EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study)

Patients with advanced heart failure with reduced ejection fraction (HFrEF) have extremely
high morbidity and mortality with 1 year outcomes of death and hospitalization of
approximately 50%. For the most advanced heart failure patients, the evidence base for
medical treatment is limited with consensus guidelines recommending consideration for either
cardiac transplant or ventricular assist device, or palliative care.

The PARADIGM-HF trial showed that LCZ696, which consists of the neprilysin inhibitor
sacubitril and the ARB valsartan, improved morbidity and mortality in patients with chronic
HFrEF in comparison to enalapril. However, limited experience with advanced heart failure
patients was gained from patients enrolled in the trial. Because the information on the
effects of sacubitril/valsartan in patients with NYHA class IV heart failure is limited, the
updated 2016 ACC/AHA/HFSA guidelines for the treatment of heart failure do not yet endorse
the use of sacubitril/valsartan in patients with NYHA class IV heart failure. Accordingly,
experience is needed on the use of, and outcomes with LCZ696 in patients unable to tolerate
target doses of angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin receptor blocker
(ARB).

This study will be a randomized, double-blinded trial of advanced heart failure subjects with
1:1 randomization to either LCZ696 (sacubitril and valsartan) or valsartan. Study drug will
be administered in a double-dummy fashion, in which subjects take active (LCZ696 or
valsartan) and placebo. Approximately 400 subjects will be randomized into the study.

Subjects will have an initial screening evaluation, including baseline laboratory tests as
well as an assessment of left ventricular (LV) ejection fraction, at which time preliminary
subject eligibility will be determined. The LV ejection fraction may have been obtained
within the prior 3 months by 2-D echocardiogram, LV angiogram or radionuclide scintigraphy.
Willing subjects meeting entry criteria will be consented. Those who meet all entry criteria
and are interested in study participation will be enrolled.

Enrolled subjects will complete baseline assessments and undergo a run-in period of 3-7 days
with LCZ696 50 mg (equivalent to Entresto™ 24/26 mg) po BID prior to randomization. For
subjects taking an ACEI, the ACEI will be withheld for ≥ 36 hours prior to first dose of
LCZ696.

Subjects who tolerate the run-in period with LCZ696 will be randomized 1:1 to LCZ696 or
valsartan.

Study treatment will be titrated to the target dose of 200 mg LCZ696 (equivalent to Entresto™
97/103 mg) as two 100 mg LCZ696 and 2 placebo tablets po BID or valsartan 160 mg (two 80 mg
valsartan and 2 placebo tablets) po BID.*

Randomized subjects will receive the first dose of study drug as follows:

- For subjects not previously taking ACEI or ARB, previously taking ACEI or ARB at a low
dose*, or subjects who have an eGFR < 30 mL/min/1.73m², the starting dose of valsartan
will be 40 mg po BID and the starting dose of LCZ696 will be 50 mg po BID.

- For subjects taking an ARB at greater than low dose†, the starting dose of valsartan
will be 80 mg po BID and the starting dose of LCZ696 will be 100 mg po BID.*

- For subjects taking an ACEI at greater than low dose†, the ACEI will be withheld for ≥
36 hours prior to randomization. The starting dose of valsartan will be 80 mg po BID and
the starting dose of LCZ696 will be 100 mg po BID.*

- At Investigator discretion, study drug may be started at the low dose
(LCZ696/placebo 50 mg po BID or valsartan/placebo 40 mg po BID) if there are any
concerns regarding tolerability at the 100 mg / 80 mg dose.)

Per package insert, the valsartan compounded in Entresto™ is more bioavailable than the
valsartan in other marketed formulations. The dose equivalence for valsartan compounded in
Entresto™ compared to valsartan prepared alone (Entresto™ dose = marketed valsartan dose) is
as follows: 26 mg=40 mg, 51 mg=80 mg, 103 mg=160 mg.

† Low dose is defined as 24 hour dose of ≤ 10 mg lisinopril, ≤ 5 mg ramipril, ≤ 50 mg
losartan, ≤ 10 mg olmesartan, or other dose equivalent.

