Results of Nicord Phase I II Trials and Plans for Phase III Trial

Results of Nicord Phase I II Trials and Plans for Phase III Trial Mitchell E. Horwitz, MD Duke Cancer Institute Duke University Medical Center June 10, 2016

Learning Objectives To provide an overview of the umbilical cord blood expansion and manipulation technologies To provide an update on the clinical experience with NiCord ex vivo expansion technology To describe plans for a phase III study of NiCord versus standard umbilical cord blood transplantation www.cordbloodsymposium.org 2

Disclosures Novartis; Consultant Gamida Cell Ltd; Research Support Sanofi; Research Support 3

NRM Limitations of Adult Umbilical Cord Blood Transplantation Slow Engraftment Graft Failure Resource Utilization Delayed Immune Recovery Infection 4

Source of Problem Donor Graft Comparison Bone Marrow Umbilical Cord Peripheral Blood Nucleated Cells 1-5 x 10 8 /kg 0.15-1 x 10 8 /kg 10-40 x 10 8 /kg CD34+ cells 0.5-2 x 10 6 /kg 0.05-0.2 x 10 6 /kg 2-20 x 10 6 /kg T-Lymphocytes 10 x 10 8 1 x 10 8 100 x 10 8

Addressing Graft Failure and Delayed Hematopoietic/Immune Recovery Improved UCB graft quality Now FDA regulated product Better understanding of cell dose threshold TNC CD34+ cell dose CFU Improved supportive care Dual cord blood strategy Ex vivo expansion or manipulation

Long-term vs. Short-term Repopulating Cells CD34+

Clinical Development of Ex Vivo Cord Blood Manipulation Strategies Compound Modality Phase I/II Completed (#pts) Lead Institution/Cor porate Partner Active Multicenter Phase II/III Notch Ligand MSC Co-culture Ex-vivo Expansion Ex-vivo Expansion Yes (15) FHCRC/- Yes Yes (32) MDACC/Mesob last Yes NiCord Ex-vivo Expansion Yes (11) Duke/Gamida- Cell Yes Copper Chelation (StemEx) StemRegenin 1 UM171 Ex-vivo Expansion Ex-vivo Expansion Yes (101) Yes (17) Gamida- Cell/Teva UMinn/Novarti s Completed Ex-vivo Expansion No Montreal --- No PGE-2 HSC modulation Yes (12) DFCI/Fate Therapeutics No Fucosylation HSC Modulation Yes (22) MDACC No

NiCord Umbilical Cord Blood Expansion Technology Developed in the laboratories of Gamida Cell Ltd. Jerusalem Israel An ex vivo expanded cell product derived from an entire single unit of umbilical cord blood unit NiCord active molecule; Nicotinamide Vitamin B3 derivative Precursor of NAD Potent inhibitor of enzymes that utilize NAD SIRT-1 (Peled et al. Exp Hematol. 2012 Apr;40) Culture system includes TPO, IL-6, FLT-3 ligand and SCF Expansion utilizes an epigenetic approach to inhibit differentiation and to increase functionality of hematopoietic stem and progenitor cells Presented by:

No. of CD34+ cells Human cells engraftment(%) Impact of Nicotinamide (NAM) on Ex Vivo Expanded CD34+ Cells; Pre-clinical Data Increased BM Homing Efficacy * 180 150 *P < 0.001 Increased Engraftment Efficacy (From limiting dilution experiments, number of cells infused; 6 x 10 3 ) *P < 0.03 120 90 60 30 0 Cultured Cultured + NAM 0.5 Noncultured Noncultured Cultured Cultured + NAM Presented by:

Preservation of Gene Expression by Nicotinamide (NAM) Gene expression profile: Clusters of genes differentially expressed in CD133 + cells expanded ±NAM for 3-weeks and their level of expression in noncultured CD133 + cells Clustered Heat Map construct

Pilot Trial of NiCord UCB Expansion Technology Duke University Medical Center/Loyola University Adult patients with high risk hematological malignancies Myeloablative conditioning regimen Total body irradiation (1350cGy) Fludarabine 160mg/m 2 Cyclophosphamide 120mg/kg (optional; n=2) Double cord configuration: NiCord + Unmanipulated unit GvHD prophylaxis: tacrolimus/mycophenolate mofetil Minimum pre-freeze TNC dose requirement NiCord unit; 1.5 x 10 7 /kg Study Design Unmanipulated unit of 2.5 x 10 7 /kg

