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FDA Approves Entresto (sacubitril/valsartan) for Pediatric Heart Failure

East Hanover, N.J., Oct. 1, 2019 – Novartis announced today that the U.S. Food and Drug Administration (FDA) has approved Entresto (sacubitril/valsartan) for the treatment of symptomatic heart failure (HF) with systemic left ventricular systolic dysfunction in pediatric patients aged 1 year and older. Entresto reduces NT-proBNP and is expected to improve cardiovascular outcomes.1

The approval was based on an analysis at 12 weeks from the 52-week PANORAMA-HF trial which demonstrated reductions in the cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients 1 to <18 years with heart failure due to systemic left ventricular systolic dysfunction with Entresto.1 Because Entresto improved outcomes and reduced NT-proBNP in adult patients in PARADIGM-HF, this effect on NT-proBNP was considered a reasonable basis to infer improved cardiovascular outcomes in pediatric patients.1,3 The reductions from baseline in NT-proBNP for Entresto (44%), and the active comparator enalapril (33%), were similar to or greater than those observed in adults, but the difference between treatment groups was not statistically significant.1 Safety and tolerability of Entresto in pediatric patients were consistent with that observed in adult patients.1,3

Children diagnosed with systolic HF face a poor prognosis.2 It has been estimated that half require a heart transplant before the age of five, and almost one-third die or require a transplant within 1 year.2

“Pediatric heart failure is extremely serious and carries a substantial burden. Given the significant unmet need for heart failure treatments that are proven safe and effective in pediatric patients, this approval and the availability of a new treatment option is great news for these children and their families,” said Andrea Baer, Executive Director at Mended Little Hearts.

“The current clinical management of pediatric systolic heart failure includes the use of several medicines based mostly on data from adult studies, and there is limited data in children with heart failure in clinical trials. PANORAMA-HF is ongoing to secure 52-week follow-up data for the full study population. We remain committed to trial completion to generate further evidence on how Entresto impacts the clinical course of pediatric HF and are grateful for the ongoing collaboration with the investigators, as well as the patients and their families,” said David Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis.

Entresto has been approved in the U.S. since 2015 to reduce the risk of cardiovascular (CV) death or HF hospitalization in adult patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction (HFrEF). It is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.1 It is a first-choice treatment for HFrEF, which affects about 50 percent of all adult HF patients.3,4,5,6

About Pediatric Systolic Heart Failure

HF is a chronic and progressive condition where the heart cannot pump enough blood to support the body’s need for blood and oxygen.7,8 Congenital malformations account for most of the HF burden in children, with cardiomyopathy (diseases of the heart muscle itself) serving as the other main cause.8 Pediatric systolic HF is caused by a structural and/or functional impairment of ventricular systole (when the heart contracts to pump blood out) and is characterized by significant morbidity and mortality, frequent hospitalization and poor quality of life.8,9

About PANORAMA-HF

PANORAMA-HF is a two-part study. Part 1 is an open-label dose determination study. Part 2 is a randomized, double-blind, 52-week study comparing Entresto to the active comparator enalapril in patients aged 1 month to <18 years old with HF (NYHA/Ross Class II-IV) due to systemic left ventricular systolic dysfunction (LVEF <40% or fractional shortening ≤20%).9 It is the largest prospective pediatric HF trial conducted to date and employs the use of a global rank primary endpoint, based on clinical events encompassing death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores) and patient-reported HF symptoms.9 The trial is ongoing and is being conducted in approximately 39 countries and 129 clinical sites across North America, Europe, Asia and Latin America.9 Each of 360 planned participants will be followed for 52 weeks after his or her respective enrollment.9 The trial is expected to be completed in 2021.

FDA approval of Entresto for the treatment of symptomatic HF with systemic left ventricular systolic dysfunction in children aged 1 year and older was based on an analysis in 110 patients evaluating the reduction from baseline to 12 weeks in NT-proBNP.1 The analysis included 90 patients aged 6 to 18 years old and 20 patients aged 1 to 6 years old.1

About Entresto

Entresto (sacubitril/valsartan) is a prescription medicine used to reduce the risk of cardiovascular death and heart failure hospitalization in people with certain types of long-lasting (chronic) heart failure (HFrEF).1 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.1 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).1,10 Most other heart failure medicines only block the harmful effects of the overactive RAAS. Entresto contains the neprilysin inhibitor sacubitril and the ARB valsartan.1 Entresto film-coated tablets are available in three dosage strengths: 24/26 mg, 49/51 mg and 97/103 mg (sacubitril/valsartan).1 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.3 An oral solution also may be compounded.1 In adult patients, the target maintenance dose of Entresto is 97/103 mg twice daily as tolerated by the patient.1 In pediatric patients, the target maintenance dose is dependent on body weight.1

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.

The side effects in pediatric patients were consistent with those observed in adults.

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.

References

  1. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; October 2019.
  2. Towbin JA, Lowe AM, Colan SD, et al. Incidence, Causes, and Outcomes of Dilated Cardiomyopathy in Children. JAMA. 2006; 296(15):1867-1876. doi: 10.1001/jama.296.15.1867.
  3. McMurray J, Packer M, Desai A, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004. doi: 10.1056/NEJMoa1409077.
  4. Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Cardiac Failure Review. 2017;3(1):7–11. doi: 10.15420/cfr.2016:25:2.
  5. Velazquez EJ, Morrow DA, DeVore, AD, et al. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019;380:539-548 doi: 10.1056/NEJMoa1812851.
  6. Yancy C, Jessup M, Butler J, 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: 10.1161/CIR.0000000000000509.
  7. What is Heart Failure? American Heart Association. Website. http://www.heart.org/HEARTORG/Conditions/HeartFailure/About-HeartFailure.... Updated March 7, 2018. Accessed July 20, 2019.
  8. Hinton R, Ware S. Heart Failure in Pediatric Patients with Congenital Heart Disease. Circ Res. 2017;120(6): 978–994. doi:10.1161/CIRCRESAHA.116.308996.
  9. Shaddy R, Canter C, Halnon N, et al. Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). Am Heart J. 2017;193:23-34. http://dx.doi.org/10.1016/j.ahj.2017.07.006.
  10. 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.

Posted: October 2019

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