Entresto® (sacubitril & valsartan) Manufacturer: Novartis Pharmaceuticals Corporation FDA Approval Date: July 7 2015

Entresto® - sacubitril/valsartan Clinical Application Indications: Neprilysin inhibitor and angiotensin II receptor blocker combination to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction Place in therapy: Patient who have progressed in severity of their heart failure on optimum ACE inhibitor therapy

Entresto® - sacubitril/valsartan Clinical Application Contraindications Hypersensitivity to any component History of angioedema related to previous ACE inhibitor or ARB therapy Concomitant use with ACE inhibitors Concomitant use with aliskiren in patients with diabetes

Entresto® - sacubitril/valsartan Clinical Application Warnings & precautions Observe for signs and symptoms of angioedema and hypotension Monitor renal function and potassium in susceptible patients

Entresto® - sacubitril/valsartan Clinical Application Pregnancy – contraindicated Lactation – not recommended Pregnancy When pregnancy is detected, discontinue Entresto as soon as possible Direct RAAS agent that can cause injury and death to the fetus Lactation Not recommended Crosses into breast milk of rats Potential for serious adverse reactions

Entresto® - sacubitril/valsartan Drug Facts Pharmacology: Sacubitril – prodrug metabolized to active metabolite (LBQ657), which inhibits neprilysin Neprilisyn – neutral endopeptidase Leads to increase in level of peptides, including natriuretic peptides Valsartan – blocks the angiotensin II type-1 (AT1) receptor Sacubitril MOA – increases concentration of natriuretic peptides Natriuretic peptides induce natriuresis – lets sodium go, letting water go In effect, sacubitril decreases blood volume

Entresto® - sacubitril/valsartan Drug Facts Pharmacokinetics: A Time to peak: 0.5 hrs Time to peak of metabolite: 2 hrs D Protein binding – 94-97% Vd: 103 L M Metabolized by esterases to active metabolite Major metabolite is not metabolized E T1/2 sacubitril: 1.4 hrs T1/2 metabolite: 11.5 hrs

Entresto® - sacubitril/valsartan Drug Interactions Precipitant Object Nature of interaction Entresto* Furosemide, levonorgestrel, HCTZ, metformin Decrease AUC and Cmax Atorvastatin Increase AUC and Cmax Entresto ACE-I Increased risk of angioedema Aliskiren Dual RAAS blockade Potassium-sparing diuretics, ACE-I Increased risk of hyperkalemia NSAID Decreased renal function Lithium Increased concentrations Drug Interactions – Object Drugs: Object drugs are affected by “the reviewed drug” List ( ##%) if available Ex: ASA (100%)

Entresto® - sacubitril/valsartan Adverse Effects Side effect Entresto Enalapril Angioedema 0.5% 0.2% Hypotension 18% 12% Impaired renal function 6% 5% Hyperkalemia 14% Cough 9% 13% Angioedema 19 pts on Entresto, 10 pts on enalapril No airway compromise or requirement for mechanical airway protection

Entresto® - sacubitril/valsartan Monitoring Parameters Efficacy Monitoring: Blood pressure at each visit and dose titration Toxicity Monitoring: Serum electrolytes (K+) SCr

Entresto® - sacubitril/valsartan Prescription Information Dosing: initial Previous ACE-I or ARB – 49/51 mg bid No ACE-I or ARB or low doses – 24/26 mg bid Dosing: target Titrate after 2-4 weeks to 97/103 mg bid as tolerated by the patient

Entresto® - sacubitril/valsartan Prescription Information Renal impairment Mild-moderate – no dose adjustment Severe – 24/26 mg bid (initial) Hepatic impairment Mild – no adjustment Moderate (Child-Pugh B) – 24/26 mg bid (initial) Severe impairment – not recommended

Entresto® - sacubitril/valsartan Prescription Information If switching from ACE-I to Entresto, 36 hour washout period is recommended Cost – Source: NY Times; Accessed 8/21/15 $4,500/year Novartis offers free 30-day supply and $10 co-pay cards

Entresto® - sacubitril/valsartan Literature Review PARADIGM-HF Purpose: To compare the combination of sacubitril/valsartan with enalapril in patients who have HFrEF Design: randomized, double-blind, phase 3 trial 1043 sites in 47 countries McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004

Entresto® - sacubitril/valsartan Literature Review Inclusion Criteria Exclusion Criteria Inclusion Criteria Exclusion Criteria Age >18 years NYHA class II-IV Ejection fraction <40% (amended to <35%) BNP >150 pg/mL or pro- BNP >600 pg/mL Treatment with ACE-I or ARB Symptomatic hypotension SBP <100 mg eGFR <30 ml/min/1.73 m2 or  eGFR >25% Serum K+ >5.2 mEq/L Hx of angioedema or unacceptable side effects during receipt of ACE-I or ARB If the patient had been hospitalized, the BNP cut-off was >100 and pro-BNP >400 For at least 4 weeks prior to screening, pts had to be on a Beta-blocker plus an ACE-I or ARB dose equivalent to at least enalapril 10 mg daily McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004

