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Press Release: Novartis PARAGON-HF analyses -3-

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*DJ Novartis PARAGON-HF analyses suggest Entresto(R) benefit beyond HFrEF

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November 17, 2019 10:45 ET ( 15:45 GMT)

Press Release: Novartis PARAGON-HF analyses suggest Entresto(R) benefit beyond HFrEF

Entresto (sacubitril/valsartan) demonstrated greatest benefit in HFpEF
patients with ejection fractions adjacent to HFrEF, compared to

Entresto, compared to valsartan, demonstrated reduced risk in total heart
failure hospitalizations and cardiovascular death in women, compared to

Among patients who had been previously hospitalized, those who were
screened during or within 30 days of hospitalization showed the greatest
treatment effect with Entresto, compared to valsartan3

Safety and tolerability of Entresto, where evaluated, were consistent
with previously reported findings1,2,4,5

New analyses follow full results from the PARAGON-HF trial, which show
overall treatment effect, despite narrow miss on statistical

The digital press release with multimedia content can be accessed here:


Basel, November 17, 2019 Novartis announced today new subgroup
analyses from its global Phase III PARAGON-HF study of patients with
heart failure with preserved ejection fraction (HFpEF), also known as
diastolic heart failure(6) . The data suggest that, in specific
subgroups, treatment with Entresto may result in greater reductions in
heart failure hospitalizations and cardiovascular death, as compared to
valsartan. This greater benefit was seen in women with HFpEF and in
HFpEF patients recently hospitalized for heart failure(2,3) . In
addition, in a pooled analysis of PARAGON-HF (HFpEF) and PARADIGM-HF
(heart failure with reduced ejection fraction (HFrEF)), greater
treatment benefit was observed in patients with left ventricular
ejection fraction (LVEF) below approximately 60%(1) . HFpEF is a type of
heart failure that has no currently approved treatment and
disproportionately affects women(6-8) . These new analyses were
presented at the American Heart Association's (AHA) Scientific Sessions
2019 with simultaneous publication of the gender analysis in Circulation
and hospitalization analysis in the Journal of the American College of

Currently, Entresto (sacubitril/valsartan) is an approved and essential
treatment for patients with HFrEF, which is typically defined as
ejection fraction less than or equal to 40%(5,7,9-11) . This is based on
its superiority to the angiotensin-converting enzyme (ACE) inhibitor
enalapril in reducing cardiovascular death and heart failure
hospitalizations, as demonstrated in the PARADIGM-HF trial(9,12,13) .

The full results of the Phase III PARAGON-HF study were presented at ESC
Congress 2019. The study showed a 13% relative reduction in the primary
composite endpoint of cardiovascular death and total (first and
recurrent) heart failure hospitalizations, but narrowly missed
statistical significance(4) .

"These new analyses show that the treatment benefit of
sacubitril/valsartan may extend to patients with a LVEF higher than the
threshold we use to define HFrEF," said Scott Solomon, M.D., Director of
Noninvasive Cardiology at Brigham and Women's Hospital, Professor at
Harvard Medical School and PARAGON-HF Executive Committee Co-Chair. "The
data help to provide a greater understanding of the heterogeneous nature
of HFpEF and the potential benefit of sacubitril/valsartan for those who
are still in need of a treatment option."

"This new research suggests that sacubitril/valsartan may provide
greater benefit in HFpEF patients who have recently been hospitalized
for heart failure and suggests the potential benefit of initiating
treatment during the vulnerable period following hospitalization in
order to reduce further events," said John McMurray, M.D., Professor of
Medical Cardiology at University of Glasgow and PARAGON-HF Executive
Committee Co-Chair. "Understanding the correlation between time since
hospitalization and treatment benefit may help inform optimization of
care for patients with heart failure."

"Novartis is committed to reimagining outcomes for people with
cardiovascular disease and advancing our scientific understanding of
heart failure," said David Soergel, M.D., Global Head of Cardiovascular,
Renal and Metabolic Drug Development at Novartis. "These new data,
suggesting potential benefit of Entresto beyond HFrEF, represent our
ongoing work to develop treatments for patients, including for HFpEF, a
complex condition with high unmet patient need."

About the PARAGON-HF subgroup analyses presented at AHA's Scientific

Data from the Phase III PARAGON-HF (n=4,796 patients with heart failure
with preserved ejection fraction (HFpEF)) and the PARADIGM-HF (n=8,399
patients with heart failure with reduced ejection fraction (HFrEF))
studies were combined in a pooled analysis to assess cardiovascular
death and total heart failure hospitalization, evaluating the effect of
Entresto compared with renin-angiotensin-aldosterone system (RAAS)
inhibition among different left ventricular ejection fraction (LVEF)
categories(1) . In the analysis of the combined groups, total heart
failure hospitalizations and cardiovascular death were reduced in
patients receiving Entresto compared with RAAS inhibition(1) .
Cardiovascular death reduction was driven by the results of the patients
with LVEF of 40% or less from the PARADIGM-HF trial(1) . These
therapeutic effects of Entresto were stronger within subgroup
populations of the study:

The greatest treatment benefits were observed in patients with LVEF below
approximately 60%1. Magnitude of reduction in heart failure
hospitalizations, cardiovascular death and all-cause mortality decreased
with increasing LVEF1. The all-cause mortality reduction was driven by
the reduction in HFrEF patients1.