+ NiCord Dual Cord Pilot Trial Schema Unit #1 CD 133+ Cell Selection Non-cultured fraction (NF) Lymphocyte Containing Cryopreserved NiCord Graft Unmanipulated Graft Unit #2 Cultured fraction (CF) Cultured 21±2d in cytokines + Nicotinamide Transported Fresh to Site TBI 1350 cgy Fludarabine +/- Cyclosphosphamide Unmanipulated Graft NiCord Graft -14-7 Day 0 +60 MMF Tacrolimus +180 Horwitz et al. JCI 2014

percent Percent Chimerism 28 42 60 100 180 365 28 42 60 100 180 365 28 42 60 100 180 365 Lineage Specific Chimerism- Pilot Trial NiCord Dual Cord Blood Transplantation Lineage Specific Chimerism- Pilot Trial NiCord Dual Cord Blood Transplantation Total Chimerism Myeloid Chimerism T Cells Chimerism Days Posttransplant NICDUK-01 NICDUK-03 7 14 21 7 14 21 7 14 21 NiCord Unmanipulated unit Host NICDUK-07 NICDUK-08 N=11 Median f/u- NICDUK-09 NICDUK-10 NICDUK-11 NICDUK-14 NICDUK-15 NICLOY-01 NICLOY-01 100 50 Host UM NIC No data No data Horwitz et al. JCI 2014 0 7 14 21 28 42 60 100 180 365 Days Horwitz et al. JCI 2014

Patient Outcomes Patient No. 1 (NICDUK-01) 2 (NICDUK-03) 3 (NICDUK-07) 4 (NICDUK-08) 5 (NICDUK-09) 6 (NICDUK-10) 7 (NICDUK-11) 8 (NICDUK-12) 9 (NICDUK-14) 10 (NICLOY-01) 11 (NICDUK-15) Clinical Outcome of Transplantation: Engraftment HLA- Recipient to NiCord 5/6 5/6 4/6 4/6 4/6 4/6 4/6 4/6 5/6 4/6 4/6 ANC>500 14 11 10 18 26 10 7 Graft Failure 14 18 7 Engraftment Day Platelet >20,000 33 30 30 36 49 30 26 41 N/A 33 Acute GvHD Grade II Grade II Grade II Grade II Grade II Chronic GvHD Moderate NiCord % Chimerism at Engraftment 79 (CD15) <2 (CD3) 98 91 2 2 98 98 -- 87 >98 >98 NiCord % Chimerism at Last Follow up 37 (CD15) 3 (CD3) >98 92 0 2 >98 >98 -- 98 (day 100) >98 >98 Clinical Outcome at Last Follow up Alive/CR (5 yr) Alive/CR (5 yr) Death/Relapse (18 mo) Alive/CR (4 yr) Alive/CR (3yrs) Alive/CR (4yrs) Alive/CR (4 yr) Alive/CR Death/Relapse (day 196) Death/Pneumonia (47 days) Alive/CR (3 yr) Horwitz et al. JCI 2014

Summary of Pilot Dual Cord NiCord Trial 11 patients have received NiCord - containing dual UCB transplantation NiCord engraftment is stable, hematopoiesis robust Median follow-up 4yrs (range 3-5yrs) NiCord engraftment shortens hematopoietic recovery (Historical Controls) Neutrophils >500 (mean days); 25 11 Platelets > 20K (mean days); 41 31 2yr overall survival; 68% 2yr progression-free survival; 65% Horwitz et al. JCI 2014

Does NiCord graft obviate the need for a second unmanipulated unit? 17

+ NiCord Phase II Multicenter Trial Schema Unit #1 CD 133+ Cell Selection Non-cultured fraction (NF) Lymphocyte Containing Cryopreserved NiCord Graft Cultured fraction (CF) Cultured 21±2d in cytokines + Nicotinamide Transported Fresh to Site MyeloablativeConditioning a. TBI based b. Chemotherapy only NiCord Graft -14-7 Day 0 +60 MMF Tacrolimus +180

