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Entresto

Generic name: sacubitril and valsartan
Treatment for: Heart Failure

Update: Entresto (sacubitril and valsartan) Now FDA Approved - July 7, 2015

New Novartis Phase II data Show LCZ696 May Provide Clinical Benefits in Patients with a Difficult-to-Treat Form of Heart Failure

PARAMOUNT study shows LCZ696 reduced a key predictor of morbidity and mortality in patients with a common form of heart failure called HF-PEF[1],[2]

Up to half of the 20 million Europeans and Americans diagnosed with heart failure have HF-PEF[3]-[5], leading to reduced life expectancy and frequent hospitalization[4]-[6]

No therapies are currently approved to reduce morbidity and mortality in patients with HF-PEF, or heart failure with preserved ejection fraction[5]-[7]

Phase III PARADIGM-HF study currently investigating LCZ696 in heart failure with reduced ejection fraction (HF-REF), the other common form of heart failure

Basel, August 26, 2012 - Novartis today announced results from the Phase II PARAMOUNT study showing that the investigational compound LCZ696 is the first therapy to significantly reduce a key predictor of morbidity and mortality in patients with a condition called heart failure with preserved ejection fraction (HF-PEF)[1],[2]. This difficult-to-treat disease affects up to half of the 20 million people with heart failure in Europe and the US [3]-[5]. The data were presented at the ESC Congress 2012 (European Society of Cardiology) in Munich, Germany[1], and published simultaneously in The Lancet[2].

The results show that after 12 weeks, LCZ696 met its primary endpoint by reducing NT-proBNP[*] - a marker of stress on the heart and a predictor of patient outcomes - significantly more than valsartan[1],[2]. The data also suggest that LCZ696 may reverse some structural changes to the heart[1],[2] that occur in patients with heart failure[8].

[*]N-terminal pro-B-type natriuretic peptide

"These Phase II results show that this novel treatment approach has the potential to reduce stress to the heart and to reduce enlargement of the left atrium of the heart, which occurs in patients with heart failure," said Dr Scott Solomon, Professor of Medicine at Harvard University and Director of Noninvasive Cardiology at Brigham and Women's Hospital in Boston, USA. "So far no treatment has been shown to reduce morbidity and mortality in patients with HF-PEF. The favorable effects seen in this study are encouraging, and further testing of LCZ696 is warranted in this patient population."

Heart failure (HF) is a disease in which the heart is unable to supply enough blood to meet the body's needs[7],[8]. There are two common types: heart failure with preserved ejection fraction (HF-PEF) and heart failure with reduced ejection fraction (HF-REF) [7],[8]. In patients with HF-PEF, the percentage of blood pumped out of the heart (also called the ejection fraction) remains within the normal range, but the heart does not relax enough to pump effectively[5],[7],[9]. This results in structural changes that progressively weaken the heart leading to a range of debilitating symptoms. Patients with HF-PEF also commonly have other conditions such as hypertension, diabetes and atrial fibrillation[7],[8].

"The results of the PARAMOUNT study are promising for patients with HF-PEF as there is no effective treatment currently available," said Tim Wright, Global Head of Development, Novartis Pharma. "We believe that thanks to its novel mode of action and these positive study results, LCZ696 could significantly benefit people living with chronic heart failure. These results support our commitment to heart failure patients at every stage of their disease through our ongoing program of clinical trials."

Heart failure affects an estimated 20 million people in Europe and the US[3], and kills around half of all patients within five years of diagnosis[10],[11] as they suffer acute episodes in which their symptoms suddenly become worse and urgent hospital treatment is needed[5],[7]. Patients suffer fatigue, shortness of breath and swollen limbs[5],[7],[8], limiting their ability to complete everyday tasks and placing an ever greater burden on caregivers. Not only does heart failure have a severe impact on patients, but it also represents a major economic burden for healthcare providers[12].

LCZ696 is the first in a new class of medicines called angiotensin receptor neprilysin inhibitors (ARNIs)[13]. It works in a different way to existing heart failure treatments by inhibiting an enzyme (neprilysin, or NEP) in order to promote the body's protective mechanisms, and blocking receptors involved in the narrowing of blood vessels (angiotensin receptors)[13]. LCZ696 therefore acts simultaneously on two important pathways in the development of the disease[13].

