Corporate Presentation. September 2015

Transcription

1 Corporate Presentation September 2015

2 Forward-looking statements This document does not constitute or form part of any offer or invitation to sell or issue, or any solicitation of any offer to purchase or subscribe for, any shares in the Company, nor shall any part of it nor the fact of its distribution form part of or be relied on in connection with any contract or investment decision relating thereto, nor does it constitute a recommendation regarding the securities of the Company. This document may contain forward-looking statements and estimates made by the Company, including with respect to the anticipated future performance of TiGenix and the market in which it operates. They include all matters that are not historical facts. Such statements, forecasts and estimates are based on various assumptions and assessments of known and unknown risks, uncertainties and other factors, which were deemed reasonable when made but may or may not prove to be correct. Actual events are difficult to predict and may depend upon factors that are beyond the Company's control. Therefore, actual results, the financial condition, performance or achievements of TiGenix, or industry results, may turn out to be materially different from any future results, performance or achievements expressed or implied by such statements, forecasts and estimates. Forward-looking statements, forecasts and estimates only speak as of the date of this document and no representations are made as to the accuracy or fairness of such forward-looking statements, forecasts and estimates. TiGenix disclaims any obligation to update any such forwardlooking statement, forecast or estimates to reflect any change in the Company s expectations with regard thereto, or any change in events, conditions or circumstances on which any such statement, forecast or estimate is based. 2

3 Management team with proven track record of success Managing Director and CEO: Eduardo Bravo, MBA More than 25 years experience in the pharma and biotech industries at Sanofi-Aventis, Recordati, Cephalon and SmithKline Beecham CFO: Claudia D Augusta, PhD More than 15 years experience in equity and debt financing at Aquanima (Santander Group), Apax Corporate Finance and Deloitte Corporate Finance CTO: Wilfried Dalemans, PhD More than 25 years experience in the pharma and biotech industries; previous engagements at GSK Biologicals and Transgène CMO: Marie Paule Richard, MD More than 25 years experience in the global pharma and biotech industries at Bristol- Myers Squibb, Sanofi Aventis, GSK, Sanofi Pasteur, Crucell and AiCuris VP Regulatory Affairs & Corporate Quality: María Pascual, PhD More than 10 years experience in cell therapy companies; specialised in regulatory affairs for advanced therapies; external adviser to EMA VP Medical Affairs & New Product Commercialisation: Mary Carmen Diez, MD More than 20 years experience in the biopharmaceutical industry at Meda Pharma, Asta Médica, Pfizer and Dupont Pharma 3

4 Key facts about TiGenix Headquarters Operations Employees Stock exchange Leuven, Belgium Madrid, Spain Around 65 employees Euronext Brussels. Ticker: TIG Market capitalisation Euro 205 million on 14 September 2015 Reference shareholders Liquidity Analyst coverage 28% held by Grifols, Genetrix and Novartis 72% free-float of which 30% held by institutional investors 6 analysts covering the stock, of which four are independent Funds available Euro 22.7M at 30 June

5 Investment highlights Positive Phase III And Advanced EU Regulatory Strategy: Cx601 Perianal fistulas in Crohn s disease patients in the US & EU represents a multi-billion dollar market opportunity Pivotal Phase III allogeneic stem cell asset (local administration of a single dose). Results met primary endpoint. Cx601 was statistically superior to placebo in achieving combined remission at week 24 (p<0.025) Fully owned asset. Filing for MAA expected in 1Q 2016 and launch expected by end of 2017 Clear US Regulatory and Clinical Strategy: Cx601 Fully owned asset. Use of data from positive pivotal Phase III trial in EU to support a BLA FDA s endorsement through SPA obtained for pivotal phase III trial in the US Lonza selected as contract manufacturing organization for Cx601 in the US Valuable Pipeline Opportunity: Cx611 Intravenously-administered allogeneic stem cell product for rheumatoid arthritis (Phase II) and severe sepsis (Phase I study completed) Positive Phase I/IIa in refractory RA; Safety and tolerability confirmed in Phase I sepsis challenge trial Proprietary Technology Platforms with Established Manufacturing Expanded allogeneic adipose-derived stem cells (eascs) and allogeneic cardiac stem cells (AlloCSC) Well-defined and fully-characterised products Consistent and robust manufacturing process Expansion in cardiology indications through recent acquisition Allogeneic cardiac stem cells being developed for cardiovascular indications Randomized, double blind, placebo controlled Phase II trail in acute myocardial infarction ongoing Interim data expected 2H16. Final one year follow up data expected 1H17 Commercialised Product: ChondroCelect First ever ATMP 1 approved by EMA; valuable experience in regulatory approval / commercialisation process Indicated for the repair of cartilage defects in the knee Established national reimbursement and partnered with Swedish Orphan Biovitrum 1 Advanced Therapy Medicinal Product 2 Investigational New Drug 5

