted in estimated direct costs of $1.18 billion in 2010.²¹

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "will, aim, look forward" or similar terms, or by express or implied discussions regarding potential marketing approvals for LCZ696, or regarding potential future revenues from LCZ696. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that LCZ696 will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that LCZ696 will receive regulatory approval or be commercially successful in the future. In particular, management's expectations regarding LCZ696 could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis Pharmaceuticals Canada Inc.is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis Pharmaceuticals Canada Inc., a leader in the healthcare field, is committed to the discovery, development and marketing of innovative products to improve the well-being of all Canadians. In 2013, the company invested close to $100 million in research and development in Canada. Novartis Pharmaceuticals Canada Inc. employs more than 600 people in Canada. For further information, please consult www.novartis.ca. Novartis Pharmaceuticals Canada Inc. is a subsidiary of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis Group of Companies offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 136,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit www.novartis.com .

References:

1. McMurray JJV et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure, N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077 
2. Ambrosy AP et al. J Am Coll Cardiol 2014;63:1123-33. doi: 10.1016/j.jacc.2013.11.053
3. Gheorghiade M, Pang P, Acute heart failure syndromes, Journal of the American College of Cardiology 2009; 53 (7):557-73
4. Harrison's 'Principles of Internal Medicine', Seventeenth Edition pages 1442 - 1455
5. 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)
6. Langenickel TH et al. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discovery Today: Therapeutic Strategies.2012, Vol 9. No.4
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12. Clinicaltrials.gov, NCT01035255 last accessed online 19 March 2014
13. 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
14. Mosterd A, Hoes, A, Clinical epidemiology of heart failure, Heart 2007;93:1137
15. Cook C, Cole G, Asaria P, Jabbour R, Francis DP. The annual global economic burden of heart failure. Int J Cardiol. 2014.;171(3):368-76
16. Neumann T, Biermann J, Erbel R, Neumann A, Wasem J, Ertl G, et al.,. Heart failure: the commonest reason for hospital admission in Germany: medical and economic perspectives. Dtsch Arztebl Int. 2009;106:269-75.
17. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail. 2002 Jun;4(3):36-71.
18. Blais C, et al. Assessing the burden of hospitalized and community-care heart failure in Canada. Can J Cardiol. 2014 Mar; 30(3):352-8 for 3.5% prevalence rate in population 40+ (p.356) in five major provinces of Canada and applying that rate to Canadian population 40+ (17.687 million) from Statistics Canada, Population by sex and age group, 2013, accessed at: http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/demo10a-eng.htm
19. Canadian Heart Failure Network, Rationale for HF Clinics - The Problem: HF, accessed at: http://www.chfn.ca/clinic-resource-manual/rationale-for-hf-clinics citing Brophy JM. Epidemiology of congestive heart failure: Canadian data from 1970 to 1989. Can J Cardiol 1992;8:495-498.
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Video with caption: "Dr. Jean-Lucien Rouleau comment: PARADIGM-HF Study ". Video available at: http://stream1.newswire.ca/cgi-bin/playback.cgi?file=20140830_C8258_VIDEO_EN_42589.mp4&posterurl=http://photos.newswire.ca/images/20140830_C8258_PHOTO_EN_42589.jpg&clientName=Novartis%20Pharmaceuticals%20Canada%20Inc%2E&caption=Dr%2E%20Jean%2DLucien%20Rouleau%20comment%3A%20PARADIGM%2DHF%20Study%20&title=NOVARTIS%20PHARMACEUTICALS%20CANADA%20INC%2E%20%2D%20Novartis%27%20investigational%20heart%20failure%20medicine%20LCZ696%20cut%20cardiovascular%20deaths%20by%2020%25%20vs%2E%20ACE%2Dinhibitor%20in%20PARADIGM%2DHF%20trial&headline=Novartis%27%20investigational%20heart%20failure%20medicine%20LCZ696%20cut%20cardiovascular%20deaths%20by%2020%25%20vs%2E%20ACE%2Dinhibitor%20in%20PARADIGM%2DHF%20trial

SOURCE: Novartis Pharmaceuticals Canada Inc.