1. Javed Butler, MD, MPH, MBA Stephen E. Epstein, MD Stephen J. Greene, MD Arshed A. Quyyumi, MD Sergey Sikora, PhD Raymond J. Kim, MD, PhD Allen S. Anderson, MD Jane E. Wilcox, MD Nikolai I. Tankovich, MD Michael J. Lipinski, MD Kenneth B. Margulies, MD Robert T. Cole, MD Hal A. Skopicki, MD, PhD Mihai Gheorghiade, MD Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Patients With Non-ischemic Heart Failure NCT02467387 Sponsor: CardioCell, LLC

2. Javed Butler: Consultant, CardioCell Stephen E. Epstein, Arshed A. Quyyumi, and Mihai Gheorghiade: Consultants and Stock Options, CardioCell Sergey Sikora, Nikolai I. Tankovich: Employees, CardioCell Stephen J. Greene, Raymond J. Kim, Allen S. Anderson, Jane E. Wilcox, Michael J. Lipinski, Kenneth B. Margulies, Robert T. Cole, Hal A. Skopicki: None Disclosures

3. Introduction Initial trials with direct myocardial injections of mesenchymal stem cells (MSCs) in patients with heart failure (HF) with reduced ejection fraction (EF) have demonstrated safety with potential efficacy. – Engraftment of directly injected MSCs is relatively modest and transient. – Catheter or surgical based delivery techniques have practical limitations, especially for multiple administrations. MSCs secrete a broad array of molecules with potential therapeutic effects, including anti-inflammatory and immune-modulatory activities that may be effective with intravenous delivery. – Both allogeneic and autologous MSCs are available for human use. – Allogeneic MSCs are well tolerated without rejection or autoimmune reactions.

4. Ischemia-tolerant bone marrow derived allogeneic MSCs (itMSC, CardioCell Inc.) derived from a single young <25 year-old healthy volunteer and grown under hypoxic conditions. Enhanced paracrine properties Preclinical studies with human itMSCs in murine ischemic cardiomyopathy and acute myocardial infarction models have demonstrated safety, improvement in LV function, and reduced inflammation. Background From M.J. Lipinski, D. Luger, and S.E. Epstein ESC: 2016

5. Aims and Hypothesis Aim: To assess the safety and preliminary efficacy of intravenous itMSC injection in patients with non-ischemic HF Hypothesis: Intravenous itMSC injection will be safe and well tolerated and will be associated with improvement in symptoms and cardiac function

6. Key Eligibility Criteria Non-ischemic cardiomyopathy Ejection fraction ≤40% NYHA class II-III symptoms No evidence hyper-enhancement on MRI Stable on evidence based medical therapy for at least 3 months.

7. Study Design Design: Phase IIa, single-blind, placebo-controlled, crossover, multi-center, RCT Subjects: 23 patients Randomization: 1:1 itMSC or placebo injection with 90 day crossover Intervention: itMSC group: Single dose 1.5 million cells/kg iv Placebo group: 1 mL/kg Lactate Ringer’s solution iv. All subjects itMSCs Placebo itMSCs Day 0 Randomization Day 90 Crossover Day 180 Testing

8. Endpoints Primary (Safety)  Procedural complications  Laboratory profile  Liver function  Renal function  Troponin and CK  Pulmonary function test  Arrhythmias (Holter monitor)  Clinical events (All-cause mortality and hospitalization) Secondary  Left ventricular ejection fraction and volumes by MRI  Kansas City Cardiomyopathy Questionnaire  Clinical Summary Score  Functional Status Score  Six minute walk distance  NYHA functional class  Inflammatory and immune markers Measured at baseline and 90 days after each treatment arm (itMSCs or placebo)

9. Steering Committee – Javed Butler, MD - Principal Investigator and Co-Chair – Mihai Gheorghiade, MD - Co-Chair – Arshed A. Quyyumi, MD – Stephen E. Epstein, MD Enrolling Centers and Site PI: – Emory University (R. Cole, MD) – Northwestern University Feinberg School of Medicine (A. Anderson, MD, J. Wilcox, MD) – University of Pennsylvania (K. Margulies, MD) – Stony Brook University (H. Skopicki, MD) Trial Conduct Data Safety Monitoring Board – Barry Greenberg, MD- Chair – James Fang, MD – Gregory Daniels, MD, PhD MRI Core Lab – Duke University (Raymond J. Kim, MD) Statistical Analysis – Emory University (Yi An Ko PhD)