6 Multiple Product Candidates Product 1 Cell Type Indication Preclinical Phase I Phase II Phase III Market Cx601 (local) Allogeneic adipose-derived stem cells Complex perianal fistulas in Crohn s disease EMA granted Orphan Drug FDA endorsed SPA AlloCSC-01 (intracoronary) Allogeneic cardiac stem cells Acute myocardial infarction Cx611 (intravenous) Allogeneic adipose-derived stem cells Rheumatoid arthritis Severe sepsis Cx621 (intralymphatic) Allogeneic adipose-derived stem cells Autoimmune disorders AlloCSC-02 (intramyocardial) Allogeneic cardiac stem cells Cardiology ChondroCelect Characterised autologous chondrocytes Knee cartilage lesions Partnered 2 1 Covered by 25 patent families 2 Distributed through Swedish Orphan Biovitrum ( Sobi ) and the Finnish Red Cross Blood Service Product on hold 6

7 easc platform 7

8 % OF CD4+CD25+++ ON TOTAL CD4 MSCs 1 interact closely with the immune system Inhibition of pro-inflammatory cytokines IFN- (ng/ml) TNF- (ng/ml) ASCs PBMCs Activated PBMCs PBMCs+ASCs activated PBMCs+ASCs * * * p<0.05 relative to supernatant from activated PBMCs Source: De la Rosa et al. Tissue Engineering 2009 Increase % of Tregs * 10 5 The ability to interact with many players in the immune system qualify MSCs (including ASCs) as a potent anti-inflammatory agent 0 ACTIVATED PBMCs ACTIVATED PBMCs + ASCs * p<0.05 relative to activated PBMCs without ASCs Source: Tigenix data 1 MSCs: Mesenchymal Stem Cells 8

9 eascs as a preferred source of MSCs Easily accessible (liposuction) Source and expansion Considerably higher yield than bone marrow Cell stability during expansion Low immunogenicity, no tissue matching needed Pharmacological profile Enables allogeneic use Demonstrated anti-inflammatory capabilities 9

10 Validated easc platform Quality Consistent and robust manufacturing process Quality control parameters defined: Identity, Purity, Potency Safety No signs of toxicity, tumorigenicity, or ectopic tissue growth in preclinical safety studies No clinical safety concern so far Efficacy Demonstrated control of inflammation in 5 different preclinical models, including different routes of administration Clinical efficacy demonstrated 10

11 Manufacturing process scheme Uniform manufacturing scheme for all products Liposuction Cell isolation and expansion Up to 360 billion cells can be obtained from 1 donor Finished product units at current doses (clinical trials): Master cell bank (cryo) 2,400 doses of Cx601 1 Frozen Drug Substance (FDS) 4,000 doses of Cx611 2 Finished Product 1 Based on ongoing Phase III trial in perianal fistula (120M cells per patient) 2 Assumes 1 million eascs/kg, average weight 80Kgs 11

