Corporate Presentation. July 2016

Transcription

1 Corporate Presentation July 2016

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 forward-looking 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. With company since: July 2005 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. With company since: April 2004 CTO: Wilfried Dalemans, PhD More than 25 years experience in the pharma and biotech industries; previous engagements at GSK Biologicals and Transgène. With company since: April 2007 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. With company since: September 2014 VP Regulatory Affairs & Corporate Quality: María Pascual, PhD More than 10 years experience in cell therapy companies; specialized in regulatory affairs for advanced therapies; external adviser to EMA. With company since: July 2003 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. With company since: September

4 Key Facts About TiGenix Headquarters / Operations Leuven, Belgium / Madrid, Spain Employees Approximately 75 employees Stock Exchange Euronext Brussels. Ticker: TIG Market Capitalization Approx. USD 190M June 27, 2016 Reference Shareholders ~20% held by Grifols and BNP Paribas Liquidity ~80% free-float, of which ~30% held by institutional investors Analyst Coverage 5 analysts covering the stock Cash and Cash Equiv. USD 19.78M at December 31st, 2015 Last Capital Increase USD 26.1M raised from US and EU investors in March 2016 Note: Numbers reflect EUR/USD = 1.10 as of 06/27/16 4

5 Compelling Investment Case Cx601: Global Agreement Ex-US with Takeda Cx601: Clear pathway to US market Valuable Pipeline Opportunities: AlloCSC-01 and Cx611 Complex perianal fistulas in Crohn s disease patients in United States & EU is a multi-billion dollar opportunity Pivotal Phase III (local administration of a single dose of allogeneic adipose derived stem cells) Primary endpoint met. Cx601 statistically superior to placebo in achieving combined remission at week 24 (p=0.024) Long term efficacy sustained at week 52 on same endpoint (p=0.019) MAA submitted to EMA in 1Q16. Launch expected 2H17 GMP process approved for commercial manufacturing by Spanish Agency in 1Q16.Takeda will co-invest in the expansion of the Madrid facility to secure supply for the initial few years Up to 380M agreement with Takeda for the exclusive ex-us rights to Cx601 for the treatment of complex perianal fistulas in Crohn s disease patients Use of data from positive pivotal Phase III trial in EU to support a BLA in the US FDA s agreement on SPA obtained for pivotal phase III trial in the US Same primary endpoint as positive EU Phase III trial US Phase III to start 1H17 Fully-owned asset; granted patent valid until 2030 Lonza selected as contract manufacturing organization for Cx601 in the US AlloCSC-01: intra-coronary administered allogeneic cardiac stem cells, being developed for acute myocardial infarction Randomized, double blind, placebo controlled Phase II trial ongoing Interim 6 months data confirmed safety. Final one-year follow up data expected 1H17 Cx611: Intravenously-administered allogeneic adipose derived stem cell product for severe sepsis Phase I study completed Severe sepsis Phase I/ll trial design has been finalized; expected to enroll first patient in 2H16 1 Advanced Therapy Medicinal Product 5

6 Multiple Product Candidates with Significant Upcoming Milestones Product 1 Indication Preclinical Phase I Phase II Phase III Market Allogeneic Adipose-Derived Stem Cells Cx601 (local) Complex Perianal Fistulas in Crohn s Disease Ex-US rights licensed to Takeda SPA agreed to by FDA Pivotal US starts 1H17 Launch EU 2H17 Cx611 (intravenous) Severe Sepsis Ph I/II starts 2H16 Allogeneic Cardiac Stem Cells AlloCSC-01 (intracoronary) Acute Myocardial Infarction Final results 1H17 Characterized Autologous Chondrocytes ChondroCelect Knee Cartilage Lesions Withdrawal of MA requested at European Commission 2 1 Covered by 29 patent families 2 Implementation of withdrawal of Marketing Authorization (pending EC confirmation) and termination of all CC related agreements anticipated by December 31,

7 Cx601 Local injection of expanded Adipose-derived Stem Cells ( eascs) for the treatment of complex perianal fistulas in Crohn s disease patients 7

