New analysis shows Entresto improved physical and social activity in patients with HFrEF

EAST HANOVER, N.J., Sept. 19, 2017 /PRNewswire/ -- Novartis announced today results of a new post-hoc analysis, which found that Entresto^® (sacubitril/valsartan) improved seven out of 10 types of physical and social activities for HFrEF patients, also known as systolic heart failure (HF), within eight months of starting treatment, compared to enalapril.^1,2 The findings are based on data from PARADIGM-HF, the largest clinical trial ever conducted in HF, and are being presented today as a late breaker at the Heart Failure Society of America (HFSA) 21^st Annual Scientific Meeting in Grapevine, Texas.³

"Chronic heart failure can severely impact the well-being of patients and can affect their independence and ability to go about their daily lives," said Scott Solomon, MD, Director of Noninvasive Cardiology, Brigham and Women's Hospital, Professor of Medicine, Harvard Medical School, and senior author on this presentation. "Our analysis showed that sacubitril/valsartan was superior to other treatments in helping patients to manage their everyday activities, including improving aspects of their social lives."

These data presented at the HFSA Annual Meeting explored the effects of Entresto on 10 individual components related to specific physical and social limitations – two out of the eight domains of health-related quality of life (HRQL) – as reported by patients, in the Kansas City Cardiomyopathy Questionnaire (KCCQ): dressing, showering, climbing a flight of stairs, walking 100 yards, visiting family or friends, jogging, gardening, hobbies, doing household chores, and intimate/sexual relationships.¹

• Among the 8,399 patients enrolled in PARADIGM-HF, 7,623 (91%) in 38 countries completed KCCQ scores at randomization.⁴
• Entresto improved nearly all activities when compared with enalapril, with the most significant changes in household chores and intimate/sexual relationships.¹
• Physical and social improvements were noted at the pre-specified eight months and continued through three years.¹

KCCQ is a self-administered HRQL measure for HF patients, with higher scores indicating fewer symptoms and physical limitations associated with HF.⁵ In the overall patient population of PARADIGM-HF, at the pre-specified endpoint of 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).⁶ Entresto was shown in PARADIGM-HF to reduce the risk of cardiovascular death or first HF hospitalization compared with enalapril among patients at baseline.⁶

"Chronic diseases, such as heart failure, can reduce patients' quality of life in a severe way," said Marcia Kayath, MD, Vice President and Head, US Clinical Development and Medical Affairs for US Pharma at Novartis Pharmaceuticals Corporation. "These results will help inform further research around Entresto's clinical benefits to improve outcomes."

While these results are an important finding, data from individual questions of the KCCQ need to be interpreted cautiously and further data are needed to confirm the benefit of Entresto on improving symptoms and activity in patients. Ongoing investigational studies are underway to further understand the benefit of Entresto on these clinically important measures.

In a separate retrospective study of 200 patients with HF presented at the Meeting, Entresto was shown to have benefits on certain commonly reported symptoms of heart failure in HFrEF patients, including fatigue and shortness of breath within four months of starting the treatment.⁷ This study was conducted in 200 HFrEF patients who were enrolled in a Medicare Advantage or commercial health plan offered by a large, national insurance company – 96.5% of whom were Medicare beneficiaries – and were treated with Entresto.⁷

Together, both these studies showed the potential impact Entresto can have for HFrEF patients.

About Heart Failure 
Heart failure (HF) is a chronic and progressive condition, which impacts 6.5 million Americans and is the leading cause of hospitalization among Americans over the age of 65.^8,9 About half of people with HF have heart failure with reduced ejection fraction (HFrEF), also known as systolic HF.^2,10 Reduced ejection fraction means the heart does not contract with enough force, so less blood is pumped out.¹¹ HF presents a major and growing health-economic burden that currently exceeds $30 billion in the United States, which accounts for both direct and indirect costs.¹² 

Novartis has established the largest global clinical program in the HF disease area across the pharma industry to date. FortiHFy, comprising more than 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 (natriuretic peptide system) while simultaneously inhibiting the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS).^13,14 Other heart failure medicines only block the harmful effects of the overactive RAAS.² Entresto contains the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan.¹³ Entresto is usually administered in conjunction with other heart failure therapies, in place of an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB).¹³ Entresto film-coated tablets are available in three dosage strengths: 24/26 mg, 49/51 mg, and 97/103 mg (sacubitril/valsartan).¹³ These doses are referred to as 50 mg, 100 mg, and 200 mg in the clinical trial literature including The New England Journal of Medicine publication of the results of PARADIGM-HF. The target maintenance dose of Entresto is 97/103 mg twice daily.¹³

Entresto is indicated in the US to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

IMPORTANT SAFETY INFORMATION 
Entresto can harm or cause death to an unborn baby. Patients should talk to their doctor about other ways to treat heart failure if they plan to become pregnant. If a patient gets pregnant while taking Entresto, she should tell her doctor right away. 

