12/17/16 Disclosures Research Contracts: Amgen, Astra Zeneca, - PDF document

12/17/16 Disclosures • Research Contracts: Amgen, Astra Zeneca, Bayer, Investigational Medical Therapies Bristol Meyer Squibb, Celyad, Cytokinetics, for Acute and Chronic Heart Failure Medtronic, Merck, Novartis, St. Jude, Trevena John R. Teerlink, M.D. • Consultant: Amgen, Astra Zeneca, Bayer, Bristol FACC, FAHA, FESC, FHFSA, FRCP(UK) Meyer Squibb, Celyad, Cytokinetics, Medtronic, Professor of Medicine, Merck, Novartis, St. Jude, Stealth, Trevena University of California San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical Center San Francisco, CA, USA Investigational Medical Therapies for Acute and Chronic Heart Failure Teaching Old Dogs New Tricks Agents with Vasodilating Properties Getting to the Heart of the Matter 1

12/17/16 Investigational Medical Therapies Risk of long-term mortality associated with diuretic treatment for Acute and Chronic Heart Failure Teaching Old Dogs New Tricks: Paren P, et al . ESC 2016 • Diuretics: Torsemide, Subcutaneous diuretics All-cause All-Cause Mortality, Mortality, Adjusted for Death Unadjusted MAGICC score N (%) HR (95% CI) P-value HR (95% CI) P-value No diuretics 788 (16%) Ref. -- Ref. -- (n=4,940) Diuretics 4,523 (36%) 2.57 <0.001 1.42 <0.001 (n=12,579) (2.38-2.77) (1.23-1.64) Investigational Medical Therapies Torsemide versus Furosemide in Patients With Acute Heart Failure (from the ASCEND-HF Trial) for Acute and Chronic Heart Failure Mentz RJ, et al. Am J Cardiol 2016;117:404-411. Teaching Old Dogs New Tricks: 87% (n=3,620) received furosemide and • Diuretics: Torsemide, Subcutaneous diuretics 13% (n=557) received torsemide • Angiotensin Receptor Neprilysin Inhibitor (ARNI): Sacubitril/ Valsartan 2

12/17/16 LCZ696 – A First-in-Class Angiotensin PARADIGM-HF: Main Results Receptor Neprilysin Inhibitor (ARNI) Heart Failure McMurray JJV, et al. N Engl J Med 2014;371:993-1004. Natriuretic Peptide System Renin Angiotensin System pro-BNP Angiotensinogen (liver secretion) Angiotensin I BNP NT-pro BNP LCZ696 Angiotensin II Neprilysin O O X X N OH O H N AT 1 receptor Inactive O H O N H O N NH fragments N O Vasodilation Sacubitril Valsartan Vasoconstriction ” blood pressure (AHU377) “ blood pressure ” sympathetic tone ↓ “ sympathetic tone ” aldosterone levels LBQ657 “ aldosterone ” fibrosis “ fibrosis ” hypertrophy “ hypertrophy Natriuresis/Diuresis Valsartan/Sacubitril: Considerations PARAGON: Study design Vodovar N, et al. Eur Heart J 2015;36(15):902-5. ≥55 yo, LVEF ≥ 45%, LAE or LVH, Symptomatic HF (NYHA II-IV), Diuretics for HF ≥30d AND either 1) Elevated BNP/ NT-proBNP; or 2) HF Hosp within 9 mo Estimated 4,300 patients 3

12/17/16 Investigational Medical Therapies TRV120027, a selective and for Acute and Chronic Heart Failure beta-arrestin-biased AT1R ligand DeWire SM, et al. Circ Res . 2011;109:205-216 Teaching Old Dogs New Tricks: • Diuretics: Torsemide, Subcutaneous diuretics • Angiotensin Receptor Neprilysin Inhibitor (ARNI): Sacubitril/ Valsartan • Biased-ligand angiotensin receptor antagonist: TRV027 B iased L igands of the A ngiotensin receptor ST udy in TRV120027, a selective and A cute H eart F ailure (BLAST-AHF) beta-arrestin-biased AT1R ligand Felker GM, et al. JACC Heart Fail 2015;3:193-201. DeWire SM, et al. Circ Res . 2011;109:205-216 • Phase-2, international, ≥ 40mg furosemide Evalua'on$of$primary$ composite$endpoint$ 1 hr before randomization dose-finding study in Each$arm$added$to$ standard$AHF$therapy$ Day$5$$ Day$30$ Day$180$ Randomiza'on $ approx. 500 patients visit $ call $ visit$ TRV027 @25 mg/hr hospitalized for acute alloca'on$ TRV027 @5 mg/hr heart failure. Equal$ AHF$$ Pa'ent$ TRV027 @1 mg/hr Placebo End$of$ Infusion $ -16 hours 48-96 hours Follow up 4