8 Cx601 Inhibits Pro-inflammatory Cytokines Mechanism of Action ( MoA ) is IDO 1 -Mediated Inhibition of pro-inflammatory cytokines IFN- (ng/ml) TNF- (ng/ml) Key Characteristics of Cx601 Cx601 PBMCs Activated PBMCs PBMCs+Cx601 Actiivated PBMCs+Cx601 * * Cx601 has the ability to balance an inflammatory milieu, through the reduction of PBMC 2 mediated secretion of pro-inflammatory cytokines among other immunological processes * p<0.05 relative to supernatant from activated PBMCs Inhibition of Immune Cell Proliferation Inhibits pro-inflammation IDO is key to the immunomodulatory properties of Cx601, as shown here by its effect on PBMC proliferation * p<0.05 relative to activated PBMCs without ASCs Source: Tigenix data IDO Mediated Activated PBMC + Cx601 1 IDO: Indoleamine 2,3-dioxygenase 2 PBMC: Peripheral Blood Mononuclear Cells Source: De la Rosa et al. Tissue Engineering

9 GMP Facility in Madrid Approved for Commercial Manufacturing Takeda 1 Will Endeavor to Take Over Manufacturing ex-us Consistent and Robust Process 1 Liposuction 2,400 Finished Products (Cx601) Manufacturing Capabilities Production facility in Madrid approved for commercial manufacturing Current capacity is about 400 patient lots of finished product per year TiGenix will initially supply Cx601 to Takeda at cost for the EEA 2 and Switzerland (CH) Takeda will co-fund the expansion of the Madrid facility to secure supply for the initial few years Takeda will endeavor to take over manufacturing asap to leverage on a global supply network Outside of the EEA and CH, Takeda is responsible for manufacturing from July 2016 Takeda will be fully responsible for distribution and logistics in the whole Territory 1 In July 2016 TiGenix and Takeda entered into an exclusive Ex-US Licensing Agreement for Cx601 2 EEA stands for European Economic Area, it includes all 28 states currently part of the European Economic Area as well as the three states Iceland, Lichtenstein and Norway 9

10 A Common and Severe Complication of Crohn s Disease Complex Perianal Fistulas Affect 1 in 12 Adult Crohn s Disease Patients 120,000 adult patients in Europe and the US alone Fistula Complex fistulas are sores or ulcers that tunnel through the affected area into surrounding tissues, and that: Affect anal sphincters Present multiple tracts Are recurrent Are often associated with perianal abscess Complex fistulas cause compromised Quality of Life (QoL), pain, depression and risk of anal epithelial carcinoma Fistula 10

11 Treatments Lack Long Term Efficacy and Present Safety Issues Optimal management remains challenging Little progress due to limited trials and poorly validated endpoints Clear gap for a clinically validated treatment with long term efficacy Treatment options Benefit Shortfall Antibiotics Improve symptoms and short term healing High relapse on cessation 1 Safety concern with prolonged use Immunosuppressants Moderate benefit reported Limited clinical trial data High relapse on cessation 2,3 Risk of infectious complications Anti-TNFs Infliximab- Remicade Adalimumab - Humira Surgery Moderate benefit in clinical trials Eliminating risk of recurrence is possible with radical, mutilating surgery 7,8 Low remission 4,6 and high relapse 4,5 Safety concern with long term use and systemic immunosuppression Conservative surgery risks recurrence Risk of complications (incontinence, non healing wounds, abscesses) 8,9 1 L.J. Brandt et al. Metronidazole Therapy for Perineal Crohn s Disease: a Follow-Up Study, 83 GASTROENTEROLOGY (1982) 2 E.S. Goldstein et al., 6 - Mercaptopurine Is Effective in Crohn s Disease Without Concomitant Steroids, 10 INFLAMM BOWEL DIS (2004) 3 B.I. Korelitz et al., Favorable Effect of 6-Mercaptopurine on Fistulae of Crohn s Disease, 30 DIGEST DIS SCI (1985) 4 B.E. Sands et al., Infliximab Maintenance Therapy for Fistulizing Crohn s Disease, 350 N ENGL J MED (2004) 5 E. Domenech et al., Clinical Evolution of Luminal and Perianal Crohn s Disease after Inducing Remission with Infliximab, 22 ALIMENT PHARMACOL THER (2005) 6 J.F. Colombel et al., Adalimumab for Maintenance of Clinical Response and Remission in Patients with Crohn s Disease: The CHARM Trial, 132 GASTROENTEROLOGY (2007) 7 C.B. Geltzeiler et al., Recent Developments in the Surgical Management of Perianal Fistula for Crohn s Disease, 27 ANN GASTROENTEROL 1-11 (2014) 8 T. Sonoda et al., Outcomes of Primary Repair of Anorectal and Rectovaginal Fistulas Using the Endorectal Advancement Flap, 45 DIS COLON RECTUM (2002) 11 9 A. Soltani and A. Kaiser, Endorectal Advancement Flap for Crypto Glandular or Crohn s Fistula-in-Ano, 53 DIS COLON RECTUM (2010)

