Regression of Fibrosis & Reversal of Diastolic Dysfunction in HFPEF Patients Treated With Allogeneic CDCs

Heart failure with Preserved Ejection Fraction (HFPEF) is a distinct clinical heart failure
syndrome and represents a critical unmet need in cardiovascular medicine. HFPEF patients have
a marked increase in morbidity and mortality and a profound clinical disability. However, to
date, no management strategies have been demonstrated to decrease morbidity and mortality or
decrease the clinical disability suffered by HFPEF patients.Investigators have postulated
that one pivotal reason that previous randomized clinical studies have failed to show
efficacy in HFPEF trials centers around the incomplete understanding of the pathophysiologic
mechanisms underlying the development of HFPEF. Studies in Veteran patients with HFPEF and in
relevant animal models of HFPEF have demonstrated that one critical mechanism contributing to
HFPEF are changes in the cardiac interstitium and extracellular matrix (ECM) fibrillar
collagen homeostasis. Preliminary studies presented in this application demonstrate that a
highly novel application of stem cell therapy to a rodent model of HFPEF results in
regression of ECM fibrosis and reversal of LV diastolic dysfunction. These preliminary
studies form the foundation for the 3 specific aims proposed in this application that targets
HFPEF in Veterans.

The primary and secondary objectives of this study are too determine the safety profile of
CAP-1002 administered by intracoronary infusion in patients with Heart Failure and a
Preserved Ejection Fraction (HFPEF) and to assess exploratory efficacy endpoints to determine
whether treatment of HFPEF patients with intracoronary allogeneic CDCs affects clinical
functional status (QOL scores), exercise tolerance (6 Minute Walk Test - 6MWT), exercise
hemodynamics (supine exercise ergometry during right heart catheterization), myocardial
interstitial fibrosis (MRI with native T1 mapping and calculation of extracellular volume
[ECV] after gadolinium administration), macroscopic fibrosis by delayed gadolinium
enhancement (DGE), and diastolic function (catheterization, echocardiography, BNP).

If a patient fulfills the inclusion criteria of clinical HF, preserved EF, increased BNP, and
increased LA size and has none of the exclusion criteria (see details below), they will be
consented and undergo CT coronary angiography (to define the coronary anatomy) and
donor-specific antibodies (DSA) screen. If significant CAD is identified by CT and confirmed
by subsequent coronary arteriography and FFR, subjects will be referred to their physician
for consideration of a revascularization procedure. If such subjects undergo a
revascularization procedure, subjects may be reconsidered and rescreened for the study, minus
a repeat CT, after a minimum of 3 months post-revascularization.

All patients will have CAP-1002 or placebo delivered through a coronary catheter inserted in
the right and left coronary arteries using standard techniques in the cardiac catheterization
laboratory. A right heart catheter will be used to obtain baseline (pre-infusion)
hemodynamics. All patients will receive 25 million cells (CAP-1002) or placebo in each of the
3 coronary arteries. Sequential dose administration of 25 million cells each suspended in10
mL of cryopreservation solution (CryoStor® CS10, BioLife Solutions, Inc.) containing 10%
dimethyl sulfoxide (DMSO), and 1800 units heparin and 45 mcg nitro will be delivered via a
coronary artery catheter. Additionally, four milliliters of an intermediate wash solution
containing saline is also administered to each patient. Patients randomized to the placebo
group will receive placebo injections consisting of CAP-1002 minus the active CDC
constituent. Each 10ml bag of 25 million cells will be infused over 1 ml/min. All procedures
will be performed by the cardiac interventionist (Dr Fernandes). The patient will receive
local anesthesia +/- gentle conscious sedation if undue anxiety. During and in between
infusions, multiple measures of gas exchange, hemodynamics, including blood pressure and
heart rate and monitoring for any arrhythmias (ventricular and supra-ventricular). Fluids are
permitted for hypotension during the procedure, as are low dose inotropes such as dobutamine
and use of inhaled nitric oxide. VPCs or NSVT can be seen with insertion of the PA catheter
as it traverses the RV and is easily remedied by catheter withdrawal. Oxygen will be used in
those patients already on O2 therapy at baseline and if needed to treat temporary hypoxia
should this occur. If significant adverse events occur, the cell infusion will be terminated.
Pre-specified infusion related events include the following within 6 hours of CDC infusion:
refractory hypotension requiring pressors and inotropes, significant hypoxemia requiring FiO2
> 0.4 or an increment of > 0.2 from baseline, new cardiac arrhythmia requiring cardioversion,
ventricular tachycardia, ventricular fibrillation, asystole or pulseless electrical activity,
acute severe transfusion reaction (immune or infection related).