Phase II Multicenter Study of NiCord as a Stand-alone Graft Objectives 1. To assess the cumulative incidence neutrophil engraftment at 42 2. To assess incidence of secondary graft failure at 180 days Design 12-65yrs old AML, ALL, MDS, CML, Lymphoma Myeloablative Conditioning regimen; Regimen A: TBI 1350cGy, Fludarabine and Cyclophosphamide/Thiotepa Regimen B: Thiotepa, Busulfan, Fludarabine Regimen C: Clofarabine, Fludarabine, Busulfan GvHD prophylaxis Mycophenolate mofetil, Tacrolimus or cyclosporine

Consort Diagram Enrollment Assessed for eligibility (n=44) Excluded (n=12) Screen Failure Pending eligibility review Allocation Allocated to intervention (n=32) Received allocated intervention* (n=27) Did not receive allocated intervention (n=5) Reasons for not receiving allocated intervention False positive gram stain during production (n=3) NiCord production cancelled (n=1) Inadequate cell dose in negative fraction (n=1) Follow-up Lost to follow-up (n=0) Withdrawal from study (n=0) Too early to eval. (n=3) Analyzed (n=24) Excluded from analysis (n=5) (did not receive allocated intervention) Analysis *Allocated Intervention- Transplantation of NiCord as a stand-alone graft

Demographic and Baseline Characteristics N % Number of evaluable patients 24 Gender Male Female 13 11 54 46 Age (years) 12-17 18-39 40 + Weight (Kg) Median (range): 85.9kg (46.0-125.0) <60 60-80 80-100 100-120 >120 HLA Match Score (Patient to NiCord ) Regimen 4/6 5/6 6/6 Regimen A (TBI, Fludarabine +/- Cy) TBI, Flu TBI, Flu, Cy Regimen B (Thiotepa, Busulfan, Fludarabine) 0 8 16 4 7 7 4 2 17 5 2 11 6 5 13 0 33 67 17 29 29 17 8 71 21 8 46 25 21 54 Disease Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Myelodysplastic Syndrome Hodgkin Lymphoma Chronic Myeloid Leukemia 6 10 5 1 2 25 42 21 4 8

Neutrophil Engraftment *All patients >95% donor p<0.0001 Controls: CIBMTR; matched (age, disease, conditioning, CBU dose), unmanipulated myeloablative cord blood transplantation between 2010-2013. n=125 Presented by:

Platelet Engraftment p=0.001 Controls: CIBMTR; matched (age, disease, conditioning, CBU dose), unmanipulated myeloablative cord blood transplantation between 2010-2013. n=125 23 December 2015

1yr. Non-relapse mortality vs. CIBMTR control p=0.02 Controls: CIBMTR; matched (age, disease, conditioning, CBU dose), unmanipulated myeloablative cord blood transplantation between 2010-2013. n=125 Presented by:

Improved Immune Reconstitution Day 100 Day 180 Day 365 350 300 NiCord (n=12) Unmanipulated Cord (n=38)* 316 500 400 NiCord (n=10) Unmanipulated Cord (n=31)* 461 453 700 600 659 NiCord Unmanipulated Cord* 250 200 150 100 50 154 100 29 27 156 15 207 300 200 100 341 165 156 55 189 240 500 400 300 200 100 461 287 403 147 450 228 203 0 T cells (CD4+) T cells (CD8+) B cells (CD19+) NK Cells (CD56+) 0 T cells (CD4+) T cells (CD8+) B cells (CD19+) NK Cells (CD56+) 0 T cells (CD4+) T cells (CD8+) B cells (CD19+) NK Cells (CD56+) *Barker et al.: Results of a prospective multicenter; myeloablative adult doubleunit cord blood transplantation trial N=56 Brit J Haem 2015 25 June 2016

NiCord Phase I/II Study Results Summary; n=24 Endpoint Time to neutrophil engraftment (median, n=23) Time to platelet engraftment (median, n=19) agvhd grade II-IV and III-IV at 100 days cgvhd Moderate-Severe at 1 year Primary hospitalization (median, n=24) Transplant Related Mortality at 1 year Disease-free Survival at 1yr Overall survival at 1yr 11 days (range 6-26) 33 days (range 26-96) 58% and 17% 13% (all moderate) 19 days 14.5% 57% 56% Median follow-up of survivors: 334 days (28-829)

