Novartis International AG: Patient-reported outcomes tool revealed significant improvement in symptom frequency and quality of life domains with Entresto®

• Overall summary score was also significantly higher for Entresto patients than for patients not taking Entresto, as measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12)[1]
   
• These improvements were reported early by Entresto patients, with a median follow-up time of 32 days[1]
   
• 21.4 percent of patients treated with Entresto in this interim data cut reported a large improvement (>20-point difference from baseline) in the overall summary score versus 12.5 percent of patients not taking Entresto[1]

Basel, May 28, 2018 - Novartis announced today new real world evidence from the CHAMP-HF registry comparing Entresto^® (sacubitril/valsartan) patients to patients not taking Entresto.[1] This pre-specified analysis of an interim data cut from the CHAMP-HF registry showed that chronic heart failure (HF) patients with reduced ejection fraction (HFrEF) taking Entresto reported early, statistically significant improvement in health status, as measured by the KCCQ-12 overall summary score (KCCQ-OS).[1] This finding was driven by statistically significant improvements in symptom frequency and quality of life domains of the KCCQ-12.[1] The study findings were presented today by lead investigator Yevgeniy Khariton, MD, MSc, Saint Luke's Hospital, Mid-America Heart Institute, University of Missouri-Kansas City, as a part of a late-breaking session at the European Society of Cardiology Heart Failure (ESC-HF) Congress in Vienna, Austria.

"Key goals in managing chronic heart failure are to improve patients' symptoms and quality of life," said CHAMP-HF Chair Gregg C. Fonarow, MD and Director of the Ahmanson-UCLA Cardiomyopathy Center, Co-Chief of UCLA's Division of Cardiology, and Co-director of UCLA's Preventative Cardiology Program. "These findings in a real world setting are important because they suggest that taking sacubitril/valsartan may help patients achieve these goals."

"In addition to the already reported reduction in risk of cardiovascular death and heart failure hospitalization in HFrEF patients treated with Entresto, we now show its potential to improve patient-reported health status," said Shreeram Aradhye, MD, Chief Medical Officer and Global Head, Medical Affairs, Novartis Pharmaceuticals. "What we find most encouraging is that both our Entresto clinical program and now this real world analysis have shown health status benefits as measured by KCCQ."

About Heart Failure
Heart failure is a debilitating and life-threatening condition, which impacts millions of people worldwide.[14] It is the leading cause of hospitalization in people over the age of 65.[8],[15]^, About half of people with heart failure have heart failure with reduced ejection fraction (HFrEF).[9] Reduced ejection fraction means the heart does not contract with enough force, so less blood is pumped out.[11] Heart failure presents a major and growing health-economic burden that currently costs the world economy $108 billion every year, which accounts for both direct and indirect costs.[15],[12]

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^® (sacubitril/valsartan) 
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).[16],[13] Other common heart failure medicines, called angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), only block the harmful effects of the overactive RAAS.[16] Entresto contains the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan.[10]

In Europe, Entresto is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction. In the United States, Entresto is indicated for the treatment of heart failure (New York Heart Association class II-IV) in patients with systolic dysfunction.[10] 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.[17] Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other angiotensin receptor blocker (ARB).[10] Approved indications may vary depending upon the individual country.

About KCCQ-12
KCCQ-12 is a self-administered, health status tool for patients with heart failure.[3] There are four domains: physical limitation (showering/bathing, walking one block on level ground, hurrying or jogging), symptom frequency (shortness of breath, fatigue and swelling of the feet, ankles and legs), social limitation (hobbies/recreational activities, working/doing household chores, visiting family/friends out of the home) and quality of life (impact on lifestyle and satisfaction of spending rest of life with current HF status).[3] Each domain is scored separately, and the overall summary score is equal to the mean of the four domain scores.[3] Higher KCCQ-12 scores from baseline represent better health status.[3] An intra-individual change in a patient's score of 3 to 5 points, or a >=5 point mean group difference, is defined as a minimal clinically important difference for the KCCQ-12 summary score.[3]

About the CHAMP-HF Registry
CHAnge the Management of Patients with Heart Failure (CHAMP-HF) is an ongoing, prospective, observational outpatient disease registry in patients with chronic HFrEF (left ventricular ejection fraction <=40%).[4] CHAMP-HF has enrolled approximately 5,000 patients  from 150 geographically diverse US sites, following these patients including those who have been hospitalized for a maximum duration of 24 months.[4] Participating sites are collecting data from providers (HF history, examination findings, and results of diagnostic studies, pharmacotherapy treatment patterns, decision-making factors, and clinical outcomes) and patients (medication adherence and patient-reported outcomes such as KCCQ-12).[4] The primary endpoint of CHAMP-HF is to examine the rationale for HF treatment changes.[4] Secondary outcomes include examining patient and provider decisions and perceptions of treatments, as well as HF related health care resource utilization.[4] Quality of life measures, such as KCCQ-12 and European Quality of Life Five Dimensions (EQ-5D) Questionnaire, and depression screening (PHQ-2), are also being examined as exploratory outcomes.[4]  This real world contemporary registry provides a unique opportunity to study practice patterns, patient-reported outcomes and the adoption of new HF therapies across a diverse mix of health care providers and practices in the US that care for HFrEF patients.[4]