12 Cx601: A Completely Different Approach; A Single Dosage Suspension of Expanded Adipose-derived Stem Cells ( easc) Product description Four (4) vials of 6ml suspension, each with 30 million cells (total dose 120 million cells) Mode of Administration Fistula curettage and closure of internal opening (sutured) Half of Cx601 dose (2 vials) injected into tissue around internal opening (small blebs) Other 2 vials injected along the walls of the fistula tracts (several small blebs) a. Fistula internal opening b. Fistula tract Injection sites: Injection sites: 12

13 Phase III ADMIRE-CD 1 Trial Double-Blind, Placebo-Controlled, Designed to Qualify as a Single Pivotal Study Study design Number of sites Enrollment Primary endpoint Secondary endpoints at Weeks 24 and 52 Trial Summary Randomized, double-blind, placebo-controlled trial All tracts treated. Single procedure 2 47 active sites in 8 countries 289 patients recruited Combined Remission 3 at week 24 with α<0.025 for all existing fistulas Combined Remission at week 52 Clinical Remission 4 Response 5 Time to Clinical Remission / to Response PDAI 6 and other scores Safety and tolerability Patients selected to ensure clear cut-off results 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 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 (Magnetic Resonance Imaging) 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 13

14 Clinical and MRI Combined Primary Endpoint at Week 24 Long Term Follow-Up for Persistence (Week 52) and Safety (up to Week 104) Screening Preparation Treatment Primary Endpoint Follow-Up W-5 W-3 D0 W6 W12 W18 W24 W36 W52 W104 week Randomization Clinical Assessment Baseline MRI W24 MRI W52 MRI MRI: Magnetic Resonance Imaging 14

15 Cx601 Phase III Patient Populations Largest Ever Study in Complex Perianal Fistulas Screened n= Wrong Inclusion / Exclusion criteria 20 Other 3 12 Informed Consent Withdrawn 2 (Serious) Adverse Events Screening Failures n=77 Randomized n=212 ITT 1 set n=212 Cx601 n=107 Placebo n=105 1 Reoccurrence of Crohn s Disease 1 Deep Vein Thrombosis 1 Informed Consent Withdrawn 1 Missing Data Not Treated n=4 Treated n=103 Safety Set 2 n=205 Treated n=102 Not treated n=3 1 Informed Consent Withdrawn 1 No Longer Met Inclusion Criteria 1 Did Not Have Postbaseline Efficiency Evaluation 1 ITT: Intention To Treat i.e. patients randomized 2 Safety Set: patients randomized and treated 3 Surgical procedures for other reasons than fistulas; Fistulas not healing/worsening of fistula symptoms; No tract found or additional blind tract found by the surgeon during preparation visit; Impossibility to administer 12 ml into the tract or to identify the primary opening; Fistula closed, etc 15

16 Good Balance Among Groups Except for Topography of Fistulas Cx601 Group Contained More Difficult to Treat Patients Similar demographics and PDAI 1 score between arms Higher proportion of multiple-tract fistulas in Cx601 group Demographics (ITT) Cx601 n= 107 Placebo 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 (ITT) Mean (SD) 68 (2.5) 6.6 (2.9) Topography of Internal & External Openings (%) (ITT) 2 One-tract fistula Multiple-tract fistula* * Primary endpoint measured combined remission on all tracts 1 Perianal Disease Activity Index 2 Fistula topography not available in seven (7) patients 16

17 Primary endpoint met at week 24 Benefit Sustained at Week 52 % Combined Remission at W24 (ITT 1 Population n= 212) 60 p = Primary endpoint met: Combined remission at W24 was 44.3% higher in treated patients versus placebo (p=0.024) % 34.3% 0 60 Combined Remission at W52 (ITT 1 Population n= 212) p = Benefit maintained at W52: Combined remission was 46% higher in treated group versus placebo (p=0.012) % 37.1% 0 80 Sustained Remission at W % of Cx601 treated patients who achieved combined remission at week 24 remained in combined remission at week 52 compared to only 55.9% in the placebo arm % 55.9% 0 1 ITT: Intention To Treat i.e. patients randomized. Efficacy results are consistent across all statistical populations Cx601 Placebo 17

