R&D Media Briefing. 30 June 2014

Transcription

1 R&D Media Briefing 30 June

2 Forward Looking Statement 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 A word on TiGenix Cell therapy company with first ever ATMP 1 approved by EMA and advanced clinical stage platform of expanded adipose derived stem cells Headquartered in Leuven (Belgium) with operations in Madrid (Spain) Circa 50 employees Quoted (TIG) on NYSE Euronext Brussels Approximately 110M market cap Reference shareholders: 30% held by Grifols, Roche and Novartis High liquidity: 70% free-float; 30% institutional investors 6 analysts covering the stock, of which four independent 25.7M of funds available end of Q Advanced Therapy Medicinal Product 3

4 Complete focus on easc 1 platform Cx601 and Cx611 will be our two key assets in clinical development Product 2 Indication Preclinical Phase I Phase II Phase III Market ChondroCelect Cartilage lesions (knee) Partnered 3 Cx601 (local) Fistulizing Crohn s Orphan Drug (EU) Cx611 (intravenous) Rheumatoid Arthritis Severe Sepsis Cx621 (intralymphatic) Autoimmune disorders (on hold) Expanded autologous chondrocytes Expanded allogeneic adipose derived stem cells 1 expanded Adipose derived Stem Cell 2 Covered by around 20 patent families 3 Distributed through Swedish Orphan Biovitrum and the Finnish Red Cross Blood Systems 4

5 Management team Managing Director and CEO: Eduardo Bravo, MBA More than 20 years experience in the pharma and biotech industries at Sanofi-Aventis, Recordati, Cephalon and SmithKline Beecham CFO: Dr 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 VP Clinical Operations & Regulatory Affairs: María Pascual, PhD More than 10 years experience in cell therapy companies; specialised in regulatory affairs for advanced therapies; external adviser to EMA 5

6 Board of Directors Jean Stéphenne (Chairman and Independent Director): permanent representative of Innosté SA; ex-chairman and President of GSK Biologicals Dirk Büscher (non-executive Director): CEO of Gri-Cel SA Willy Duron (Independent Director): ex-ceo of KBC Groep NV Russell Greig (Independent Director): permanent representative of Greig Biotechnology Global Consulting Inc.; ex-president of SR One Eduard Enrico Holdener (Independent Director): ex-chief Medical Officer & Global Development Head of the Pharma Division of F. Hoffmann-La Roche AG Dirk Reyn (Independent Director): permanent representative of R&S Consulting BVBA; ex-ceo of Movetis NV José Terencio (non-executive Director): COO of Gri-Cel SA Eduardo Bravo (executive Director): CEO of TiGenix NV 6

7 ChondroCelect First ever ATMP approved by EMA (2009) First, and so far, only cell therapy product with national reimbursement Suspension of characterised autologous chondrocytes injected intra-articularly Indicated for the repair of single symptomatic cartilage defects of the femoral condyle of the knee (ICRS III or IV) in adults Potential avoidance of knee replacement and use of wheelchair in the long run Market: Between 17,000 and 28,000 new patients per year in Europe Additional deal flow possible ex-europe and Middle East Currently on the market in BL, NL, ES, UK and Finland => 2013 gross sales of 4.3M Further market penetration to be achieved through distribution agreement with Swedish Orphan International (Sobi), effective as of 1st June Sobi Territory: European Union (excl. Finland), Switzerland, Norway, Russia, Turkey and the MENA region, whereby certain countries within MENA will only become part of Sobi s territory as of Nov. 12 th,

8 Licensed to Swedish Orphan Biovitrum (Sobi) Leading European specialty pharmaceutical company focused on niche disease areas Excellent track record in securing market access and commercialising partners products - around 25% of total revenue comes from doing this Highly focused sales force in place in a broad territory Solid financial position and capability to invest in further market roll-out Deal merits Increased penetration of ChondroCelect (CC) in existing markets and potentially swift opening of new markets 20% royalty on CC net sales (22% in year 1) and reimbursement of almost all CC expenses => CC becomes a cash-flow positive asset for TiGenix Significant resources are freed up to invest in the development of the easc platform and new product pipeline 8

9 eascs Stem cells sourced from the adipose tissue of universal healthy donors Expanded to reach therapeutic doses in TiGenix facilities Targeting the treatment of inflammatory and autoimmune conditions MECHANISM OF ACTION CONSISTENCY SAFETY PROVEN REPRODUCIBILITY EFFICACY 9

