Novartis PARAGON-HF analyses suggest Entresto® benefit beyond HFrEF

EAST HANOVER, N.J., Nov. 17, 2019 /PRNewswire/ --

• 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 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 findings^1,2,4,5
   
• New analyses follow full results from the PARAGON-HF trial, which show overall treatment effect, despite narrow miss on statistical significance⁴

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%.^5,6,9 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.^5,9,10

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 LVEF.¹ The all-cause mortality reduction was driven by the reduction in HFrEF patients.¹
• Treatment benefits persisted up to a higher level of LVEF in women compared with men.¹

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.¹¹ 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.^4,11 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-HF.^4,5
• Hypotension occurred more frequently with Entresto (n=2407; 15.8%) than with valsartan (n=2389;10.8%).⁴
• 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 compromise.⁴
• 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 ongoing.

About Entresto for heart failure with reduced ejection fraction
Entresto (sacubitril/valsartan) is a prescription medicine used to reduce the risk of cardiovascular death and heart failure hospitalization in people with long-lasting (chronic) heart failure (HFrEF).¹² Entresto is usually used with other heart failure therapies, in place of an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin II receptor blocker (ARB) therapy.¹² Entresto is a twice-a-day prescription medicine that works by enhancing the beneficial neurohormonal systems (natriuretic peptide system) while simultaneously inhibiting the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS).^12,13 Most other heart failure medicines only block the harmful effects of the overactive RAAS. Entresto contains the neprilysin inhibitor sacubitril and the ARB valsartan.¹² Entresto film-coated tablets are available in three dosage strengths: 24/26 mg, 49/51 mg and 97/103 mg (sacubitril/valsartan).¹² 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.⁵ In adult patients, the target maintenance dose of Entresto is 97/103 mg twice daily as tolerated by the patient.¹²

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 an ACE inhibitor or 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; or a history of hereditary angioedema; 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 in adults 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; 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 www.novartis.com.

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