18 Faster Time to Remission Cx601 Achieves Remission Twice as Fast as Placebo Cx601-treated patients achieved Clinical Remission after 6.7 weeks 50% sooner that placebo-treated patients The placebo-treated patients achieved Clinical Remission after 14.6 weeks (HR 1.75, 95% CI ( )) ITT Population 1 n=212 1 ITT: Intention To Treat i.e. patients randomized 18

19 Safety Profile Maintained Over the Long Term Product is Free From Serious Side Effects of Biologic Treatments Overview of TEAEs up to Week 24 & Week 52 (Safety population n= 205) Number of Patients with (%) Cx601 Placebo n= 103 n=102 W24 W52 W24 W52 *TEAEs 68 (66.0) 79 (76.7) 66 (64.7) 74 (72.5) Related TEAEs 18 (17.5) 21 (20.4) 30 1 (29.4) 27 1 (26.5) Withdrawn due to a TEAEs 5 (4.9) 9 (8.7) 6 (5.9) 9 (8.8) **TESAEs 18 (17.5) 25 (24.3) 14 (13.7) 21 (20.6) Related TESAEs 5 (4.9) 7 (6.8) 7 (6.9) 7 (6.9) Withdrawn due to TESAEs 4 (3.9) 6 (5.8) 4 (3.9) 7 (6.9) Note: 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. *Most common TEAEs: Anal Abscess; Proctalgia; Nasopharyngitis; Diarrhoea; Abdominal pain; Pyrexia **TE(S)AE: Treatment-Emergent (Serious) Adverse Events 1 Figures are cumulative; however prior AEs reevaluated at W52 as non-related are not adjusted retroactively. 19

20 Cx601: Communication of ADMIRE-CD Results ECCO (Amsterdam, th March 2016) Oral presentation in Plenary Session by Dr. Panés (March 17, 2016) Satellite Symposium chaired by Dr. Van Assche (March 18, 2016) 1 European Crohn s and Colitis Organization 20

21 Cx601: Communication of ADMIRE-CD Results ECCO 2016 (Amsterdam, th March 2016) 21

22 Cx601 s Approach to the US Market Leveraging EU Data With Approved Phase III Protocol Preparing for US BLA 1 Filing with clear pathway to US Market Solid regulatory and clinical development strategy Type B meeting with FDA 2 confirmed: Adequacy of existing non-clinical package to support an IND 3 filing Acceptability of using data from the ADMIRE-CD trial to support BLA SPA 4 for US Phase III protocol agreed with FDA: 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 by 1H17 Lonza selected as contract manufacturing organization for Cx601 in the US, technology transfer ongoing 1 BLA: Biological License Application 2 FDA: Food and Drug Administration 3 IND: Investigational New Drug 4 SPA: Special Protocol Assessment 22

23 Cx601: Estimated Potential Patient Population (EU & US) An Attractive Commercial Opportunity Crohn s Disease Patients * 1-9 = % 7,8 Adult Crohn s Disease Patients = 1,432,860 11% Perianal fistulas = 157,615 Non-Perianal fistulas = 109,529 (41% of fistulas are not perianal 13,14 ) 66% 19 75% 15,18 Complex fistulas # of cases = 118,211 Controlled luminal CD # of cases = 78,019 90% 19, 20 Refractory fistulas # of cases = 70,217 25% Simple fistulas # of cases = 39,404 34% Non-Controlled luminal CD # of cases = 40,192 10% Non-refractory fistulas # of cases = 7,802 A total of 267,144 CD patients experience fistulas 34-61% of CD patients with fistulas experience 2 fistulizing episodes 13,14 or 90, ,958 patients 33% of CD patients with perianal fistulas experience 2 fistulizing episodes 13 or 52,013 patients 1 Stone MA et al Hein R et al Lucendo AJ et al Dal Pont E et al Cottone M et al Herrinton LJ et al Kappelman MD et al Kappelman MD et al Molodecky NA et al SEESGCD Gibson PR et al Dranga M et al Schwartz DA et al Bell SJ et al (Further details on references provided in Appendix ) 15 Eglinton TW et al Gray BK et al Galandiuk S et al Molendijk I et al Sands BE et al Domènech E et al * Estimated prevalence in US: 190/100,000 (average from US nationwide studies comprising study periods post year 2000) 6-9 Estimated average prevalence in EU: 180/100,000 (no nationwide studies available; average of regional studies conducted in EU5 comprising study periods post year 2000, weighed by country populations) 1-5, 9 23