About the Real World Evidence Analysis
Presented today was a pre-specified analysis of an interim data cut from CHAMP-HF.[1] The aim of this analysis was to assess short-term, health status benefits of Entresto in real world US clinical practice.[1] Propensity score matching was conducted using 365 Entresto patients and 730 patients not receiving Entresto (1:2 match).[1]

Patients taking Entresto had statistically significant improvement in health status as measured by the mean group difference in KCCQ overall summary score (KCCQ-OS) compared to those not taking Entresto (6.01±19 vs. 3.55±17, p=0.014).[1] This improvement in the KCCQ score was seen early with a median follow up of 32 days reported (interquartile range 26, 53).[1] Patients on Entresto scored numerically higher on all domains compared to patients not taking Entresto, but the improvement in the KCCQ-OS score was driven by statistically significant improvements in two domains: symptom frequency (5.07 vs. 1.60, p=0.007) and quality of life (7.53 vs. 4.09, p=0.021).[1] The proportion of patients with a large improvement in overall score (defined as a greater than 20-point improvement from baseline) was 21.4% (78 out of 365 patients) for those taking Entresto vs. 12.5% (91 out of 730 patients) for those not taking Entresto, suggesting a number needed to treat (NNT) of 11.[1]

The overall findings of this real world matched analysis are in line with the KCCQ findings in the PARADIGM-HF study, which showed that Entresto had a positive impact on the health status of patients with chronic heart failure.[5],[6]

Methods
Study Design[1]

• This is a comparative real world effectiveness analysis in which Entresto and non-Entresto groups were propensity matched based on 6 sociodemographic characteristics, 25 clinical characteristics and most recent KCCQ
• Study sample: Patients in the CHAMP-HF registry, who were not previously taking Entresto prior to enrollment, had >=1 KCCQ assessment before their Entresto start and no contraindications to Entresto
• Cohort definition:
  • Entresto use: New Entresto starts (any report of use after enrollment)
  • No Entresto use: Patients with no report of any use of Entresto after enrollment
• Outcome evaluated:
  • KCCQ-12 overall summary scores (primary) and 4 domain scores (secondary) at first assessment after Entresto initiation

It is important to note that the nature of this real world evidence has some limitations:

• 50% of patients in the comparison arm did not receive an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) during matching, which may impact the findings
• Observational analyses have the potential for residual confounding and can only test for associations as opposed to causality (tested via randomized clinical trials)
• It was not possible to exclude patient bias resulting from open-label Entresto use, which could cause a placebo effect on the Entresto arm

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; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, 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, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2017, the Group achieved net sales of USD 49.1 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 124,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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References
      [1]    Khariton, Y, Fonarow, GC, et al. Association Between Sacubitril/Valsartan Initiation and Health Status Outcomes in Heart Failure with Reduced Ejection Fraction: Findings from the CHAMP-HF Registry. Data presented at the European Society of Cardiology Heart Failure (ESC-HF); 2018 May 26-29; Vienna, Austria.
      [2]    ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; November 2017.
      [3]    Spertus, JA, Jones, PG. Development and Validation of a Short Version of the Kansas City Cardiomyopathy Questionnaire. Circulation: Cardiovascular Quality and Outcomes. 2015;8:469-476. DOI: 10.1161/CIRCOUTCOMES.115.001958.
      [4]    DeVore, AD, Thomas, L, et al. Change the management of patients with heart failure: Rationale and design of the CHAMP-HF registry. Am Heart J 2017;189:177-183.
      [5]    Chandra, A, Lewis AF, et al. Effects of Sacubitrill/Valsartan on Physical and Social Activity Limitations in Patients with Heart Failure A Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiology. 2018;3(5):1-8. doi:10.1001/jamacardio.2018.0398. 2014;371(11):993-1004.
      [6]    Lewis, EF, Claggett , BL, et al. Health-Related Quality of Life Outcomes in PARADIGM-HF. Circulation: Heart Failure. 2017;10:e003430. DOI: https://doi.org/10.1161/CIRCHEARTFAILURE.116.003430.
      [7]    Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492.
      [8]    Weir LM, Pfuntner A, Maeda J, et al. HCUP Facts and Figures: Statistics on Hospital-based Care in the United States, 2009. Agency for Healthcare Research and Quality. 2011;1-3.
      [9]    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.  
      [10]  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.    
      [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 April 13, 2018.
      [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]  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.        
      [14]  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; 386(9995):743-800.
      [15]  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.
      [16]  Entresto Prescribing Information.
      [17] 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.

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