Heart failure treatment (Pr)ENTRESTO(TM) (LCZ696) shown to reduce the risk of cardiovascular death and hospitalization(1) approved by Health Canada

• ENTRESTO™ approval based the pivotal PARADIGM trial - the largest ever heart failure study of its kind, stopped early due to significance of the results

DORVAL, QC, Oct. 6, 2015 /CNW/ - ENTRESTO™ (sacubitril/valsartan), previously known as LCZ696 has been approved by Health Canada for the treatment of heart failure with reduced ejection fraction (HFrEF) in patients with NYHA Class II or III, to reduce the incidence of cardiovascular death and heart failure hospitalization. The approval of the Novartis treatment is based on results from the 8,442-patient PARADIGM-HF study which was stopped early when it showed ENTRESTO™ significantly reduced the incidence of cardiovascular death versus ACE-inhibitor enalapril, a standard of care treatment.

According to the Heart and Stroke Foundation, heart failure is a very serious health problem that is on the rise. More than 600,000 Canadians are living with heart failure, and each year 50,000 new patients are diagnosed. "Currently half of people diagnosed with heart failure will die within five years," says Dr. Gavin Arthur, Senior Manager for Promote Recovery at the Heart and Stroke Foundation. "There is no cure for heart failure and the cost of managing moderate and severe heart failure patients in Canada amounts to $2.89 billion annually. Progression of symptoms can be slowed with appropriate medical therapy and lifestyle modifications, both of which can prolong and improve quality of life, however there is a critical need for better ways to treat and support these patients."

ENTRESTO™ was granted a Priority Review by Health Canada due to the positive nature of the results demonstrated by the PARADIGM-HF study.  In the study, the benefit of ENTRESTO™ was seen early, and patients with reduced ejection fraction who were given the treatment were more likely to be alive and less likely to have been hospitalized for heart failure than those given enalapril. A new treatment qualifies for Priority Review when it appears to have the potential to offer significant clinical benefit, defined as "outcomes that have an overall positive impact on the treatment" of diseases that are "serious, life-threatening or severely debilitating."² 

"The reduction in cardiovascular mortality and heart failure hospitalization we saw with ENTRESTO™ in the PARADIGM-HF trial were very significant.  The survival advantage associated with ENTRESTO™ treatment was in a range that we have not seen for heart failure treatment in the entire past decade, said Dr. Peter Liu, Chief Scientific Officer, University of Ottawa Heart Institute. "I'm also hopeful for what this treatment will mean for our patients. If our patients can be alive, stay out of the hospital, and enjoying daily living, it's a win-win situation all around."

"One in every five Canadians is affected by heart failure in their lifetime - it is a major health challenge frequent hospitalizations and rehospitalization weigh heavily on the Canadian healthcare system. While there are treatment options available, it's not an easy disease for Canadian physicians to manage," said Dr. Jonathan Howlett, Clinical Professor of Medicine at the Libin Cardiovascular Institute in Calgary, Alberta and President of the Canadian Heart Failure Society. "This approval is encouraging. There has been great anticipation in the community since the positive study results announced last year showed that ENTRESTO™ could give Canadian patients the chance to live better and longer lives with fewer hospitalizations."

"The approval of ENTRESTO™ is an important development in the treatment of this major health problem," said Dr. Andrew Ignaszewski, Head of Cardiology and the Heart Centre at St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia. "At the end of the day my job is to help heart failure patients lead the best possible life, help them to be more active, keep them out of hospital and live longer. Having this option will help me manage patients living with this very serious condition."

"Heart failure progressively robs patients of the ability to perform activities of everyday life and inevitably results in hospitalizations, often repeatedly, and ultimately death. The goal of any treatment for heart failure should be hold back the course of disease progression, and the data we've seen with ENTRESTO™ looks promising," said Dr. Miroslaw Rajda, Medical Director, Heart Failure and Transplant Program and Associate Professor of Medicine, Division of Cardiology, Queen Elizabeth II Health Science Centre, Dalhousie University, Halifax, Nova Scotia.

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.³ More than 600,000 Canadians have heart failure⁴ and it is responsible for 9 per cent of all deaths in Canada or about 22,000 per year ⁵ which is almost equal to the number of deaths from breast, colorectal, prostate and pancreatic cancer combined.⁶ It is the second leading cause of hospitalization in Canada for patients over 65⁷ and resulted in estimated direct costs of $2.89 billion in 2012.⁸

About ENTRESTO™
ENTRESTO™ is a first-in-class medicine containing sacubitril, a neutral endopeptidase inhibitor and valsartan, an angiotensin II AT₁ receptor blocker. A twice-a-day tablet, it has a unique mode of action which is thought to reduce the strain on the failing heart^9,10,11 by enhancing the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS).¹⁰

ENTRESTO™ is indicated for treatment of heart failure with reduced ejection fraction in patients with NYHA (New York Heart Association) Class II or III heart failure to reduce the incidence of cardiovascular death and heart failure hospitalization. Ejection fraction is a measurement of how well the heart is pumping blood.¹² About half of heart failure patients have a reduced ejection fraction.¹³

ENTRESTO^TM should be administered in combination with other heart failure therapies, in place of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB). ENTRESTO^TM should be initiated, and up-titration conducted by a physician experienced with the treatment of heart failure.

