Important new analysis shows that Novartis' Entresto® is associated with higher relative health-related quality of life scores among HFrEF patients

• New analysis of PARADIGM-HF data shows that among patients who had been hospitalized for heart failure, those on Entresto reported higher relative health-related quality of life (HRQL) scores compared to those taking ACE inhibitor enalapril[1]
   
• In the overall study population, declines in HRQL scores were associated with an increased risk of worse outcomes, including CV death or heart failure hospitalization, a second analysis reported[2]
   
• Findings further support clinical benefits of Entresto and reinforce the urgency to treat appropriate patients with reduced ejection fraction (HFrEF)

Basel, September 19, 2016 - A new post-hoc analysis demonstrates that the decline in health-related quality of life (HRQL) scores associated with a heart failure (HF) hospitalization among patients taking Novartis' Entresto^® (sacubitril/valsartan) was lower - approximately 50% less of a decline - compared to those taking ACE inhibitor enalapril[1]. A second post-hoc analysis in the overall study population shows an association between decline in HRQL score and increased risk of cardiovascular (CV) death and HF hospitalization[2]. The findings are based on data from PARADIGM-HF, the largest clinical trial ever conducted in HF[3], and are being presented at the Heart Failure Society of America (HFSA)'s 20^th Annual Scientific Meeting in Orlando.

"Heart failure hospitalizations can significantly decrease a patient's quality of life and lead to poorer outcomes," said Eldrin F. Lewis, MD, MPH, Associate Physician at Brigham and Women's Hospital and Associate Professor of Medicine, Harvard Medical School. "Heart failure management must focus on strategies to reduce this decline by better managing symptoms which can lead to hospitalization. These analyses suggest that sacubitril-valsartan may help mitigate the impact of heart failure hospitalization on a patient's health-related quality of life, and make a strong case for it as part of optimal treatment of heart failure with reduced ejection fraction."

Regardless of treatment, patients experienced a decrease in HRQL following a HF hospitalization[1]. The first analysis demonstrated that the decline in HRQL associated with a HF hospitalization among Entresto patients was significantly less compared to that of patients taking enalapril[1].

• 6,981 patients in PARADIGM-HF completed a Kansas City Cardiomyopathy Questionnaire (KCCQ) to measure HRQL at baseline and at eight months of treatment; during those eight months, 305 patients were hospitalized for HF[1].
• Among patients who had been hospitalized for HF, those on Entresto experienced lower declines in HRQL (approximately half) compared to those on enalapril (5.11 point decline vs. 10.77 point decline in KCCQ Clinical Summary Score (KCCQ-CSS) for Entresto and enalapril, respectively; p=0.003)[1].

Patients in the PARADIGM-HF study completed a KCCQ at randomization, four months, eight months and annually[1]. KCCQ is a self-administered HRQL measure for HF patients, and the clinical summary score of the KCCQ uses a scale from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with HF[4]. In the overall patient population of PARADIGM-HF, at eight months of treatment, HRQL, as measured by the KCCQ clinical summary score, declined less in patients treated with Entresto than those patients treated with enalapril (2.99 point decline vs. 4.63 point decline for Entresto and enalapril, respectively; least squares mean of the between-group difference 1.64; 95% CI 0.63-2.65; p=0.001)[4].

A second post-hoc analysis examined the association between HRQL and patient outcomes in the overall patient population, and found that clinically meaningful worsening in HRQL scores (defined as a >= 5 point decrease in the KCCQ clinical summary score) after four months of treatment was associated with an increased risk of worse clinical outcomes, including CV death or HF hospitalization[2].

• 7,155 patients completed a KCCQ at baseline and at four months of treatment[2].
• Patients with a decline in HRQL, defined by a decrease of at least five points in the KCCQ clinical summary score at four months, were subsequently at a 24% higher risk of CV death (p=0.009) or 28% higher risk of HF hospitalization (p=0.004)[2].