Inclusion Criteria:

1. ≥ 50 years old, male or female

2. LVEF ≥ 50%

3. Symptoms and physical findings of chronic heart failure (NYHA class II- ambulatory IV)

4. Treatment with a stable, maximally-tolerated dose of diuretic(s) for a minimum of 30
days prior to randomization.

5. Left atrial (LA) enlargement defined by at least one of the following: LA width
(diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or
LA volume index ≥ 29 mL/m2

6. BNP > 125 pg/ml for patients in NSR or > 150 pg/ml for patients in AF (BNP are BMI
corrected) or resting PCWP > 15 mmHg, or exercise PCWP > 18 mmHg

Exclusion criteria-Specific to HFPEF

1. Any prior echocardiographic measurement of LVEF < 40 %

2. Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery, or
percutaneous coronary intervention (PCI) within the 3 months prior to randomization

3. Unrevascularized, hemodynamically significant CAD (FFR < 0.75)

4. Current acute decompensated HF

5. Alternative diagnoses that in the opinion of the investigator could account for the
patient's HF symptoms (i.e., dyspnea, fatigue) such as severe pulmonary disease (i.e.,
requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy);
hemoglobin (Hgb) < 10 g/dl; body mass index (BMI) > 40 kg/m2

6. Use of investigational drugs or treatments at the time of enrollment

7. Systolic blood pressure > 150 mmHg but < 180 mmHg unless receiving 3 or more
antihypertensive drugs

8. History of any dilated cardiomyopathy; right sided HF in the absence of left-sided
structural heart disease; Pericardial constriction, genetic hypertrophic
cardiomyopathy, or infiltrative cardiomyopathy; clinically significant congenital
heart disease; hemodynamically significant valvular heart disease

9. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3
months

10. Uncontrolled dysrhythmia; symptomatic or sustained ventricular tachycardia or atrial
fibrillation or flutter with a resting ventricular rate > 110 beats per minute (bpm)

11. Prior major organ transplant or intent to transplant (i.e., on transplant list)

12. Hepatic disease as determined by any one of the following: SGOT (AST) or SGPT (ALT)
values exceeding 3x the upper limit of normal (ULN), bilirubin > 1.5 mg/dl; history of
chronic viral hepatitis

13. Chronic Kidney Disease with eGFR < 30 mL/min/1.73 m2; serum potassium > 5.5 mmol/L
(mEq/L)

14. History or presence of any other disease with a life expectancy of < 3 years

15. Non-compliance to medical regimens

16. Drug or alcohol abuse within the last 12 months

17. History of malignancy within the past 5 years

18. Pregnant or nursing (lactating) women confirmed by a positive human chorionic
gonadotropin (hCG); women of child-bearing potential (physiologically capable of
becoming pregnant), unless using highly effective contraception methods during study

Exclusion criteria-Specific to CAP-1002 (not listed above)

1. Diagnosis of active myocarditis

2. Known hypersensitivity to contrast agents or previous H/O HIT

3. Known hypersensitivity to dimethyl sulfoxide (DMSO)

4. Known hypersensitivity to bovine products

5. Active infection not responsive to treatment

6. Active allergic reactions, connective tissue diseases or autoimmune disorders

7. History of cardiac tumor or cardiac tumor demonstrated on screening

8. History of previous stem cell therapy

9. History of treatment with immunosuppressive agents, including chronic systemic
corticosteroids, biologic agents targeting the immune system, anti-tumor and
anti-neoplastic drugs or anti-VEGF within 6 months prior to enrollment (not including
drug-eluting coronary stents)

10. Human Immunodeficiency Virus (HIV) infection