12 A growing patent portfolio in cell therapy 24 patent families related to cell therapy products Pending & granted patents in over 20 jurisdictions including the US; expiry dates 2024 onwards Patent covering easc population and therapeutic uses granted in EU recently Key patent for Cx601 (PCX007) granted in US, AU, RU, MX, IL and NZ Patent protects use of ASCs in treatment of fistula Complementary protection possible through additional patents under review Portfolio covers key features of TiGenix s chondrocyte and stem cell platforms Expanded cell compositions and preparations Use of expanded cells in treatment of broad range of indications Cell preparation methods & delivery systems FTO for indications in clinical development confirmed by external counsels US: Morrison & Foerster Europe: Carpmaels & Ransford 12

13 Cx601 Local injection of eascs for the treatment of complex perianal fistulas in Crohn s disease patients 13

14 Perianal Fistulas A common severe complication of Crohn s disease Fistulas: sores or ulcers that tunnel through the affected area into surrounding tissues Around 12% of Crohn s disease patients are affected by perianal fistulas 70-80% of these are complex affect anal sphincters present multiple tracts Fistula are recurrent are often associated with perianal abscess Almost 100,000 Crohn s disease patients suffer from complex perianal fistulas every year in Europe and the US alone => compromised QoL, pain, depression and risk of anal epithelial carcinoma 14

15 Perianal Fistulas: Treatment Options and Shortfalls Treatment options Antibiotics Immunossuppressants Infliximab / Adalimumab Efficacy High rate of relapse on drug cessation: 72% 1 Low remission rate: 33% after 6 months of treatment 2 High rate of relapse: 66% 2 Low remission rate: 23% after 54 weeks of treatment 3 High rate of relapse: 54% after 54 weeks of treatment 3, and 67% one year after drug discontinuation 4,5 Safety Safety concern with prolonged use High risk of infectious complications and cancer Safety remains a concern with long term use of biologics Surgery High rate of relapse: 50% 6 High risk of anal incontinence 7 1 Brandt et al. Metronidazole Therapy for Perineal Crohn s Disease: a Follow-Up Study, 83 GASTROENTEROLOGY (1982) 2 Goldstein et al. 6 - Mercaptopurine Is Effective in Crohn s Disease Without Concomitant Steroids, 10 INFLAMM BOWEL DIS (2004) 3 Sands et al. Infliximab Maintenance Therapy for Fistulizing Crohn s Disease, 350 N ENGL J MED (2004) 4 Domenech et al. Clinical Evolution of Luminal and Perianal Crohn s Disease after Inducing Remission with Infliximab:22 ALIMENT PHARMACOL THER (2005) 5 Colombel et al. Adalimumab for Maintenance of Clinical Response and Remission in Patients with Crohn s Disease: The CHARM Trial, 132 GASTROENTEROLOGY (2007) 6 Sonoda et al. Outcomes of Primary Repair of Anorectal and Rectovaginal Fistulas Using the Endorectal Advancement Flap, 45 DIS COLON RECTUM (2002) 7 Soltani and Kaiser, Endorectal Advancement Flap for Crypto Glandular or Crohn s Fistula-in-Ano, 53 DIS COLON RECTUM (2010) 15

16 Cx601: Estimated Market Potential Opportunity in a sizable market Assumptions: Population EU28 + US: 824 million Prevalence of Crohn s disease: 0.105% (865,200 patients) 1 Launch EU: 2017 Launch US: 2020 $ Milllion % CD patients with fistula 2 (approximately 121,100 patients) 12% 14% 16% % Complex fistula all fistula 3 (approximately 97,000 patients) 60% 80% 100% % Patients failing biologic 4 (approximately 77,500 patients) 70% 80% 90% % Market share (approximately 27,100 patients) 20% 35% 50% Average selling price $21k $34k $48k Note: Patient numbers refer to mid-point of the range given 1 TiGenix epidemiology report based on multiple publications 2 Schwartz et al, 2002, Vavricka et al., 2010, Pittet et al., 2010, KOL Interviews 3 Pittet et al., 2010, KOL Interviews 4 Sands et al., 2004, Lichtiger et al., 2010, KOL Interviews 16