24 Kuvan Adempas Revolade Esbriet Kalydeco Cx601: Pricing Considerations Lower Prevalence Would Suggest Higher Price Ex-manufacture price per year (000) 1 Tysabri Xyrem Samsca Zavesca Soliris Prevalence per 10,000 patients vs. prices for selected drugs Orphan drugs Non-orphan drugs Ex-manufacturer prices per patient per year, including mandatory published discounts, obtained from CMS, L Assurance Maladie, G-BA, Gazzetta Ufficiale, Spanish MoH, British National Formulary. $1 = Indications for select products: Kalydeco, G551D-mutation cystic fibrosis; Kuvan, Phenylketonuria; Adempas, Chronic thromboembolic pulmonary hypertension; Revolade, Low blood platelet count in adults with chronic immune thrombocytopenic purpura; Esbriet, idiopathic pulmonary fibrosis. Full list of references provided at back. 24

25 Takeda exclusive Ex-US Licensing Agreement for Cx601

26 Takeda Pharmaceutical The Partner of Choice in the GI Space Global pharmaceutical company, with a focus on GI, Oncology and CNS Market presence in over 70 countries and regions; with more than 30,000 employees Total sales in FY 2015 (as of March 2016) amounted to 15Bn. Major regions by sales are Japan (38%), the US (29%) and Europe (17%) In 2015, Takeda formed a GI drug discovery unit. The aim of this unit is to further develop internal GI projects as well as execute deals which will complement Takeda s GI franchise FY 2015 sales for Takeda s GI franchise amounted to 720M. Takeda recently disclosed that Entyvio is the company's No. 4 selling drug targeting sales >$2Bn by 2018 Takeda is already among the top 10 companies by sales in GI space 1 Cx601 is the perfect fit with Takeda s GI focus, with clear synergies with Entyvio 1 BioCentury, 30 th May

27 Licensing Agreement with Takeda Summary of Key Terms Takeda acquires the exclusive ex-us rights to Cx601 for the treatment of complex perianal fistulas in Crohn s disease patients TiGenix retains 100% rights to the US market, estimated at 50% of Cx601 global market and the rights to develop Cx601 in new GI indications Upfront payment of 25 million and 10 million of equity investment Regulatory and sales milestones payment for up to a potential total of 355 million, of which 15 million at marketing approval of Cx601 in Europe expected in 2H17 Following Marketing Authorization in the European Union, Takeda will become the marketing authorization holder (MAH) and will be responsible for all commercialization and regulatory activities Takeda will also be responsible for additional development activities of Cx601 for the indication of complex perianal fistulas in Crohn s disease and will eventually take over manufacturing for Cx601 within the licensed territory A deal for a potential total of 380 million (excluding US) the best partner to secure Cx601 commercial success 27

28 Cell Therapy Product Deals to Date The Largest Product Licensing Deal in Cell Therapy Deal Indication/ Phase Territory Upfront Total deal Comments TiGenix licenses Ex-US rights of Cx601 to Takeda (2016) Complex Perianal Fistulas in Crohn s disease patients; MAA submitted to EMA Worldwide Ex-US 25M 10M in equity Up to 380M TiGenix maintains 100% rights to US market, ( 50% market) and full rights to develop Cx601 in other indications Mesoblasts acquires MSC business from Osiris (2013) Janssen options rights to CAP-1002 from Capricor (2014) Chugai licenses Multistem from Athersys (2015) United Therapeutics licenses PLX-PAD from Pluristem (2011) Prochymal: Acute GvHD in children (approved in Canada and NZ) Large myocardial infarction (in Ph. II) Ischemic stroke (in Ph. II) Pulmonary hypertension (in Ph. I) Worldwide $20M $100M > 50% potentially payable in stock Worldwide $12.5M Up to $337.5M Japan $10M Up to $205M Exclusive right to license CAP at any time until 60 days post 6-month follow-up data from Phase II Worldwide $7M $55M Agreement ended by UT December

29 Cx601 a Major Breakthrough Clear Plan to Secure Even Further Upside Cx601 addresses a severe and common unmet need in Crohn s Disease Current treatment options lack long term efficacy and present safety concerns European Phase III clinical trial results show clear superiority in efficacy vs. standard of care with just one single treatment Clinical effect is significantly quicker and efficacy persists at 52 weeks Product has good safety profile and is easy to administer Approval and launch in Europe expected 2H17 US Pivotal Phase III trial agreed with FDA (SPA) to start 1H17 29

30 AlloCSC-01: Phase ll Data To Be Announced 1H 17 Intracoronary administration of allogeneic cardiac stem cells for the treatment of acute ischaemic heart disease 30

