Norbert Weiss (1), Sigrid Nikol (2), Yael Rosen (3), Dan Peres (3), Zami Aberman (3), Manesh R Patel (4), for the PLX-PAD Study Group

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A Phase II, Randomized, Double-Blind, Multicenter, Multinational, Placebo- Controlled, Parallel-Groups Study to Evaluate the Safety and Efficacy of Intramuscular Injections of Allogeneic

for the PLX-PAD Study Group (1) Center for Vascular Medicine & Department of Medicine Section Angiology, University Hospital Carl Gustav Carus at the Technische Universität Dresden,

1 A Phase II, Randomized, Double-Blind, Multicenter, Multinational, Placebo- Controlled, Parallel-Groups Study to Evaluate the Safety and Efficacy of Intramuscular Injections of Allogeneic PLX- PAD Cells for the Treatment of Subjects With Intermittent Claudication (IC) Norbert Weiss (1), Sigrid Nikol (2), Yael Rosen (3), Dan Peres (3), Zami Aberman (3), Manesh R Patel (4), for the PLX-PAD Study Group (1) Center for Vascular Medicine & Department of Medicine Section Angiology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Germany (2) Department of Angiology, Asklepios Klinik St. Georg, Hamburg, Germany (3) Pluristem Ltd., Haifa, Israel (4) Division of Cardiology, Duke University Health System, Durham, NC, USA

2 BACKGROUND Intermittent claudication (IC) due to peripheral arterial disease impairs function and quality of life and is associated with increased cardiovascular morbidity and mortality. Endovascular or surgical revascularization improves symptoms, but leads to an increased amputation rate. Limited non-invasive therapies exist. Previous angiogenesis trials to improve IC were negative. Intramuscular administration of placenta-derived adherent stromal cells (PLX-PAD) increased angiogenesis and blood flow in a murine hind-limb ischemia model, and demonstrated to be safe in clinical phase I studies.

3 MATERIALS & METHODS Ethically accepted Rich & Diverse Highly potent Young donors Unlimited source Easy to collect Technology Allogeneic offthe-shelf Simple IM administration Adaptive slow release secretion of cytokines Long term regenerative effect Placenta

inflammation. Factors which directly support angiogenesis and muscle regeneration.

4 MATERIALS & METHODS PROPOSED MOA Immunomodulatory cytokines which support the induction of M2 macrophages and elevate the level of circulating regulatory T cells leading to elevation in IL-10 and resolution of inflammation. Factors which directly support angiogenesis and muscle regeneration. Enzymes with antioxidant activity, which can protect blood vessels from oxidative damage. ECM remodeling enzymes which enable regeneration.

5 STUDY OBJECTIVES & ENDPOINTS OBJECTIVE: To evaluate the optimal dosing regimen, efficacy and safety of intramuscular injections of PLX-PAD cells in patients with IC, Rutherford categories 2-3, due to femoro-popliteal disease (NCT ) Primary efficacy endpoint: Change in Log-Maximum Walking Distance (Log-MWD) at week 52 compared to baseline Key secondary endpoint: Change in Log-MWD at week 52 in patients treated with 2 administrations of PLX-PAD originating from different placentae compared to baseline Safety

6 KEY INCLUSION - EXCLUSION CRITERIA INCLUSION 45 to 85 years of age. Peripheral artery disease, secondary to atherosclerosis, with moderate to severe claudication, resting ankle-brachial index (ABI) < 0.80 or ABI < 0.90 with >20% decrease in exercise or (TBI) < 0.60, significant (>50%) stenosis of infrainguinal arteries. Screening MWD between 1 and 10 minutes. Optimal medical treatment. EXCLUSION Advanced dis. - Rutherford category 4-6. Failed procedure within one month. Planned revascularization. Buerger s disease. Uncontrolled hypertension / DM. Life-threatening ventricular arrhythmia. Abnormal labs: Creat, Liver Panel, CBC. MI/unstable angina, (TIA)/Stroke, severe CHF, prosthetic heart valve, severe pulmonary dis., infection, of malignancy, Asthma, Immunocompromised. Allergies to IMP. (HIV), syphilis, active hepatitis B, or hepatitis C infection.

STUDY DESIGN, IP & CLINICAL SITES Douglas Denham, DO David L Fried, MD James Hampsey, MD Alan T Hirsch, MD William Schulyer Jones, MD Nadarajah Janaki, M.D Bret Weichmann, MD Robert L.