Question: Is rapid hematopoietic recovery after NiCord transplantation associated with clinical benefit in the early post-transplantation period compared to a historical control of standard UCB patients? Endpoints: Infectious complications in the first 100 days Length of hospital stay in the first 100 days Sarah Anand, MD

Baseline patient characteristics Nicord (N=18) Standard UCB (N=88) N (%) N (%) Age Median (IQR) 45 (42-56) 38 (28-51) 0.035 Pre-Transplant Weight Median (IQR) 91.15 (76-98.1) 77.78 (65.4-91.4) NS Male Sex 9 (50%) 47 (53.4%) NS CMV + 13 (72.2%) 49 (55.7%) NS KPS Median (IQR) 90 (80-90) 90 (80-90) NS Transplant Diagnosis Acute Leukemia/MDS 16 (88.9%) 78 (88.6%) Lymphoid Malignancy 2 (11.1%) 10 (11.4%) P NS Disease Status 1 NS Early 8 (44.4%) 30 (34.1%) Non-Early 10 (55.6%) 58 (65.9%) 1 Early defined as acute leukemia transplanted in first complete remission (CR), MDS transplanted untreated or in first CR, CML in first chronic phase, and NHL and MM transplanted either untreated or in first CR per EBMT risk score

Bacterial infections per patient in first 100 days post-transplantation * * * p = 0.005 Total Grade 1 Grade 2-3 Anand et al. Unpublished

Viral infections per patient in first 100 days post-transplantation Total Grade 1 Grade 2-3 Anand et al. Unpublished

Adjusted relative infection density Total Infection Moderate to severe infection Bacterial infection Moderate to severe bacterial infection 0.72 (0.54, 0.95; p=0.026) 0.32 (0.17, 0.57; p<0.001) 0.36 (0.18, 0.67; p=0.003) 0.21 (0.06, 0.52; p=0.003) 0.0 0.5 1.0 1.5 2.0 Favors NiCord Favors Standard UCB Relative risk of infection adjusted for age, disease status, and severe acute GVHD by Poisson regression (95% CI; p) Anand et al. Unpublished

Days alive and out of the hospital in first 100 days post-transplantation NiCord 73.7 days (61.3-86.1) Standard UCB 52.9 days (46.9-58.9) 0 20 40 60 80 100 Mean days alive and out of the hospital adjusted for age, KPS, and severe acute GVHD by ANCOVA (95% CI; p=0.002) Anand et al. Unpublished

Summary of NiCord Clinical Studies to Date Transplantation of NiCord resulted in: Significantly shorter time to engraftment of neutrophils and platelets Robust and durable engraftment Prompt immune reconstitution Compared to standard dual cord blood transplantation reduced risk of bacterial infections (Anand et al. EBMT 2016) Fewer days in hospital during first 100 days post transplantation (Anand et al. EBMT 2016)

NRM Limitations of Adult Umbilical Cord Blood Transplantation; Impact of Ex Vivo Expansion Slow Engraftment Graft Failure?? Resource Utilization Delayed Immune Recovery -Myeloid?- T-cell Infection 34

NiCord Phase III Study to Begin in Mid-2016 Randomized controlled Phase III Study Adult patients with high-risk hematological malignancies including AML, ALL, MDS and CML 60 patients 60 patients + Primary endpoint Time to engraftment NiCord Control un-manipulated cord Randomized controlled Phase III study to begin in Q4 2016 in U.S. and EU and Asia (n=30 sites) FDA and EMA have agreed to study design outline Expected time to recruit is 2 years with a 1 year of follow-up Key secondary endpoints to support clinical benefit 35 May 2016

NiCord Phase III Study Scheme

Acknowledgments Duke Adult BMT Program Co-Investigators Nelson Chao Gwynn Long David Rizzieri Cristina Gasparetto Keith Sullivan Richard Lopez Staphanie Sarantopolous Anthony Sung Janet Adcock Barbara Waters-Pick Tony Peled David Snyder Einat Galamidi Iddo Peled Efrat Landau Dorit Harati Etty Friend Manufacturing team G. Sanz (protocol Co-Chair) P. Montesinosi- Valencia D. Valcarcel- Barcelona M. Jagasia- Nashville D Cilloni- Turin JJ Boelens, Utrecht All Rights Reserved, Duke Medicine 2011