31 AlloCSC-01: Preventing Chronic 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 Acute Myocardial Infarctions ( AMI ) has increased short term survival but contributed to a Chronic Heart Failure (CHF) epidemic (26M patients worldwide 3 ) CHF post-ami is a terminal disease with an annual mortality rate of ~5% after the first episode, for which no curative treatment exists with the exception of heart transplantation Myocardial repair is the only feasible treatment to address the post-acute phase of the disease and prevent 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:

32 AlloCSC-01: Efficacy Demonstrated in Pig Model 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 Efficacy Data from MRI 1 Histological Analysis CARDIAC REMODELING CARDIAC FUNCTION CONTROL * * * AlloCSC-01 * p-value < MRI: Magnetic Resonance Imaging 2 EDVi: End-Diastolic Volume Index 3 ESVi: End-Systolic Volume Index 4 EF: Ejection Fraction 32

33 CAREMI Phase I/II Trial Final Results Expected 1H17 Safety and Efficacy of Intracoronary Infusion of Allogeneic Cardiac Stem Cells in Patients with Acute Myocardial Infarction ( AMI ) PATIENT SELECTION Initial clinical pre-screening: Males, females 18 years and 80 years Patients who present a STEMI 1 Killip 2 on admission Successful revascularization by PCI (TIMI 2 = 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 3 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 Condition Study design Recruitment # of centers 8 sites Primary endpoint Secondary endpoints (6 and 12 months) TRIAL SUMMARY Acute Myocardial Infarction AlloCSC-01 administered 5-7 days after PCI 4 Phase 1. Open label dose escalation in 6 patients Phase 2: Placebo controlled, 49 patients randomized 2:1 (35M cell dose in active arm) Phase 1: Completed Phase 2: Completed recruitment in 4Q15 Mortality and MACE 5 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 6 scale Completion 1H17 (Interim data announced June 16) 1 STEMI: ST-Segment-Elevation Myocardial Infarction 2 TIMI: Thrombolysis In Myocardial Infarction 3 LV: Left Ventricle 4 PCI: Percutaneous Coronary Intervention 5 MACE: Major Adverse Cardiac Events 6 NYHA: New York Heart Association 33

34 CAREMI Phase I/II Trial Positive Preliminary Results from Phase I Presented at ESC In the dose-escalation open-label phase, 6 patients were treated and 5 of them were followed up for 6 months Patients received a single injection of 11 million (M), 22M or 35M cells of AlloCSC-01 (n=2 each) by intracoronary infusion 5 to 7 days after Percutaneous Coronary Intervention (PCI) Data presented at the European Society of Cardiology meeting in London, showed that AlloCSC-01 has a good safety profile as no adverse events or Major Adverse Cardiac Events (MACE) were observed during the 6 month follow-up period * p-value < 0.1 ** p-value < 0.05 Preliminary data from this treated group showed a reduction in infarct size, and a LVEF improvement on MRI, over the 6-month follow-up period (n=5 4 ; p<0.05 for both parameters) LVEF (%): Left Ventricular Ejection Fraction % change versus screening MRI 2 IS (ml): Infarct Size 3 IS (% of LV): Infarct Size as % of Left Ventricular mass 4 The patient lost to follow-up received the 11 million dose 34

35 CAREMI Phase I/II Trial Interim Results at 6 Months Confirm Safety Profile of AlloCSC patients were evaluated: 34 patients received AlloCSC-01 (35 M cells) and 17 patients received placebo Primary endpoint met: No mortality of any cause within one month was recorded for both placebo and AlloCSC-01 groups No major adverse cardiac event (MACE) was recorded within one month in either group Importantly for the long term safety evaluation, no mortality of any cause nor MACE was recorded in either group at six months Preliminary secondary efficacy data at six months was limited to infarct size evolution, defined as a percent of the left ventricular mass measured by magnetic resonance imaging. The mean absolute change in infarct size from baseline to six months was similar in both groups The final full set of safety and efficacy study results at twelve months will be reported in first half of