17 Cx601Phase III ADMIRE-CD 1 Trial Robust Phase III study designed to qualify as a single pivotal study TRIAL SUMMARY Condition Study design Status Enrolment Number of sites Primary endpoint Secondary endpoints at Weeks 24 and 52 Complex perianal fistulas in Crohn s disease patients Randomised, double-blind, placebo-controlled trial All tracts treated. Single injection 2 24 weeks primary analysis finalized. Follow up ongoing 289 patients recruited 50 active sites in 8 countries Combined Remission 3 at week 24 with α<0.025 Clinical Remission 4 Response 5 Time to Clinical Remission / to Response PDAI 6 and other scores Safety and tolerability 1 Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulising Crohn s Disease million cells 3 Closure of all treated external openings draining at baseline despite gentle finger compression, and absence of collections > 2cm by MRI 4 Closure of all treated external openings draining at baseline despite gentle finger compression 5 Closure of at least 50% of all treated external openings draining at baseline despite gentle finger compression 6 Perianal Disease Activity Index 17

18 Patients Selection: Key Eligibility Criteria Men and women aged 18 years or older Non active or mildly active luminal Crohn s disease (CDAI 220) diagnosed for 6 months Patients with complex perianal fistulas with 2 internal openings and 3 external openings Fistula draining 6 weeks prior to inclusion Patients with inadequate response to at least one of the following: antibiotics, immunosuppressants or anti-tnfs Medical standard of care was allowed to continue without modification of treatment dose or regimen 18

19 Design: Double-Blind, Placebo-Controlled Screening Preparation Treatment Primary Endpoint Follow-Up W-5 W-3 D0 W6 W12 W18 W24 W36 W52 week Randomisation Clinical Assessment Baseline MRI W24 MRI W52 MRI MRI: Magnetic Resonance Imaging 19

20 Demographics, PDAI and Fistula Topography Cx601 Placebo Demographics (ITT) n= 107 n= 105 Age (years) mean (SD) 39.0 (13.1) 37.6 (13.1) Men (%) 60 (56.1) 56 (53.3) Caucasian (%) 100 (93.5) 96 (91.4) Weight (kg) mean (SD) 73.9 (15.0) 71.3 (14.9) PDAI 1 (ITT) Mean (SD) Topography of Internal & External Openings (%) (Safety set) Cx601 n= 103 Placebo n= 102 One-tract fistula Multiple-tract fistula Similar demographics and PDAI score between arms Higher proportion of multiple-tract fistulas in Cx601 group 1 Perianal Disease Activity Index 20

21 Cx601: A Major Breakthrough Primary endpoint met % 60 (ITT 1 Population n= 212) p < % 60 (mitt 2 Population n= 204) p < % % % % Cx601 Placebo Cx601 Placebo Cx601 significantly superior to placebo in achieving Combined Remission Patients receiving Cx601 have 44% more chances to achieve Combined Remission than placebo patients Efficacy results consistent across all statistical populations 1 ITT: Intention To Treat i.e. patients randomised 2 mitt: modified ITT i.e. patients randomized and treated, and with at least one post-baseline efficacy value 21

22 Overview Of TEAEs Up To W24 (Safety Population n= 205) Number of Patients with (%) Cx601 Placebo n= 103 n=102 TEAEs 68 (66.0) 66 (64.7) Related TEAEs 16 (15.5) 26 (25.5) Withdrawn due to a TEAEs 4 (3.9) 4 (3.9) TESAEs 17 (16.5) 13 (12.7) Related TESAEs 5 (4.9) 6 (5.9) Withdrawn due to TESAEs 3 (2.9) 2 (2.0) TE(S)AE: Treatment-Emergent (Serious) Adverse Events If a patient has multiple events of the same severity, relationship or outcome, then they are counted only once in that severity, relationship or outcome. However, patients can be counted more than once overall. Favourable safety and tolerability profile of Cx601 and comparable to placebo 22