"We have already seen from PARADIGM-HF that Entresto significantly reduces the risk of cardiovascular death and heart failure hospitalization in heart failure patients with reduced ejection fraction." said Vasant Narasimhan, Global Head, Drug Development and Chief Medical Officer, Novartis. "This new analysis of the data demonstrates that Entresto can also help reduce the serious impact on quality of life associated with heart failure, and further reinforces the potential of this medicine to improve the outlook for patients living with this debilitating condition."

About Heart Failure
Heart failure is a debilitating and life-threatening condition, which impacts over 60 million people worldwide[5]. It is the leading cause of hospitalization in people over the age of 65[6],[7]. About half of people with heart failure have HFrEF[8]. Reduced ejection fraction means the heart does not contract with enough force, so less blood is pumped out[9]. Heart failure presents a major and growing health-economic burden that currently costs the world economy $108 billion every year[6],[10], which accounts for both direct and indirect costs.

Novartis has established the largest global clinical program in the heart failure disease area across the pharma industry to date, FortiHFy, comprising over 40 active or planned clinical studies designed to generate an array of additional data on symptom reduction, efficacy, quality of life benefits and real world evidence with Entresto, as well as to extend understanding of heart failure.

About Entresto
Entresto is a twice-a-day medicine that reduces the strain on the failing heart. It does this by enhancing the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS)[11],[12]. Other heart failure medicines only block the harmful effects of the overactive RAAS[13]. Entresto contains the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan[11]. 

In Europe, Entresto is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction. In the US Entresto is indicated for the treatment of heart failure (NYHA class II-IV) in patients with systolic dysfunction[11]. It has been shown to reduce the rate of cardiovascular death and heart failure hospitalization compared to enalapril, and also to reduce the rate of all-cause mortality compared to enalapril. Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other angiotensin receptor blocker (ARB). Approved indications may vary depending upon the individual country. 

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "support," "being presented," "can," "lead to," "strategies," "suggest," "may," "make a strong case," "potential," "outlook," "growing," "planned," or similar terms, or by express or implied discussions regarding potential 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. Nor can there be any guarantee that Entresto will be commercially successful in the future. 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; unexpected safety, quality or 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
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 2015, the Group achieved net sales of USD 49.4 billion, while R&D throughout the Group amounted to approximately USD 8.9 billion (USD 8.7 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit http://www.novartis.com.

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References
[1] Lewis EF, Claggett B, McMurray JJ, et al. Sacubitril/Valsartan Associated with Lower Declines in Health-Related Quality of Life Compared with Enalapril in Patients with Heart Failure Hospitalization. J Card Fail (2016), doi: http://dx.doi.org/10.1016/j.cardfail.2016.06.080.
[2] Lewis EF, Claggett B, McMurray JJ, et al. Association between Baseline, and Changes in, Health-Related Quality of Life and Death and HF Hospitalization in PARADIGM-HF. J Card Fail (2016), doi: http://dx.doi.org/10.1016/j.cardfail.2016.06.293.
[3] McMurray JJ, Packer M, Desai AS, Gong J, 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 (doi:10.1002/ejhf.1s15).
[4] 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.
[5] Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013, Lancet 2015
[6] Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A report from the American Heart Association. Circulation. 2015;133;e38-e360. doi: 10.1161/CIR.0000000000000350.
[7] Weir LM, Pfuntner A, Maeda J, et al. HCUP facts and figures: statistics on hospital-based care in the United States, 2009. Rockville, MD: Agency for Healthcare Research and Quality, 2011.
[8] Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251-259.
[9] Ejection Fraction Heart Failure Measurement. American Heart Association Website.http://www.heart.org/HEARTORG/Conditions/HeartFailure/SymptomsDiagnosisofHeartFailure/Ejection-Fraction-Heart-Failure-Measurement_UCM_306339_Article.jsp. Published March 24, 2015. Accessed March 10, 2016.
[10] Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606-619.
[11] Entresto Prescribing Information
[12] Langenickel T, Dole W. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discovery Today. 2012:4: e131-9.
[13] Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation. 2013;128:e240-e327.

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