Treatment benefits persisted up to a higher level of LVEF in women
compared with men1.

A pre-specified subgroup analysis of PARAGON-HF assessed gender
differences in heart failure hospitalization and cardiovascular death,
compared to valsartan, among patients with HFpEF (n=4,796; 2,479 women
and 2,317 men) (2) . In women, Entresto reduced the risk of total heart
failure hospitalization, with a 33% relative rate reduction (95% CI:
15-47), and an absolute reduction of 4 events per 100 person-years. In
men, there was a 7% relative rate increase in the Entresto group versus
the valsartan group, with an absolute increase of 0.9 events per 100
person-years(2) . Men saw improved treatment benefits with Entresto in
exploratory secondary endpoints including change in the New York Heart
Association (NYHA) class and less worsening in quality of life based on
KCCQ Clinical Summary Score at 8 months(2) .

In a separate post-hoc analysis in patients from PARAGON-HF (n=4,796),
the effect of Entresto on total heart failure hospitalizations and
cardiovascular death was compared with that of valsartan, evaluating
patients by the time from their last hospitalization(3) . The effect of
Entresto on total heart failure hospitalizations and cardiovascular
death was greatest among patients screened during or shortly after
hospitalization(3) . Entresto was associated with a gradient of risk
reduction ranging from patients hospitalized within 30 days of screening
(rate ratio, 0.73; 95% CI: 0.53-0.99) to patients never hospitalized
(rate ratio, 1.00; 95% CI: 0.80-1.24) (3) . Shorter times from prior
heart failure hospitalization were associated with higher risk of total
heart failure hospitalizations or cardiovascular death(3) .


PARAGON-HF is the largest clinical trial in heart failure with preserved
ejection fraction (HFpEF) conducted to date(14) . The Phase III
randomized, double-blind, parallel group, active-controlled, 2-arm,
event-driven trial compared the long-term efficacy and safety of
Entresto versus valsartan in 4,822 patients with HFpEF(4,14) . The
patients in the study represented ambulatory patients with established
HFpEF being treated for symptoms and comorbidities, approximately half
of whom had a history of heart failure hospitalizations(4) . Results
showed a 13% relative reduction in the primary composite endpoint
compared to valsartan of total (first and recurrent) heart failure
hospitalizations and cardiovascular death, narrowly missing statistical
significance (RR=0.87; 95% CI: 0.75, 1.01; p=0.06) (4) . Absolute rate
reduction was 1.8 events per 100 person-years. More pronounced effects
on the primary endpoint were observed for certain pre-defined subgroups:
individuals with an ejection fraction less than or equal to the median
of 57% (22% relative reduction; RR=0.78; 95% CI: 0.64, 0.95) (absolute
rate reduction = 6.6 events per 100 person-years) and women (27%
relative reduction; RR=0.73; 95% CI: 0.59, 0.9) (absolute rate reduction
= 3.9 events per 100 person-years) as well as in investigator-reported
(non-adjudicated) events (16.3% relative reduction; RR=0.84; 95% CI:
0.74, 0.97) (absolute rate reduction = 2.7 events per 100 person-years)
(4) .

Secondary endpoint analyses, exploratory in nature, showed that Entresto
patients experienced less worsening in quality of life than valsartan
patients based on KCCQ Clinical Summary Score (CSS) at 8 months. Change
in the New York Heart Association (NYHA) class was also more favorable
in the Entresto group than in the valsartan group. Additionally,
treatment with Entresto resulted in a reduction in the risk of the
composite renal endpoint. No difference in all-cause mortality was
observed between groups(4) .

Safety and tolerability analyses found:

Entresto was safe and well tolerated in HFpEF patients, largely as
observed in heart failure with reduced ejection fraction (HFrEF) patients

Hypotension occurred more frequently with Entresto (n=2407; 15.8%) than
with valsartan (n=2389;10.8%)4.

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Press Release: Novartis PARAGON-HF analyses -2-

Overall incidence of confirmed angioedema events was low in the two
treatment arms, with 14 events in the Entresto arm (0.6%) and 4 events in
the valsartan arm (0.2%); no angioedema events resulted in airway

Entresto resulted in lower rates of worsening renal function (1.4% versus
2.7% compared to valsartan); and serious adverse events of hyperkalemia
compared to valsartan (0.8% versus 1.8%)4.

PARAGON-HF follows PARAMOUNT-HF, the Phase II trial in HFpEF. Additional
studies investigating Entresto on other relevant endpoints in HFpEF are

About Entresto for heart failure with reduced ejection fraction

Entresto is a twice-a-day medicine that reduces the strain on the
failing heart(12) . 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) (12,15) . 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. Entresto contains the neprilysin
inhibitor sacubitril and the ARB valsartan(12,16) .