Gosset, MD Farrell Owen Mendelsohn, MD Berthold Amann, MD Norbert Weiss, MD Sigrid Nikol, MD Holger Reinecke, MD Oliver Müller, MD Thomas Zeller, MD Christine Espinola-Klein, MD Reuven Zimlichman, MD

7 STUDY DESIGN, IP & CLINICAL SITES Douglas Denham, DO David L Fried, MD James Hampsey, MD Alan T Hirsch, MD William Schulyer Jones, MD Nadarajah Janaki, M.D Bret Weichmann, MD Robert L. Wilensky, MD Kathleen Cullen, MD Malcolm Foster, MD Karen J. Ho, MD James B. Gosset, MD Farrell Owen Mendelsohn, MD Berthold Amann, MD Norbert Weiss, MD Sigrid Nikol, MD Holger Reinecke, MD Oliver Müller, MD Thomas Zeller, MD Christine Espinola-Klein, MD Reuven Zimlichman, MD Asaf Rabin, MD Sang Hoon Kim, MD You Sun Hong, MD Weonyong Lee, MD Sung Woon Chung, MD Kwang-Jo Cho, MD Do Kyun Kim, MD Clinical Trials of Texas, Inc. Omega Medical Research Tampa Bay Medical research Clinical and Translational Science Institute University of Minnesota Duke University Aiyan Diabetes Cente Florida Research Network Hospital of the University of Pennsylvania DMI Research, Inc. Turkey Creek Medical Center Northwestern University Medical College of Wisconsin Cardiology, P.C. Franziskus-Krankenhaus, Berlin Universitätsklinikum Carl Gustav Carus, Dresden ASKLEPIOS Klinik St. Georg, Hamburg Universitätsklinikum Münster Universitätsklinikum Heidelberg Medizinische Universtiäts-Herzzentrum Freiburg und Bad- Krozingen Universitätsmedizin der Johannes Gutenberg-Universität Mainz Edith Wolfson Medical Center Horev Center CHA Bundang Medical Center Ajou University School of Medicine Hallym University Sacred Heart Hospital Pusan National University Hospital Dong-A University Hospital National Health Insurance Service Ilsan Hospital

8 BASELINE DEMOGRAPHICS Variable PBO-PBO 300M-PBO 150M-150M 300M-300M ALL-PLX Statistics (n=52) (n=39) (n=38) (n=51) (n=128) (n=180) Age (yrs) 65.9 ± ± ± ± ± ± 8.6 Sex, [n (%)] Female 13 (25.0) 8 (20.5) 10 (26.3) 9 (17.6) 27 (21.1) 40 (22.2) Male 39 (75.0) 31 (79.5) 28 (73.7) 42 (82.4) 101 (78.9) 140 (77.8) Race [n (%)] Asian 6 (11.5) 5 (12.8) 5 (13.2) 5 (9.8) 15 (11.7) 21 (11.7) Black or African American 6 (11.5) 7 (17.9) 2 (5.3) 5 (9.8) 14 (10.9) 20 (11.1) White/Caucasian 40 (76.9) 27 (69.2) 31 (81.6) 41 (80.4) 99 (77.3) 139 (77.2) Hispanic or Latino (2.0) 1 (0.8) 1 (0.6) BMI (kg/m 2 ) 28.4 ± ± ± ± ± ± 4.46 Smoking [n (%)] 49 (94.2) 36 (92.3) 35 (92.1) 48 (94.1) 119 (93.0) 168 (93.3) Diabetes Mellitus [n (%)] 25 (48.1) 15 (38.5) 11 (28.9) 21 (41.2) 47 (36.7) 72 (40.0) Hypertension [n (%)] 41 (78.8) 33 (84.6) 31 (81.6) 41 (80.4) 105 (82.0) 146 (81.1) Hyperlipidemia [n (%)] 20 (38.5) 14 (35.9) 15 (39.5) 21 (41.2) 50 (39.1) 70 (38.9) Total