Entresto® - sacubitril/valsartan Literature Review Intervention: LCZ696 200 mg bid vs. enalapril 10 mg bid Primary endpoint: composite of death from cardiovascular causes or a first hospitalization for HF Secondary endpoint: Time to death from any cause Change from baseline to 8 months in clinical summary score (KCCQ) Time to new onset atrial fibrillation Time to first occurrence of a decline in renal function Dose of enalapril chosen based on CONSENSUS and SOLVD trials Run in period – 2 weeks of enalapril and then 4-6 weeks of Entresto Withheld each a day before switching treatments Powered for cardiovascular death – not for primary endpoint in general or for their claim to fame of decreasing hospitalization by 21% McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004

Entresto® - sacubitril/valsartan Literature Review Baseline characteristics Entresto (N=4187) Enalapril (N=4212) Age 63.8 Female 879 (21.0%) 953 (22.6%) White 2763 (66.0%) 2781 (66.0%) Medical History: HTN Afib Hospitalization for HF MI Pretrial use of ACE-I Pretrial use of ARB 2969 (70.9%) 1517 (36.2%) 2607 (62.3%) 1818 (43.4%) 3266 (78.0%) 929 (22.2%) 2971 (70.5) 1574 (37.4%) 2667 (63.3%) 1816 (43.1%) 3266 (77.5%) 963 (22.9%) Treatment at randomization: Diuretic Beta-blocker Mineralocorticoid antagonist 3363 (80.3%) 3899 (93.1%) 2271 (54.2%) 3375 (80.1%) 3912 (92.9%) 2400 (57.0%) NYHA class II 2998 (71.6%) 2921 (69.3%) McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004

Entresto® - sacubitril/valsartan Literature Review Results Entresto (N=4187) Enalapril (N=4212) HR or Difference (95% CI) P-value Composite outcome 914 (21.8) 1117 (26.5) 0.80 (0.73-0.87) <0.001 Death from cardio-vascular causes 558 (13.3) 693 (16.5) 0.80 (0.71-0.89) 1st hospitalization for worsening HF 537 (12.8) 658 (15.6) 0.79 (0.71-0.89) Death from any cause 711 (17.0) 835 (19.8) 0.84 (0.76-0.93) Change in KCCQ clinical summary score at 8 mo -2.99 -4.63 1.64 (0.63-2.65) 0.001 New-onset afib 84 (3.1) 83 (3.1) 0.97 (0.72-1.31) 0.83 Decline in renal fxn 94 (2.2) 108 (2.6) 0.86 (0.65-1.13) 0.28 NNT – primary event – 21 pts NNT – death from cardiovascular causes – 32 pts NYHA class at randomization had an effect on primary endpoint (nominal; p=0.03) Not seen for death from cardiovascular causes McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004

Entresto® - sacubitril/valsartan Literature Review Safety endpoints Entresto (N=4187) Enalapril (N=4212) P-value Hypotension Symptomatic 588 (14.0) 388 (9.2) <0.001 Symptomatic w/ SBP <90 mmHg 112 (2.7) 59 (1.4) SCr > 2.5 mg/dl 139 (3.3) 188 (4.5) 0.007 Serum K >6.0 mmol/L 181 (4.3) 236 (5.6) Cough 474 (11.3) 601 (14.3) SCr >3.0 mg/dL not significant Serum K >5.5 mmol/L not significant Angioedema not significant McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004

Entresto® - sacubitril/valsartan Literature Review Conclusions Entresto’s dual inhibition was more effective in reducing the risk of death from cardiovascular causes or hospitalization for HF than ACE inhibition with enalapril The only significant side effect was symptomatic hypotension, though this did not increase the rate of discontinuation McMurray JJV, et al. N Engl J Med. 2014;371(11): 993-1004

Entresto™ - sacubitril/valsartan Summary Entresto™ inhibits neprilysin and angiotensin receptors Indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction Initial dose is based on receipt of ACE-I or ARB therapy prior to initiation Avoid use in combination with an ACE-I or in patients with a history of angioedema Most common side effect is hypotension

Entresto® - sacubitril/valsartan References Entresto [sacubitril and valsartan] package insert. Novartis Pharmaceutical Corporation. July 2015. McMurray, J, et al. PARADIGM-HF Study. New England Journal of Medicine. 2014;371;11:993- 1004. Pollack, A. The New York Times Website. F.D.A. Approves Heart Drug Entresto Said to Cut Death Risk by 20%. http://www.nytimes.com/2015/07/08/business/inte rnational/fda-approves-heart-drug-entresto-after- promising-trial-results.html. Published July 7, 2015. Accessed August 21, 2015.