Press Release: Novartis PARAGON-HF trial suggests Entresto(R) benefit in HFpEF patients but narrowly misses primary endpoint

-- Entresto (sacubitril/valsartan) reduced the composite of total (first and

recurrent) heart failure hospitalizations and cardiovascular death

although narrowly missed statistical significance (p = 0.059)[1]

-- Totality of evidence, including improvement in various measures of

symptoms, quality of life, and renal function, suggests clinically

important benefits in HFpEF[1]

-- Entresto was well tolerated and the overall safety profile was comparable

to previous findings in HFrEF patients[1]

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

https://novartis.gcs-web.com/Novartis-PARAGON-HF-trial-suggests-Entresto-benefit-in-HFpEF-patients-but-narrowly-misses-primary-endpoint

Basel, September 1, 2019 -- Novartis announced today full results from

its global Phase III PARAGON-HF study, investigating the efficacy and

safety of Entresto (sacubitril/valsartan) versus the active comparator

valsartan in heart failure patients with preserved ejection fraction

(HFpEF). Entresto reduced the composite primary endpoint of total (first

and recurrent) heart failure hospitalizations and cardiovascular (CV)

death by 13 percent (p = 0.059)[1].

The result was primarily driven by a nearly 15 percent reduction (p =

0.056) in total heart failure hospitalizations (first and recurrent)

[1].

The full body of evidence from the trial suggests that treatment with

Entresto may result in clinically important benefits in HFpEF, a

heterogeneous type of heart failure with no approved treatment, in

particular subgroups[2;3]. Pre-specified subgroup analyses suggest even

greater effects in individuals with a left ventricular ejection fraction

equal to or below the median of 57% (22 percent reduction in primary

endpoint; 95% CI: 0.641, 0.949) and in women (27.5 percent reduction in

primary endpoint; 95% CI: 0.588, 0.895)[1]. Safety and tolerability were

consistent with previously reported findings in HFrEF patients[1].

Currently, Entresto is an approved and essential treatment for patients

with HFrEF, which is typically defined as ejection fraction less than

40%[2;4-7]. These results were presented at the ESC Congress 2019, the

annual meeting of the European Society of Cardiology, and published in

The New England Journal of Medicine[1].

"Novartis is proud of PARAGON-HF's significant contribution to the body

of scientific evidence in HFpEF. This study highlights the critical need

for treatment options for this complex disease," said David Soergel,

M.D., Global Head of Cardiovascular, Renal and Metabolic Drug

Development at Novartis. "Novartis is committed to reimagining heart

failure treatment, and our next step is to further explore these results

from PARAGON-HF. We also look forward to continuing conversations with

clinical experts and regulators to determine next steps."

"While the reduction in the primary endpoint was not statistically

significant, the totality of evidence from PARAGON-HF suggests potential

overall benefit of sacubitril/valsartan compared with valsartan in HFpEF,

particularly in patients with ejection fraction below normal. It also

highlights the complexity of HFpEF and may suggest that some treatments

have a more pronounced impact in certain patient groups, including women,

who are more likely to suffer from this condition than men," said Scott

Solomon, M.D., Director of Noninvasive Cardiology at Brigham and Women's

Hospital, Professor, Harvard Medical School, and PARAGON-HF Executive

Committee Co-Chair.

"PARAGON-HF provides a wealth of data that will advance our

understanding of HFpEF and the patients it affects," said John McMurray,

M.D., Professor of Medical Cardiology at University of Glasgow and

PARAGON-HF Executive Committee Co-Chair. "When considered in the context

of the PARADIGM-HF trial, it is not surprising that sacubitril/valsartan

might have a greater treatment effect in HFpEF patients with an ejection

fraction in the lower part of the range we studied in PARAGON-HF."

Sacubitril/valsartan (approved as Entresto(R) since 2015) is a

first-choice and essential treatment in HFrEF[2;4-7], based on its

superiority to the angiotensin-converting enzyme (ACE) inhibitor

enalapril and its ability to significantly reduce CV death and HF

hospitalizations[5;8;9].