36 Cx611: Phase li Ready Intravenous injection of eascs for the treatment of severe sepsis 36

37 Discharges thousands Severe Sepsis - A High Unmet Medical Need Sepsis is a life-threatening complication of infection leading to systemic inflammation and organ failure Between 15M to 19M sepsis cases occur worldwide each year 1 Mortality reaches 50% for severe sepsis raising to 80% in septic shock 2 In the US, sepsis generates USD 20 billion in hospital-related costs and is the most expensive condition billed to Medicare 3 Cx611 s novel mechanism of action may offer an innovative alternative to the treatment of severe sepsis Soon to start Phase II trial has received the support of the Horizon 2020 European Commission Program and the endorsement of key opinion leaders in Europe Diagnosed cases and mortality of Sepsis vs. Breast Cancer, Prostate Cancer & AIDS Sepsis Diagnosis Deaths Breast, Prostate Cancer & AIDS Trend in U.S. hospital stays with septicemia % CAGR The Lancet Infectious Diseases; Volume 12; issue 2; page 89; February Martin GS Expert Rev Anti Infect Ther June ; 10(6): Torio et al. National inpatient hospital costs: the most expensive conditions by payer. AHRQ, Healthcare Cost Brief No. 160 August Adapted from Lagu, T., et al. Critical Care Medicine, 40(3): ; Adapted from: Elixhauser et al. Septicemia in U.S. Hospitals 2009, AHRQ, Healthcare Cost Brief No. 122 October

38 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 LPS 1 Model CLP 2 Model Source: Gonzalez-Rey, 2009 * p < LPS: lipopolysaccharide. LPS model is based on endotoxemia induced by high-dose of endotoxin 2 CLP: cecal ligation and puncture. This model mimics the clinical situation of patients with colonic leakage following surgical procedures or diffused peritonitis 38

39 LPS model Cx611 Has an Effect at 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):

40 Cx611: Phase I/II in Severe Sepsis Expected to Start 2H16 CELLULA Phase I trial results 250k, 1M, 4M easc/kg and placebo administered to 32 healthy volunteers (8 per group) Favorable safety and tolerability profile of Cx611, consistent with Phase I/IIa in refractory RA 1 patients SEPCELL Phase I/II study in severe sepsis to start 2H16 Randomized, double blind, parallel groups, placebo controlled, multicenter study 180 patients (90 per group) with scabp 2 requiring mechanical ventilation and/or vasopressors, admitted to the ICU. At least 50 centers in at least 4 countries 160M easc or placebo on days 1 and 3 (320M in total) in addition to standard of care therapy. 90 days follow up Primary endpoint: Adverse event and potential immunological host responses against the administered cells Secondary endpoint: Reduction in the duration of mechanical ventilation and/or vasopressors needed and/or improved survival, and/or clinical cure of the CAPB, and other infection-related endpoints Partially funded with EUR 5.4 million from the European Commission through its Horizon 2020 Program 1 Rheumatoid Arthritis 2 Severe community-acquired bacterial pneumonia 40

41 IP, Key Milestones and Compelling Investment Case 41

42 Key Intellectual Property Patent Portfolio in Cell Therapy 29 patent families related to cell therapy products Pending & granted patents in over 20 jurisdictions including the US; expiry dates 2024 onwards for the products in development 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 stem cell and chondrocyte 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 reviewed by external counsel US: Morrison & Foerster Europe: Carpmaels & Ransford 42

43 Key Milestones Product Cx601 (local) Europe US 4Q14 Phase 3 enrollment completed 3Q14 CMO selection 4Q14 SPA submission 3Q15 Phase 3 primary endpoint met (24 weeks) 3Q15 positive SPA 1Q16 study results (1 year follow-up) 1Q16 EMA filing Takeda Deal 2H16 tech transfer finalized 2H17 EMA approval 2H17 launch 1Q17 IND filing 1H17 start US Phase 3 AlloCSC-01 (intracoronary) acute myocardial infarction 1Q15 Phase 2 enrollment initiated 4Q15 Phase 2 enrollment completed 2H16 Phase 2 interim analysis 1H17 Phase 2 study results Cx611 (IV) severe sepsis 4Q14 Phase 1 initiated 2Q15 Phase 1 study results 2H16 Phase 2 enrollment initiated ChondroCelect 1Q14 manufacturing facility sold 2Q14 licensed to SOBI Termination of agreement with SOBI Withdrawal of MAA requested 43