Dose adjustments will be performed every 2 weeks by doubling the dose of LCZ696 or valsartan
up to the target maximum dose. The doses of LCZ696 are 50 mg (one 50 mg active and 1 placebo
tablet), 100 mg (one 100 mg active and 1 placebo tablet) and 200 mg (two 100 mg active and 2
placebo tablets). These doses are equivalent to 24/26 mg, 49/51 mg, and 97/103 mg commercial
Entresto™, respectively. The doses of valsartan are 40mg (one 40 mg active and 1 placebo
tablet), 80 mg (one 80 mg active and 1 placebo tablet), and 160 mg (two 80 mg active and 2
placebo tablets). The criteria for doubling the dose will be based on systolic blood pressure
(a SBP > 90 mmHg is required for up titration), changes in renal function (maximum serum
creatinine of 2.0 mg/dL), and the absence of symptoms of hypotension. For those not
tolerating the current dose of study drug, the dose will be down-titrated to the previous
tolerated dose. Subjects will return to clinic for follow-up visits at 2, 4, 8, 12, and 24
weeks after randomization.

Assessments at the follow-up visits include some or all of the following: medical history,
review of medications, physical examination with the New York Heart Association (NYHA) class
assessment, Kansas City Cardiomyopathy Questionnaire (KCCQ) quality of life questionnaire,
local laboratory testing (creatinine, Blood Urea Nitrogen (BUN), electrolytes), Core
laboratory testing (Cystatin C, NT-proBNP), adherence and tolerance assessment, and adverse
event monitoring.

Follow-up phone calls will be made at 10, 16, and 20, weeks after randomization to assess
dosing compliance, record the occurrence of applicable adverse events and events of interest,
and remind the subject of the date and time of their next in-person visit.

A final phone visit is conducted 2 weeks after the last dose of study drug (26 weeks after
randomization) to assess clinical stability and any applicable adverse events.

During the consent process, subjects will be asked if interested in donating samples and data
for research purposes via a biorepository and/or genetic study. Based on site and IRB
preference, this optional part of the study may be incorporated into the main consent or may
be a separate consent and Institutional Review Board (IRB) application.

Inclusion Criteria:

1. Advanced HFrEF defined as including ALL

1. LVEF≤ 35% documented during the preceding 12 months

2. NYHA class IV symptomatology, defined as chronic dyspnea or fatigue at rest or on
minimal exertion in the previous 3 months, or patients who require chronic
inotropic therapy

3. Minimum of 3 months GDMT for HF and/or intolerant to therapy

2. Systolic blood pressure ≥ 90 mmHg

3. Serum NT-proBNP ≥ 800 pg/mL OR BNP ≥ 250 pg/mL (most recent - less than 3 months old)

4. Any one or more of the following objective findings of advanced HF including:

1. Current inotropic therapy or use of inotropes in the past 6 months

2. ≥ 1 hospitalization for heart failure in the past 6 months (not including the
index hospitalization for inpatient participants)

3. LVEF ≤ 25% (within the past 12 months)

4. Peak VO2 < 55% predicted or peak VO2 ≤ 16 for men or ≤ 14 for women (Respiratory
Exchange Ratio (RER) ≥ 1.05) (within the past 12 months)

5. 6 min walk test distance < 300 m (within the past 3 months)

5. Age ≥18 years and ≤ 85 years

6. Signed Informed Consent form

Exclusion Criteria:

1. Currently taking Entresto™

2. History of hypersensitivity or intolerance to Entresto™, an ACEI or ARB as well as
known or suspected contraindications to the study drugs.

3. Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m2 at baseline

4. Co-morbid conditions that may interfere with completing the study protocol (e.g.
recent history of drug or alcohol abuse) or cause death within 1 year

5. Symptomatic hypotension at randomization or systolic blood pressure < 90 mmHg

6. Serum potassium > 5.5 mmol/L

7. Severe liver dysfunction (Childs-Pugh Class C)

8. Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG)
changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate
clinical setting (chest discomfort or anginal equivalent)

9. Planned or recent (≤ 4 weeks) PCI, coronary artery bypass grafting, or biventricular
pacing

10. Currently hospitalized and listed 1A or 1B for transplant

11. Current or scheduled for LVAD implantation within 30 days of study enrollment

12. Active infection (current use of oral or IV antimicrobial agents)

13. Primary hypertrophic or infiltrative cardiomyopathy, acute myocarditis, constrictive
pericarditis or tamponade

14. Complex congenital heart disease

15. Concomitant use of aliskiren in patients with diabetes or renal impairment (eGFR <60
mL/min/1.73 m²)

16. Known pregnancy or anticipated pregnancy within the next 6 months or breastfeeding
mothers

17. Enrollment in any other investigational clinical trial within 30 days prior to
screening

18. Inability to comply with study procedures