9 BASELINE CHARACTERISTICS (CONT D) ABI treated leg ABI contralateral leg Baseline MWD Baseline ICD Hemoglobin A1c (HbA1c) SF 36 physical role score Placebo-Placebo Placebo Total PLX Total N Mean + SD 0.6 ± ± ± ± ± ± 0.2 N Mean + SD 0.8 ± ± ± ± ± ± 0.2 N Mean + SD ± ± ± ± ± ± N Mean + SD ± ± ± ± ± ± 82.9 N Mean + SD ± ± ± ± ± N Mean + SD 37.0 ± ± ± ± ± ± 6.2

10 RESULTS: CHANGE IN MAXIMUM WALKING DISTANCE (N=153) For the arm: change from baseline at week 52 = 32.7%; p=0.0008

11 RESULTS: CHANGE IN MAXIMUM WALKING DISTANCE USA * p = ** p = 0.035,

RESULTS: PLX-PAD FROM 2 DONOR IN THE 300-300 GROUP * p

12 RESULTS: PLX-PAD FROM 2 DONOR IN THE GROUP * p = 0.032, ** p = 0.019, *** p = 0.044, 0.017

13 CLINICALLY DRIVEN REVASCULARIZATION BY WEEK 65 At least 1 Revascularization Event n (%) PBO-PBO (N=50) 300M-PBO (N=37) 150M-150M (N=37) 300M-300M (N=48) 300M-300M (N=11) 2 Donors Week 65 6 (12.0) 6 (16.2) 7 (18.9) 3 (6.3) 0 (0) Hazard Ratio* NA 95% CI 0.48, , , 2.05 p-value Odds Ratio** NA 95% CI 0.36, , , 2.49 p-value

14 C-REACTIVE PROTEIN & HEMOGLOBIN A1c (HbA1c) CRP HbA1c Estimate SE P-Value All patients PLX-PAD from 2 donors PLX-PAD (IC) - Week 65 ANCOVA of Change from Baseline in HbA1C (mmol/mol) Difference of Adjusted Means 300M-300M - PBO-PBO * p = ** p = 0.038,

15 SAFETY - ADVERSE EVENTS PBO-PBO (n=51) 300-PBO (n=36) (n=37) (n=48) Death 0 % 0 % 0 % 2.1 % Major amputations 3.9 % 0 % 0 % 0 % Malignancies 7.8 % 5.6 % 10.8 % 2.1 % Infections 33.3 % 22.2 % 32.4 % 33.3 % Injection site pain hematoma leading to discontinuation 39.2 % 9.8 % 0 % 30.6 % 2.8 % 2.8 % 40.5 % 5.4 % 2.7 % 47.9 % 6.3 % 4.2 % Peripheral vascular disorders 29.4 % 27.8 % 27.0 % 22.9 % Cardiac disorders 9.8 % 11.1 % 8.1 % 6.3 % Neurologic disorders 27.5 % 13.9 % 18.9 % 20.8 % Blood and lymphatic disorders 9.8 % 8.3 % 2.7 % 2.1 % Renal disorders 9.8 % 8.3 % 5.4 % 6.3 % Ophthalmologic disorders 11.8 % 5.6 % 5.4 % 4.2 % Respiratory tract disorders 17.6 % 2.8 % 10.8 % 8.3 % Abnormal lab findings 13.7 % 8.3 % 8.1 % 6.3 % Gastrointerstinal disorders 23.5 % 25.0 % 18.9 % 20.8 % Musculosceletal disorders 39.2 % 41.7 % 35.1 % 31.1 % Psychiatric disorders 7.8 % 5.6 % 0 % 4.2 %

16 CONCLUSIONS PLX-PAD treatment demonstrated increased MWD at 52 weeks compared to baseline for all doses across all territories PLX-PAD high dose (300X10 6 x 2) demonstrated superiority over other tested regimes In the USA high-dose PLX-PAD demonstrated superiority over placebo to increase MWD at 52 weeks High-dose PLX-PAD composed of 2 administrations, each from a different donor demonstrated superiority over placebo across all territories IM administration of PLX-PAD cells was safe and well tolerated A phase III clinical trial will test the efficacy and safety of two administrations of PLX-PAD from different donors in patients with CLI unsuitable for revascularization

17 THANK YOU!

No option-patients : Is angiogenesis with gene or cell therapy still an option?

No option-patients : Is angiogenesis with gene or cell therapy still an option? Professor Sigrid Nikol Clinical and Interventional Angiology Asklepios-Klinik St. Georg Hamburg, Germany Angiogenic gene