23 Cx601: A Regulatory De-risked And Fully-owned Asset Preparing for the European launch in 2017 Clear and fast pathway to the market built on a solid regulatory strategy Letter of intent submitted to the EMA 1 and MAA 2 filing planned for 1Q Scientific Advice Meetings held with EMA (2 pre-clinical, 2 CMC, 1 clinical) Team with previous experience in obtaining MAA of cell therapy product Major commercial opportunity 50,000 new patients every year in Europe with high medical need Protection obtained through EU patent and orphan designation Fully-owned commercial rights 1 EMA: European Medicines Agency 2 MAA: Marketing Authorisation Application 23

24 Cx601: Capturing The Value Of The Biggest Market Preparing for the US launch in 2020 Clear and fast pathway to the market built on a solid regulatory and clinical development strategy Type B meeting with FDA 1 confirmed: Adequacy of existing non-clinical package to support an IND 2 filing Acceptability of using data from the ADMIRE-CD trial to support BLA 3 FDA endorsement through SPA 4 of US Phase III protocol: Primary end-point identical to ADMIRE-CD trial p-value < 0.05 (vs p-value <0.025 in ADMIRE-CD trial) US Phase III trial scheduled to start 2H 2016 Lonza selected as US contract manufacturing organisation for Cx601 in the US Major commercial opportunity 50,000 new patients every year in the US with high medical need Protection obtained through US patent until 2030 Fully-owned commercial rights 1 FDA: Food and Drug Administration 2 IND: Investigational New Drug 3 BLA: Biological License Application 4 SPA: Special Protocol Assessment 24

25 AlloCSC-01 Intracoronary administration of allogeneic cardiac stem cells for the treatment of acute ischaemic heart disease 25

26 AlloCSC-01: Preventing Congestive Heart Failure Myocardial repair may be the only feasible alternative 1,9M Acute Myocardial Infarctions (US+EU) 1 occur annually, mostly treated by PCI 2 and stent implantation Successful treatment of AMI has contributed to a Chronic Heart Failure epidemic (26M patients worldwide 3 ) CHF post-ami is a terminal disease with an annual mortality rate of ~18% after the first episode, for which no curative treatment exists with the exception of heart transplantation In 2010, the AHA estimated that the direct and indirect cost of heart failure in the United States was $39 billion, half of which was related to repeated hospitalizations, and by 2030 the total cost of heart failure in the United States is projected to increase to $70 billion 4 An attractive market for a treatment able to mitigate or delay the onset of CHF 1. Datamonitor: Stakeholder Insight: Acute coronary syndromes, DMHC2347, PCI: Percutaneous Coronary Intervention 3. Ambrosy PA et al.. J Am Coll Cardiol. 2014;63: LloydJ ones et al Circulation 2010 Feb 23;121(7):e46-e

27 AlloCSC-01: A Regenerative Treatment Post-AMI Preventing the onset of chronic disease The formation of a non-functional scar tissue gives rise to a process of ventricular remodeling whereby the myocardium tries to compensate the effect of the injury Over time the heart dilates losing its contractile capacity causing the onset of CHF. This is a terminal condition with no treatment other than transplantation The severity of this process is related to the size of the scar resulting from the AMI. Smaller scars are related to better outcomes 1 Myocardial repair seems to be the only feasible treatment to address the post-acute phase of the disease and prevent the onset of chronic heart failure (CHF) 1. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging. 2011;4:

28 AlloCSC-01: A Regenerative Treatment Post-AMI The three axes of the mechanism of action Cardioprotection Inflammatory control Tissue regeneration Secretion of protective factors in the recently damaged myocardium reduce cell death produced by acute ischemia and reperfusion, thus salvaging valuable tissue Reduced scarring of cardiac tissue during healing of the infarcted region through control of the inflammatory process, leading to improved prognosis New viable tissue appears following treatment with CSCs ameliorating the functional capacity of the myocardium 28