The PARAMOUNT study showed that after 12 weeks of treatment, reduction in NT-proBNP was 23% greater with LCZ696 than valsartan (p=0.005)[1],[2]. In addition, there was a greater reduction (p=0.003) in left atrial size (cardiac remodeling) in LCZ696-treated patients at the end of the 36-week study[1],[2]. This suggests that LCZ696 could provide an effective treatment for patients with HF-PEF. The study also showed that LCZ696 had an acceptable safety profile and was well tolerated in patients with HF-PEF[1],[2].

LCZ696 is one of several compounds being developed by Novartis across the spectrum of heart failure. In addition to HF-PEF, LCZ696 is also being investigated for the treatment of heart failure with reduced ejection fraction (HF-REF) in the Phase III PARADIGM-HF study[14]. A recent Phase II study also showed that LCZ696 is more effective than valsartan in reducing blood pressure[15], and a Phase III program has been launched for the first-line treatment of hypertension in Asia.

PARAMOUNT was an international 36-week, randomized, double-blind, multicenter, parallel group, active-controlled study to compare the efficacy, safety, and tolerability profile of LCZ696 with valsartan in patients with HF-PEF[1],[2]. The study consisted of a 12-week core study and a 24-week extension phase[1],[2]. The study included 301 patients (mean age 71 years) with HF-PEF (left ventricular ejection fraction >45%)[1],[2]. They all had elevated NT-proBNP (>400 pg/ml) and at least one of the following symptoms of HF-PEF: shortness of breath on exertion, shortness of breath when lying flat, episodes of shortness of breath at night, and swollen ankles[1],[2]. After stopping any treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), they were randomized to LCZ696 (50 mg twice-daily) or valsartan (40 mg twice-daily), an ARB indicated for heart failure[1],[2]. Doses of both drugs were doubled after one week and doubled again after a further week to a maximum dose of 200 mg and 160 mg twice-daily, respectively[1],[2].

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "could," "currently investigating," "suggest," "may," "potential," "encouraging," "promising," "believe," "commitment," "suggests," "being investigated," "launched," or similar expressions, or by express or implied discussions regarding potential marketing submissions or approvals for LCZ696 or regarding potential future revenues from LCZ696. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with LCZ696 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that LCZ696 will be submitted or approved for sale in any market, or at any particular time. Nor can there be any guarantee that LCZ696 will achieve any particular levels of revenue in the future. In particular, management's expectations regarding LCZ696 could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; unexpected manufacturing issues; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. 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, 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 2011, the Group achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 126,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

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References
[1] Solomon S. PARAMOUNT: Efficacy and Safety of LCZ696, a First-in-Class Angiotensin Receptor Neprilysin Inhibitor, in Patients with Heart Failure and Preserved Ejection Fraction: Primary Results from the PARAMOUNT Study. Presentation at ESC Congress 2012 (European Society of Cardiology), Munich, Germany, August 26, 2012.
[2] Solomon S, 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. www.thelancet.com Published online August 26, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61227-6.
[3] Metra M, Brutsaert D, Dei Cas L, Gheorghiade M. (2011) ESC Intensive and Acute Cardiac Care Textbook - acute heart failure: epidemiology, classification, and pathophysiology. Chapter 49.
[4] Steinberg BA, Zhao X, Heidenreich PA, et al. Trends in patients hospitalised with heart failure and preserved left ventricular ejection fraction: prevalence, therapies and outcomes. Circulation. 2012;126:65-75.
[5] Blanche C, Fumeaux T, Polikar R. Heart failure with normal ejection fraction (HFNEF): is it worth considering? Swiss Med Wkly. 2010;140:66-72.
[6] Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007:50:768-777.
[7] McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-1847.
[8] Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009; 53:e1-90.
[9] Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008.
[10] Loehr LR, Rosamond WD, Chang PP, et al. Heart failure incidence and survival (from the Atherosclerosis Risk in Communities Study). Am J Cardiol 2008;101:1016-22.
[11] Roger VL, Go AS, Lloyd-Jones DM, et al. Heart Disease and Stroke Statistics - 2012 Update: A Report from the American Heart Association. Circulation. 2012;125:e2-e220.
[12] O'Connell JB, Bristow MR. Economic impact of heart failure in the United States: Time for a different approach. J Heart and Lung Trans. 1993:13(4):S107-112.
[13] Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharm. 2010;50:401-14.
[14] Clinicaltrials.gov: Prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in patients with heart failure (PARADIGM-HF) http://clinicaltrials.gov/ct2/show/NCT01035255; Accessed August 2012.
[15] Ruilope LM, Dukat A, Böhm M, et al. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomized, double-blind, placebo-controlled, active comparator study. Lancet 2010;375:1255-66.

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Eric Althoff
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John Taylor
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Posted: August 2012

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