Patients are not to take Entresto if they are allergic to sacubitril or valsartan or any of the ingredients in Entresto; have had an allergic reaction including swelling of the face, lips, tongue, throat or trouble breathing while taking a type of medicine called angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB); or take an ACE inhibitor medicine. Patients are not to take Entresto for at least 36 hours before or after they take an ACE inhibitor medicine. Patients should talk with their doctor or pharmacist before taking Entresto if they are not sure if they take an ACE inhibitor medicine. Patients are not to take Entresto if they have diabetes and take a medicine that contains aliskiren. 

Before they take Entresto, patients should tell their doctor about all of their medical conditions, including if they have kidney or liver problems; are pregnant or plan to become pregnant; are breastfeeding or plan to breastfeed. Patients should either take Entresto or breastfeed. They should not do both. 

Patients should tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. They should especially tell their doctor if they take potassium supplements or a salt substitute; nonsteroidal anti-inflammatory drugs (NSAIDs); lithium; or other medicines for high blood pressure or heart problems such as an ACE inhibitor, ARB, or aliskiren. 

Entresto may cause serious side effects including serious allergic reactions causing swelling of the face, lips, tongue, and throat (angioedema) that may cause trouble breathing and death. Patients are to get emergency medical help right away if they have symptoms of angioedema or trouble breathing. Patients are not to take Entresto again if they have had angioedema while taking Entresto. People who are black or who have had angioedema may have a higher risk of having angioedema if they take Entresto. Entresto may cause low blood pressure (hypotension). Patients are to call their doctor if they become dizzy or lightheaded, or they develop extreme fatigue. Entresto may cause kidney problems or an increased amount of potassium in the blood. 

The most common side effects were low blood pressure, high potassium, cough, dizziness, and kidney problems. 

Please see full Prescribing Information, including Boxed WARNING available at http://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf. 

Patients are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. 

Novartis is committed to providing patients with affordable access and resources through Entresto Central. For more information, please call 1-888-ENTRESTO or visit www.entresto.com. 

Disclaimer 
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations 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 the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payer and general public pricing and reimbursement pressures; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; 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 
Located in East Hanover, NJ Novartis Pharmaceuticals Corporation is an affiliate of Novartis which 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, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 119,000 full-time-equivalent associates. Novartis products are available in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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References

1. Chandra, A, Lewis, EF, Claggett, BL, et al. The Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in patients with Heart Failure: The PARADIGM-HF. Oral presentation presented at: Heart Failure Society of America 21st Annual Scientific Meeting; 2017 Sep 16-19; Dallas, TX.
2. 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.
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. Lewis EF, Claggett BL, McMurray JJV, et al. Health-Related Quality of Life Outcomes in PARADIGM-HF. Circ Heart Fail. 2017;10(8). pii: e003430.
5. Green, CP, Porter, CB, Bresnahan, DR. Development and Evaluation of the Kansas City Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure. J Am Coll Cardiol. 2000;35:1245–55.
6. 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.
7. Casebeer, AW, Antol, DD, DeClue, RW, et al. A reduction in physician-recorded heart failure signs and symptoms and all-cause hospitalizations following initiation of sacubitril/valsartan treatment among patients with heart failure and reduced ejection fraction in a real-world setting. Poster presented at: Heart Failure Society of America 21st Annual Scientific Meeting; 2017 Sep 16-19; Dallas, TX.
8. Benjamin EJ, Blaha MJ, Chiuve SE, et al. e. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135:00-00. doi: 10.1161/CIR.0000000000000485.
9. 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.
10. 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.
11. 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 (link is external). Published March 24, 2015. Accessed February 2, 2017.
12. 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.
13. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
14. Langenickel T, Dole W. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discov Today. 2012:4: e131-139.

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