44 Compelling Investment Case Cx601: Global Agreement Ex-US with Takeda Cx601: Clear pathway to US market Valuable Pipeline Opportunities: AlloCSC-01 and Cx611 Complex perianal fistulas in Crohn s disease patients in United States & EU is a multi-billion dollar opportunity Pivotal Phase III (local administration of a single dose of allogeneic adipose derived stem cells) Primary endpoint met. Cx601 statistically superior to placebo in achieving combined remission at week 24 (p=0.024) Long term efficacy sustained at week 52 on same endpoint (p=0.019) MAA submitted to EMA in 1Q16. Launch expected 2H17 GMP process approved for commercial manufacturing by Spanish Agency in 1Q16.Takeda will co-invest in the expantion of the Madrid facility to secure supply for the initial few years Up to 380M agreement with Takeda for the exclusive ex-us rights to Cx601 for the treatment of complex perianal fistulas in Crohn s disease patients Use of data from positive pivotal Phase III trial in EU to support a BLA in the US FDA s agreement on SPA obtained for pivotal phase III trial in the US Same primary endpoint as positive EU Phase III trial US Phase III to start 1H17 Fully-owned asset; granted patent valid until 2030 Lonza selected as contract manufacturing organization for Cx601 in the US AlloCSC-01: intra-coronary administered allogeneic cardiac stem cells, being developed for acute myocardial infarction Randomized, double blind, placebo controlled Phase II trial ongoing Interim 6 months data confirmed safety. Final one-year follow up data expected 1H17 Cx611: Intravenously-administered allogeneic adipose derived stem cell product for severe sepsis Phase I study completed Severe sepsis Phase I/ll trial design has been finalized; expected to enroll first patient in 2H16 1 Advanced Therapy Medicinal Product 44

45 References 45

46 References 1. Stone MA et al. Prevalence and management of inflammatory bowel disease: A cross-sectional study from central England. European Journal of Gastroenterology & Hepatology 2013; 15: Hein R et al. Prevalence of inflammatory bowel disease: estimates for 2010 and trends in Germany from a large insurance-based regional cohort. Scandinavian Journal of Gastroenterology 2014; 49: Lucendo AJ et al. Epidemiology and temporal trends ( ) of inflammatory bowel disease in adult patients in a central region of Spain. European Journal of Gastroenterology & Hepatology 2014; 26: Dal Pont E et al. Inflammatory bowel diseases (IBD) incidence and prevalence in a North East limited area of Italy. Digestive Liver Disease 2010; S Cottone M et al. Incidence of Crohn s disease and CARD 15 mutation in a small town in Sicily. European Journal of Epidemiology 2006; 21: Herrinton LJ et al. Estimation of the period prevalence of inflammatory bowel disease among nine health plans using computerized diagnoses and outpatients pharmacy dispensings. Inflammatory Bowel Disease 2007; 13: Kappelman MD et al. The prevalence and geographic distribution of Crohn s disease and ulcerative colitis in the United States. Clinical Gastroenterology & Hepatology 2007; 5: Kappelman MD et al. Recent trends in the prevalence of Crohn s disease and ulcerative colitis in a commercially insured US population. Digestive Diseases & Sciences 2013; 58: Molodecky NA et al. Increasing incidence and prevalence of inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: Spanish Epidemiological and Economic Study Group on Crohn s disease. Epidemiological and clinical features of Spanish patients with Crohn s disease. European Journal of Gastroenterology & Hepatology 1999; 11: Gibson PR et al. Relationship between disease severity, quality of life and health care resource use in a cross-section of Australian patients with Crohn s disease. Journal of Gastroenterology & Hepatology 2007; 22: Dranga M et al. Are there any particularities in Crohn s disease in North-Eastern Romania? Revista Medico-Chirurgicala a Societatii de Medici si Naturalisti din Iasi 2015; 119: Schwartz DA et al. The natural history of fistulizing Crohn s disease in Olmsted county, Minnesota. Gastroenterology 2002; 122: Bell SJ et al. The clinical course of fistulating Crohn s disease. Alimentary Pharmacology & Therapeutics 2003; 17: Eglinton TW et al. The spectrum of perianal Crohn s disease in a population-based cohort. Diseases of the Colon & Rectum 2012; 55: Gray BK et al. Crohn s disease of the anal region. Gut 1965; 6: Galandiuk S. Perianal Crohn s disease. Predictors of need for permanent diversion. Annals of Surgery 2005; 241: Molendijk I et al. Disappointing durable remission rates in complex Crohn s disease fistula. Inflammatory Bowel Disease 2014; 20: Sands BE et al. Infliximab maintenance therapy for fistulizing Crohn s disease. The New England Journal of Medicine 2004; 350: Domènech E et al. Clinical evolution of luminal and perianal Crohn s disease after inducing remission with infliximab: how long should patients be treated? Alimentary Pharmacology & Therapeutics 2005; 22: Gammie T et al. Comprehensive Review of Legislations, Regulations and Policies in 35 Countries. PLoS One. 2015;10(10):e ,

47 Corporate Presentation July