29 AlloCSC-01: Biodistribution In Pig Model High heart retention demonstrated in pig model Infarcted animals pcsc1/hcsc2 18 F-FDG3 labeled IC4 administration at day 7 Analysis at 4h 20 Biodistribu on quan fica on %of injected dose Spleen Liver Heart Lung 1 Lung 2 Bladder PET 5 data shows strong cardiac tropism, coronary clearance and myocardial retention of AlloCSC-01 AlloCSC-01 is suitable for coronary injection and compatible with PTCA6 standard of care 1. pcsc: Pig cardiac stem cells 2. hcsc: Human cardiac stem cells F-FDG: [fluorine-18]fluoro- D-glucose 4. Intra coronary 5. Positron emission tomography 6. Percutaneous transluminal coronary angioplasty. 29

30 AlloCSC-01: Efficacy Demonstrated in Pig Model Efficacy data from MRI 1 CARDIAC REMODELING CARDIAC FUNCTION Histological analysis CONTROL EDVi ESVi EF * * * AlloCSC CONTROL 25M 50M 30 CONTROL 25M 50M 30 CONTROL 25M 50M * p-value < 0,05 AlloCSC-01 prevents cardiac remodelling after infarction preserving heart function AlloCSC-01 reduces scar size promoting formation of new contractile tissue Significant dose effect observed 1. MRI: Magnetic Resonance Imaging 2. EDVi: End-Diastolic Volume Index 3. ESVi: End-Systolic Volume Index 4. EF: Ejection Fraction 30

31 AlloCSC-01: CAREMI Phase I/IIa Trial Safety and efficacy of intracoronary infusion of allogeneic cardiac stem cells in patients with Acute Myocardial Infarction (AMI) TRIAL SUMMARY Completion 1H 2017 (Interim data 2H 2016) Condition Study design Recruitment Acute Myocardial Infarction AlloCSC-01 administered 5-7 days after PCI 1 Phase 1. Open label dose escalation in 6 patients Phase 2: Placebo controlled, 49 patients randomised 2:1 (35M cell dose in active arm) Phase 1: Completed Phase 2: 36 of 49 treated, set to complete recruitment in 4Q 2015 # of centers 8 sites Primary endpoint Secondary endpoints (6 and 12 months) Mortality and MACE 2 from any cause at 30 days Safety: Mortality and MACE Efficacy: evolution of infarct size, biomechanical parameters by MRI Clinical parameters: 6m walk test, NYHA 3 scale PATIENT SELECTION Initial clinical pre-screening: Males, females 18 years and 80 years Patients who present a STEMI 4 Killip 2 on admission Successful revascularization by PCI (TIMI 5 = 3) within 12h after the onset of symptoms EF 50% by echocardiography (day 2 after infarct symptoms) EF 45% by MRI on D3-5 post-stemi Infarct size (1 st MRI) >25% in LV 6 Bare-metal stents or second generation drug eluting stent at PCI The infarct culprit coronary artery is adequate for treatment administration and the procedure is technically feasible The patient is stable and in adequate clinical condition to undergo the procedure 1 PCI: Percutaneous Coronary Intervention 2 MACE: Major Adverse Cardiac Events 3 NYHA: New York Heart Association 4 STEMI: ST-Segment-Elevation Myocardial Infarction 5 TIMI: Thrombolysis In Myocardial Infarction 6 LV: Left Ventricle 31

32 Cx611 Intravenous injection of eascs for the treatment of severe sepsis 32

33 Severe sepsis: a high unmet medical need Systemic illness due to an attack of host pro-inflammatory cytokines and other humoral substances commonly induced by a bacterial infection Incidence forecasted to grow at 1.5% p.a. 4 An estimated 15 19M sepsis cases occur worldwide each year 1 Incidence is estimated at approx. 300 cases per 100,000 population p.a. 2 Incidence has dramatically increased over the last decade (CAGR of 8-13%) 3 Sepsis mortality was estimated at 36% in a recent major European study 3 In the case of septic shock, mortality can reach up to 80% (28 50% of patients die within the first month of diagnosis) 4 1 The Lancet Infectious Diseases; Volume 12; issue 2; page 89; February Hall MJ et al. Inpatient care for septicemia or sepsis: NCHS data brief, no 62. Hyattsville, MD: National Center for Health Statistics Vincent JL et al Sepsis in European intensive care units. Critical Care Medicine 2006; 34: University Hospital of Valme & Biomedical Research Institute of Seville: Presentation at Farmaindustria meeting July