About PARAGON-HF

PARAGON-HF is the largest clinical trial in heart failure with preserved

ejection fraction (HFpEF) conducted to date[10]. 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[10]. 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[1;10]. Results showed a

13% reduction in the primary composite endpoint of total (first and

recurrent) heart failure hospitalizations and cardiovascular death,

narrowly missing statistical significance (RR=0.870; 95% CI: 0.753,

1.005; p=0.059). More pronounced effects on the primary endpoint were

observed for additional pre-defined subgroups, including individuals

with an ejection fraction less than or equal to the median of 57% (22%

reduction; RR=0.780; 95% CI: 0.641, 0.949) and women (27.5% reduction;

RR=0.725; 95% CI: 0.588, 0.895) as well as in investigator-reported

(non-adjudicated) events (15.7% reduction; RR=0.843; 95% CI: 0.736,

0.966; p=0.0140)[1].

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 significant reduction in the risk

of the composite renal endpoint. No difference in all-cause mortality

was observed between groups[1].

Safety and tolerability analyses found:

-- Entresto was safe and well tolerated in HFpEF patients, largely as

observed in HFrEF patients in PARADIGM-HF.

-- Hypotension occurred more frequently with Entresto (23.2%) than with

valsartan (17%), but rates of discontinuation due to hypotension were

similar (2.4% and 2.3%, respectively).

-- Overall incidence of confirmed angioedema events was low in the two

treatment arms, with 15 events in the Entresto arm (0.58%) and 4 events

in the valsartan arm (0.17%); no angioedema events resulted in airway

compromise or death.

-- Entresto resulted in lower rates of renal dysfunction and hyperkalemia

compared to valsartan, as well as lower rates of discontinuation of study

medication due to these events[1].

PARAGON-HF follows the only positive, previously announced, Phase II

trial in HFpEF, PARAMOUNT-HF, which demonstrated that Entresto reduced

NT-proBNP (a biomarker of cardiac strain) to a greater extent than

valsartan at 12 weeks and was associated with improvement in NYHA class

at 36 weeks. Additional studies investigating Entresto on other relevant

endpoints in HFpEF are ongoing[11;12].

About Heart Failure

Heart failure (HF) is a progressive and serious condition, affecting

approximately 26 million people worldwide, where the heart cannot pump

enough blood to the body[2;13;14]. There are two distinct types of heart

failure: preserved ejection fraction (HFpEF) and reduced ejection

fraction (HFrEF)[15].

About HFpEF

HFpEF is a distinct type of heart failure where the heart muscle

contracts normally but the ventricles do not relax as they should during

ventricular filling (or when the ventricles relax)[16]. HFpEF can be

associated with high hospitalization rates, poor quality of life and

increased mortality[17], and it is emerging as the predominant form of

HF[18]. There is currently no approved treatment for HFpEF[2;3].

About HFrEF

HFrEF is a certain type of long-lasting heart failure, also known as

systolic HF[19;20]. HFrEF means the heart does not contract with enough

force, so less blood is pumped out[16]. There are approved treatment

options for people living with HFrEF[2;21].

About Entresto for Heart Failure with Reduced Ejection Fraction (HFrEF)

Entresto is a twice-a-day medicine that reduces the strain on the

failing heart[8]. 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)[8;22]. 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

[8;23].

In Europe, Entresto is indicated in adult patients for the treatment of

symptomatic chronic heart failure with reduced ejection fraction[8]. 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[23]. 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[4;7;24]. Entresto is usually

administered in conjunction with other heart failure therapies, in place

of an ACE inhibitor or other ARB[8;23]. Approved indications may vary

depending upon the individual country.

Disclaimer

This press release contains forward-looking statements within the

meaning of the United States Private Securities Litigation Reform Act of

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September 01, 2019 08:30 ET (12:30 GMT)