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17.11.2019 16:44:46

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

valsartan1

-- Entresto, compared to valsartan, demonstrated reduced risk in total heart

failure hospitalizations and cardiovascular death in women, compared to

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men2

-- 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

significance4

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

https://novartis.gcs-web.com/Novartis-PARAGON-HF-analyses-suggest-Entresto-benefit-beyond-HFrEF

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

Cardiology.

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

Sessions

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).

About PARAGON-HF

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

in PARADIGM-HF4,5.

-- Hypotension occurred more frequently with Entresto (n=2407; 15.8%) than

with valsartan (n=2389;10.8%)4.

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