34 The Challenge: a disease-modifying agent that targets the underlying immune dysfunction Current molecular approaches to the treatment of sepsis have inadequately addressed the complex immuno-modulatory pathways involved in sepsis pathogenesis. Cellular therapies offer a novel multifaceted mechanism of action that is potentially able to address the underlying immune dysregulation through multiple pathways. Editor's summary A Swiss Army knife for treating sepsis 34

35 eascs can protect in severe sepsis LPS Model CLP Model Source: Gonzalez-Rey, 2009 * p<0.001 Cx611 reduces mortality in animal models of sepsis This effect is due to a combination of reducing pro-inflammatory and increasing antiinflammatory mediators, production of anti-microbial effectors, and increased phagocytosis 35

36 LPS model easc effect at the cytokine and cellular level * p<0.001 of pro-inflammatory mediators of anti-inflammatory mediator of inflammatory cells CLP model Source: Gonzalez-Rey et al. Gut Jul;58(7):

37 Phase I trial synopsis and rationale: CELLULA 1 study Evaluation of the therapeutic effect of eascs on the inflammatory response to LPS 2 in healthy volunteers TRIAL SUMMARY Start Q Expected completion Objective Study design Enrolment # of centres Primary endpoint Q effect of eascs on inflammatory response to LPS parallel groups: 0,250M, 1M and 4M eascs/kg and placebo randomisation scheme: 3:1 32 healthy volunteers 1 (Academic Medical Center, University of Amsterdam) vital signs and symptoms laboratory measures and functional assays of innate immunity Rationale Model mimics clinical signs of sepsis fever, chills headache, myalgia nausea mild tachycardia insignificant change in blood pressure Genomic response similar as in sepsis (not the case for animal studies) Provides proof-of-principle: essential information on the mechanism of action of eascs to counteract the consequences of an LPS exposure Results will guide for a proposed phase II study in severe sepsis 1 The effect of expanded human allogeneic adipose-derived mesenchymal adult stem cells on the human response to lipopolysaccharide in human volunteers 2 lipopolysaccharide 37

38 Cx611: CELLULA trial results and next steps Phase II in severe sepsis expected to start 4Q 2015 CELLULA trial results Favourable safety and tolerability profile of Cx611, consistent with Phase I/IIa in refractory RA patients No significant effect of Cx611 on the short-term lipopolysaccharide-induced symptoms could be detected Phase II study in severe sepsis to start in 4Q

39 Key milestones 39

40 Key milestones Product Cx601 (local) Cx611 (IV) Europe US severe sepsis 4Q14 Phase 3 enrolment completed 3Q14 CMO selection 4Q14 SPA submission 4Q14 Phase 1 initiated 3Q15 Phase 3 primary endpoint met (24 weeks) 3Q15 positive SPA 2Q15 Phase 1 study results 4Q15 Phase 2 enrolment initiated 2Q16 study results (1 year follow-up) 1Q16 EMA filing 2H16 tech transfer finalised 2H16 pivotal Phase 3 initiated 2H16 File IND 2H17 EU launch 2Q17 Phase 2 enrolment completed YE17 Phase 2 study results AlloCSC-01 (IC) acute myocardial infarction 1Q15 Phase 2 enrolment initiated 4Q15 Phase 2 enrolment completed 2H16 Phase 2 interim analysis 1H17 Phase 2 study results ChondroCelect 1Q14 manufacturing facility sold 2Q14 licensed to SOBI increase market penetration in existing countries expand geographic reach through new market entry 40

41 Corporate Presentation September