Analysis of the safety data from PARADIGM-HF showed ENTRESTO™ side effects were manageable in the study. Fewer patients on ENTRESTO™ discontinued study medication for any adverse event compared to those on enalapril (10.7% vs 12.2%, respectively). The ENTRESTO™ group had more hypotension and non-serious angioedema but cough, elevation of serum creatinine and serum potassium levels were reported less frequently in the ENTRESTO™ group than in the enalapril group.¹

ENTRESTO™ has also been approved in the United States and is under review in other jurisdictions.

About the PARADIGM-HF study
PARADIGM-HF was a randomized, double-blind, phase III study evaluating the efficacy and safety profile of ENTRESTO™ versus enalapril (a widely studied ACE inhibitor) in 8,442 patients with HFrEF.^9,14 The baseline characteristics showed that the patients enrolled were typical HFrEF patients with NYHA Class II-IV heart failure.⁹

Patients received ENTRESTO™ 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 date.⁹

The PARADIGM-HF results showed that ENTRESTO™, when added to current optimal care and compared to adding the ACE-inhibitor enalapril to optimal care: 

• reduced the risk of death from cardiovascular causes by 20% (p=0.00004)
• reduced first heart failure hospitalizations by 21% (p=0.00004)
• reduced all heart failure hospitalizations by 23% (p=0.0004)
• 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). The effect was seen early and was generally consistent across subgroups.¹

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "hope," "will," "as soon as possible," "expected," or similar terms, or by express or implied discussions regarding potential additional marketing approvals or new indications or labeling for ENTRESTO™, or regarding potential future revenues from ENTRESTO™. 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 ENTRESTO™ will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that ENTRESTO™ will be submitted or approved for sale in any additional markets or at any particular time. Nor can there be any guarantee that ENTRESTO™ will be commercially successful in the future, or will achieve any particular level of revenue. In particular, management's expectations regarding ENTRESTO™ 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 and reimbursement issues; unexpected safety issues; 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 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 Pharmaceuticals Canada Inc.
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 2014, the company invested $76 million in research and development in Canada. Novartis Pharmaceuticals Canada Inc. employs approximately 700 people in Canada. For further information, please consult www.novartis.ca.

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care and cost-saving generic pharmaceuticals. Novartis is the only global company with leading positions in these areas. In 2014, the Group achieved net sales of USD 58.0 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 120,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit www.novartis.com.

ENTRESTO is a trademark of Novartis Pharmaceuticals Canada Inc.

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References:

¹ McMurray JJV, Packer M, Desai AS, et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure, N Engl J Med 2014;371:993-1004. DOI: 10.1056/NEJMoa1409077.

² Health Canada, Guidance for Industry, Priority Review of Drug Submissions, Ottawa, September 16, 2002, updated December 18, 2008, page 2, accessed at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/priordr-eng.pdf

³ Fauci A, Longo D. Disorders of the Heart. Harrison's Principles of Internal Medicine. 17th ed. 2008;4:1442-55.

⁴ 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 and 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

⁵ Brophy JM. Epidemiology of congestive heart failure: Canadian data from 1970 to 1989. Can J Cardiol 1992;8:495-498.

⁶ Canadian Cancer Society's Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2015, p. 47, Toronto: Canadian Cancer Society; 2015.

⁷ Canadian Institute for Health Information (CIHI), A Snapshot of Health in Canada as Demonstrated by Top 10 Lists, 2011, p. 10, accessed at: https://secure.cihi.ca/free_products/Top10ReportEN-Web.pdf.

⁸ Cook C. et al., The Annual Global Economic Burden of Heart Failure, Int J Cardiol (2014), Table 5.

⁹ 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).

¹⁰ Langenickel TH, Dole WP. 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.

¹¹ Solomon SD 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.

¹² American Heart Association, heart.org, Ejection Fraction Heart Failure Measurement, accessed at: http://www.heart.org/HEARTORG/Conditions/HeartFailure/SymptomsDiagnosisofHeartFailure/Ejection-Fraction-Heart-Failure-Measurement_UCM_306339_Article.jsp#

¹³ Owan TE et al, Trends in Prevalence and Outcome of Heart Failure with Preserved Ejection Fraction, N Engl J Med 2006; 355:251-259July 20, 2006DOI: 10.1056/NEJMoa052256

¹⁴ Clinicaltrials.gov, NCT01035255 last accessed online 17 August 2015.

SOURCE Novartis Pharmaceuticals Canada Inc.

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