In Europe, Entresto is indicated in adult patients for the treatment of
symptomatic chronic heart failure with reduced ejection fraction(12) .
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(16) . It has been shown to reduce the rate of
cardiovascular death, heart failure hospitalization and 30-day hospital
readmission compared to enalapril, to reduce the rate of all-cause
mortality compared to enalapril, and to improve aspects of
health-related quality of life (including physical and social
activities) compared to enalapril(5,11,17) . Entresto is usually
administered in conjunction with other heart failure therapies, in place
of an ACE inhibitor or other ARB(12) . Approved indications may vary
depending upon the individual country.


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 and requirements for increased pricing transparency; 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 is reimagining medicine to improve and extend people's lives.
As a leading global medicines company, we use innovative science and
digital technologies to create transformative treatments in areas of
great medical need. In our quest to find new medicines, we consistently
rank among the world's top companies investing in research and
development. Novartis products reach more than 750 million people
globally and we are finding innovative ways to expand access to our
latest treatments. About 109,000 people of more than 140 nationalities
work at Novartis around the world. Find out more at


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1. Solomon S, Packer M, Rouleau J, et al. Effect Of Sacubitril/Valsartan
Across The Spectrum Of Ejection Fraction In Heart Failure. Data presented
at: AHA Scientific Sessions 2019, Nov 16-18; Philadelphia, USA.

2. McMurray J, Lam C, McGrath M, et al. Effects Of Sacubitril/Valsartan In
Women Compared To Men With Heart Failure And Preserved Ejection Fraction.
Circulation. 2019.

3. Vaduganathan M, Claggett B, Desai A, et al. Prior Heart Failure
Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan
Compared with Valsartan in HFpEF. JACC 2019. doi:

4. Solomon S, McMurray J, Anand I, et al. Angiotensin-Neprilysin in Heart
Failure with Preserved Ejection Fraction. N Engl J Med.
2019;38 1:16 09-1620. doi: 10.1056/NEJMoa1908655.

5. McMurray J, Packer M, Desai A, et al. Angiotensin-neprilysin inhibition
versus enalapril in heart failure. N Engl J Med. 2014;37 1:99 3-1004. doi:

6. Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the
Management of Heart Failure. J Am Coll Cardiol. 2013;62(16):e147-e239.
doi: 10.1016/j.jacc.2013.05.019.

7. Ponikowski P, Voors A, Anker SD, et al. 2016 ESC Guidelines for the
diagnosis and treatment of acute and chronic heart failure. Eur Heart J.
2016;3 7:21 292200. doi:10.1093/eurheartj/ehw128.

8. Treatment for Heart Failure: Endpoints for Drug Development Guidance for
Industry. U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER) and Center
for Biologics Evaluation and Research (CBER). June 2019. Available at:
https://www.fda.gov/media/128372/download. Accessed July 17, 2019.

9. Seferovic P, Ponikowski P, Anker S, et al. Clinical practice update on
heart failure 2019: pharmacotherapy, procedures, devices and patient
management. An expert consensus meeting report of The Heart Failure
Association of the European Society of Cardiology. Eur J Heart Fail.
2019;21(10);1169-1186. doi: 10.1002/ejhf.1531.

10. Velazquez E, Morrow D, DeVore, A, et al. Angiotensin-Neprilysin
Inhibition in Acute Decompensated Heart Failure. N Engl J Med.
2019;38 0:53 9-548. doi: 10.1056/NEJMoa1812851.

11. Chandra A, Lewis E, Claggertt B, et al. The Effects of
Sacubitril/Valsartan on Physical and Social Activity Limitations in Heart
Failure Patients: The PARADIGM-HF Trial. JAMA Cardiol. 2018;3(6):498-505.
doi: 10.1001/jamacardio.2018.0398.

12. EMA. Entresto (sacubitril/valsartan). Summary of product characteristics.
Available at:
Accessed July 2019.

13. Yancy C, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of
the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report
of the American College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines and the Heart Failure Society of
America. Circulation. 2017;136:e137-161. doi:

14. Solomon S, Rizkala A, Gong J, et al. Angiotensin Receptor Neprilysin
Inhibition in Heart Failure with Preserved Ejection Fraction: Rationale
and Design of the PARAGON-HF Trial. JACC Heart Fail. 2017;5(7):471-482.
doi: 10.1016/j.jchf.2017.04.013.

15. Langenickel T, Dole W. Angiotensin receptor-neprilysin inhibition with
LCZ696: a novel approach for the treatment of heart failure. Drug Discov
Today. 2012;9(4):e131-139. doi: 10.1016/j.ddstr.2013.11.002.

16. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis
Pharmaceuticals Corp; October 2019.

17. Desai A, Claggett B, Packer M, et al. Influence of Sacubitril/Valsartan
(LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. JACC.
2016;68(3):241-248. doi: 10.1016/j.jacc.2016.04.047.

# # #

Novartis Media Relations

E-mail: media.relations@novartis.com

Peter Züst Meghan O'Donnell

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November 17, 2019 10:45 ET ( 15:45 GMT)

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