10. Screened (N = 34) Patients with stable non-ischemic HFrEF and LVEF ≤ 40% by CMR Screened (N = 34) Patients with stable non-ischemic HFrEF and LVEF ≤ 40% by CMR 90-day endpoints (N=10) 90-day endpoints (N=10) itMSCs (n = 11) 90-day endpoints (N=12) 90-day endpoints (N=12) Placebo (n= 12) Randomized (n=23) Enrollment 10 Screen Failure (n =11) Did not undergo infusion (n=1) Did not undergo 180 day assessments 1 withdrawal after 90 day evaluation, before cross-over infusion 1 Protocol violation after 90 day evaluation, before cross-over infusion 1 Protocol violation after cross-over infusion – no show for Day 180 tests. Tests performed on Day 240 visit. Did not undergo 180 day assessments 1 withdrawal after 90 day evaluation, before cross-over infusion 1 Protocol violation after 90 day evaluation, before cross-over infusion 1 Protocol violation after cross-over infusion – no show for Day 180 tests. Tests performed on Day 240 visit. 180-day endpoints (N=7) 180-day endpoints (N=7) Placebo ( n = 8) 180 day endpoints (N=12) 180 day endpoints (N=12) itMSC (n = 12)

11. Patient Population Characteristics Age, yr (SD)47 (13) Male, N (%)13 (59%) Weight, kg (SD)92·5 (19·9) Body mass index (SD)32·2 (7·5) Race – White N (%)15 (68%) NYHA Class II N (%)21 (96%) Systolic BP, mmHg (SD)120 (17) Heart rate, bpm (SD)78 (14) NT-proBNP, pg/mL (IQR)212 (841) Troponin I, ug/mL (SD)0·009 (0·003) Serum sodium, mmol/L (SD)138 (2) Serum creatinine, mg/dL (SD)0·96 (0·23) Medical History N (%) Hypertension5 (23%) Diabetes3 (14%) Atrial fibrillation2 (9%) Chronic kidney disease1 (5%) Baseline Cardiac Magnetic Resonance Data LVEF, % (SD)31.6 (9.8) LVESV, mL (SD)189.6 (114.2) LVEDV, mL (SD)264.9 (120.4) Baseline Medications Loop diuretic N (%)16 (73%) ACEI or ARB N (%)22 (100·0%) MR Antagonist N (%)18 (82%) Beta-blockers N (%)22(100·0%)

12. Safety Placebo (n=22) itMSC (n=22) Adverse events3340 Serious adverse events00 Cell related adverse events* 02 All-cause hospitalization10 All-cause death00 * Both infusion related; 1 superficial thrombophlebitis; 1 bruising at iv site No significant changes in 1.Holter monitor 2.Liver function (ALT, AST, Alk Phos, bilirubin, and albumin) 3.Renal function (creatinine, GFR) 4.Pulmonary function (FVC, FEV1, FEV1/FVC, DLCO)

13. Six Minute Walk Distance 6 Minute Walk Test Differences between groups, itMSC minus placebo (95% CI) P value Distance (m) 36·47 (5·98-66·97)0·02 Distance (% change from baseline) 15·94 (1·63-30·24)0·03

14. Kansas City Cardiomyopathy Questionnaire KCCQ Differences between groups, itMSC minus placebo (95% CI) P value Functional Status Score5·65 (-0·11-11·41)0·06 Clinical Summary Score5·22 (0·70-9·74)0·02

15. Left Ventricular Function VariableDifference95% CIP LVEF (%) 2.31-0.094.710.06 LVEDV (ml) -17.86-35.03-0.690.04 LVESV (ml) -16.60-33.220.020.05 VariableDifference95% CIP LVEF (%) 1.62-0.824.050.17 LVEDV (ml) -10.56-30.549.430.27 LVESV (ml) -8.90-27.409.600.31 VariableDifference95% CIP LVEF (%) -0.69-3.932.540.66 LVEDV (ml) 7.30-18.0232.610.55 LVESV (ml) 7.70-16.0931.490.50 Initial Injection: itMSC (N=10) Initial Injection: Placebo (N=12) Initial Injection: difference itMSC - placebo Second injection post crossover - 22 itMSC, 12 placebo VariableDifference95% CIP LVEF (%) 0·01-1.501.54 0·99 LVEDV (ml) 1·67-8.6011.93 0·75 LVESV (ml) 0·67-7.288.62 0·87

16. New York Heart Association Class NYHA Class BaselineitMSCsP value I050·014 II1915 III10 NYHA Class BaselinePlaceboP value II 11120.32 III 10 itMSCs (n=22) Placebo (n=12) The difference in improvement in 90 day NYHA functional class between itMSC and placebo was not significant (p=0.33)

17. itMSC Treatment Reduces NK Cells itMSC-induced decrease in natural killer (NK) cells correlates with improvement in LV function

18. Summary Single administration of IV itMSCs in patients with non-ischemic HFrEF was Safe (clinical, PFT, LFT, arrhythmias) Improved 6-minute walk test Improved KCCQ Clinical Summary score and trend for Functional Status score No significant change in LV function Significant reduction in NK cells that correlated with improvement in EF Future studies Confirm findings in larger non-ischemic cohort with hard endpoints Explore effectiveness in ischemic cardiomyopathy Explore whether multiple IV treatments lead to further improvement, including changes in cardiac function