12/17/16 Investigational Medical Therapies for Acute and Chronic Heart Failure Felker GM, et al. ESC Heart Failure 2016. 1 mg/hr 5 mg/hr 25 mg/hr Teaching Old Dogs New Tricks: (n=128) (n=182) (n=125) All Cause Death through day 30 • Diuretics: Torsemide, Subcutaneous diuretics HF re-hospitalization through day 30 • Angiotensin Receptor Neprilysin Inhibitor (ARNI): Worsening HF through day 5 Valsartan/sacubitril Change in dyspnea VAS (AUC) through day 5 • Biased-ligand angiotensin receptor antagonist: TRV027 Length of initial hospital stay • Mineralocorticoid Receptor Antagonists Average Z-score -0.5 0 0.5 -0.5 0 0.5 -0.5 0 0.5 Z-score Z-score Z-score Negative Z-score favors Placebo Treatment Treatment of Preserved Cardiac Function Heart Failure TOPCAT: Regional Outcomes with an Aldosterone Antagonist (TOPCAT) • Randomized, double-blind, placebo- Pitt B, et al. N Engl J Med 2014;370:1383-1392. Pfeffer MA, et al. Circulation 2015;131:34-42. controlled, multicenter trial • Target 3515 pts with ≥1 sign and ≥1 symptom of HF, LVEF ≥45%, SBP <140 mm Hg (or ≤160 mm Hg if ≥3 BP meds), serum K <5.0 mmol/L; either HF hosp ≤12 months or BNP ≥100 pg/mL or NTproBNP ≥360 pg/mL • 3445 pts randomized to Placebo or Spironolactone 15-45 mg qd • Potassium monitored baseline, weeks 1 & 4, then q4 months • Hyperkalemia: Spiro 18.7%, vs. 9.1% Placebo Hypokalemia: Spiro 16.2%, vs. 22.9% Placebo Worsening renal function: Spironolactone 10.2%, vs. 7.0% in Placebo group; p <0.001. 5

12/17/16 FINESSE-HF: Study Design Finerenone: Non-steroidal MRA Bayer: www.investor.bayer.com/securedl/13158 Bärfacker L, et al. ChemMedChem 2012;7:1385-1403. • Current MRAs limited by concerns about renal failure, hyperkalemia, and progestogenic effect (spironolactone) • Finerenone has demonstrated superior selectivity compared with spironolactone and improved affinity for the MR compared with eplerenone • Pre-clinical studies demonstrated more pronounced cardiorenal end-organ protection than the steroidal MRAs • PEARL-HF Pilot study provided preliminary support for safety and pharmacologic differences • ARTS provided dosing and safety information Also FIDELIO-DKD (4800 pts) and FIGARO-DKD (6400 pts) Investigational Medical Therapies Agents with Vasodilating Properties… for Acute and Chronic Heart Failure Teaching Old Dogs New Tricks: Agents with Vasodilating Properties: • Natriuretic peptides: Ularitide, Cenderitide 6

12/17/16 TRUE-AHF: TRial of Ularitide’s Efficacy and safety in patients Urodilatin (Ularitide) with AHF • 2,157 patients with unplanned hospitalization or ED visit for ADHF with • Recently discovered (1988) dyspnea at rest, Radiological evidence of HF on a chest x-ray, BNP > 500 pg/mL • Natriuretic peptide or NT-proBNP > 2000 pg/mL, Systolic blood pressure (SBP) ≥ 110 mmHg. synthesized in the kidneys. • 1° endpoint: Clinical composite at 48°; all cause mortality; • N-terminal last 4 amino Multiple 2° endpoints acids only difference from PCWP ANP, which are maintained from pro-ANP. N-terminal prolongation may • be responsible for a higher resistance to endopeptidases with more powerful vasodilating and renal effects. Clinicaltrials.gov NCT01661634 (last updated 02.August, 2016) TRUE-AHF 1°: Clinical Composite TRUE-AHF 1°: Cardiovascular Mortality Packer M, et al. AHA 2016 Late-breaking Clinical Trial . Packer M, et al. AHA 2016 Late-breaking Clinical Trial . 60 1.0 Placebo 32 P=0.82 Proportion Free From Cardiovascular Death 225 deaths Ularitide 45 0.8 % Patients 236 deaths 0.6 30 0.4 HR = 1.03 (96% CI:0.85-1.25) 0.2 15 P=0.75 0.0 0 6 12 18 24 30 36 Months After Randomization 0 Improved Unchanged Worse 7

12/17/16 Investigational Medical Therapies TRUE-AHF: Secondary Endpoints for Acute and Chronic Heart Failure Packer M, et al. AHA 2016 Late-breaking Clinical Trial . Teaching Old Dogs New Tricks: Placebo Ularitide P (n=1069) (n=1088) Value Agents with Vasodilating Properties: Length of stay (hr) in intensive care 69.8 68.0 0.24 during first 120 hours, (50.3, 94.3) (49.3, 93.6) • Natriuretic peptides: Ularitide, Cenderitide Length of stay (hr) in the 148.2 160.8 0.16 hospital during first 30 days, (94.0, 216.8) (96.0, 228.9) • Soluble Guanylate Cyclase (sGC) Stimulator: Vericiguat Episodes of in-hospital worsening HF 126 115 0.63 during first 120 hr Proportion with in-hospital worsening HF 94 (8.8%) 90 (8.3%) 0.70 during first 120 hr Rehospitalization for HF within 30 days 74 (7.0%) 75 (7.1%) 1.00 of hospital discharge Duration (hours) of IV therapy for HF 68.9 70.5 0.53 during index admission, (44.6, 115.5) (42.7, 115.4) All-cause mortality or CV hospitalization 398 (37.2%) 443 (40.7%) 0.10 at 6 months Vericiguat: sGC Stimulation as a Novel Soluble Guanylate Cyclase Stimulator in Heart Failure Mechanism with a Dual Mode of Action Studies (SOCRATES) Program Pieske B, et al. Eur J Heart Fail 2014;16:1026–1038. Symptomatic HF (NYHA II-IV); Hospitalized for Worsening HF; Elevated BNP/ NT-proBNP REDUCED: LVEF <45% PRESERVED: LVEF ≥45%, LAE by echo cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; sGC, soluble guanylate cyclase Stasch, et al. Nature 2001;410:212–215; Evgenov, et al. Nature Rev Drug Discov 2006;5:755–768; Stasch JP & Evgenov OV, Handb Exp Pharmacol 2013;218:279–31. 8