10 MSCs 1 (including ASCs) and the immune system The ability to interact with many players in the immune system qualify MSCs (including ASCs) as a potent anti-inflammatory agent From: Singer and Caplan, Mesenchymal Stem Cells 10

11 eascs as a preferred source of MSCs Source and expansion Easily accessible Considerably higher yield than bone marrow High rate of expansion Maintenance of stability during expansion Pharmacological profile Low immunogenicity (low or no HLA, co-stimulatory molecules and ligands for NK receptors) Possibility of allogeneic use 11

12 % of PBMC proliferation eascs mechanism of action Control of inflammation through: Inhibition of T-cell proliferation modulation of immune cell function (i.e. inhibition of T-cell proliferation) reduction of pro-inflammatory cytokine secretion increase of immune cells with 20 regulatory function 0 (i.e. regulatory T cells) control 1-MT * Inhibition of pro-inflammatory cytokines ASC PBMC Activated PBMC PBMC+ASC IFN- (ng/ml) TNF- (ng/ml) CT TW Source: De la Rosa et al. Tissue Engineering 2009 Activated PBMC+hASC Increase number of Tregs activated PBMC+ASC * * Source: De la Rosa et al. Tissue Engineering 2009 Source: TiGenix data * 1-MT: 1 methyl L-tryphtophan (inhibitor of IDO activity) is blocking the anti-proliferative effect of ASCs, confirming the key role of IDO in the inhibition of proliferation 12

13 Safety Preclinical package with a clean profile Full spectrum of studies conducted: Pharmacodynamics, biodistribution, toxicology, tumorigenicity, immunotoxicity, studies on differentiation potential 5 animal models evaluated:mouse CIA, TNBS and DSS in mouse, DSS in rat, LPS and caecal ligation and puncture (CLP) in mouse Effect of eascs administered through 5 different routes: local (perianal), rectovaginal, intraperitoneal, intravenous and intralymphatic No indication of toxicity No indication of tumorigenicity No indication of immuno-suppression No indication of ectopic tissue growth 13

14 Safety: biodistribution and persistence of ASCs eascs can be detected in inflamed tissues and lymphoid organs (mouse model of colitis) In vivo distribution at 48h IL IP IV eascs have a limited persistence Migration to inflamed tissue (colitis mouse model) Migration to organs and tissues of lymphatic system Source: González et al. Gastroenterology 2009 Source: TiGenix data, Delgado,

15 Efficacy Therapeutic efficacy established in animal models 1 1. Administering human ASCs to prevent and treat experimental arthritis; Zhou et al. Clin Immunol Dec; 141(3): Transforming growth factor β-transduced MSCs ameliorate experimental autoimmune arthritis through reciprocal regulation of Treg/Th17 cells and osteoclastogenesis; Park et al. Arthritis Rheum Jun;63(6): Treatment of experimental arthritis by inducing immune tolerance with human ASCs; González et al. Arthritis Rheum Apr;60(4): Cell therapy using allogeneic bone marrow MSCs prevents tissue damage in collagen-induced arthritis; Augello et al. Arthritis Rheum Apr;56(4): Intraperitoneal but not intravenous cryopreserved mesenchymal stromal cells home to the inflamed colon and ameliorate experimental colitis; Castelo-Branco et al. PLoS One. 2012;7(3):e MSC-induced immuno-regulation involves FAS-ligand-/FAS-mediated T cell apoptosis; Akiyama et al. Cell Stem Cell May 4;10(5): ASCs alleviate experimental colitis by inhibiting inflammatory and autoimmune responses; González et al. Gastroenterology Mar;136(3): Human ASCs protect against experimental colitis and sepsis; González-Rey et al. Gut Jul;58(7): Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production; Németh et al. Nat Med Jan;15(1): Human MSCs reduce mortality and bacteremia in gram-negative sepsis.; Krasnodemskaya et al. Am J Physiol Lung Cell Mol Physiol May 15;302(10):L Antibacterial effect of human MSCs is mediated in part from secretion of the antimicrobial peptide LL-37; Krasnodemskaya et al. Stem Cells Dec;28(12): Selected publications of efficacy in RA (1 4), IBD (5 8) and Sepsis (8-11) using Mesenchymal Stem Cells (MSCs) 15

16 Efficacy Confirmed in TiGenix clinical trials Phase I III studies in perianal fistula with autologous product (Cx401) 1,2,3 Phase II study in fistulizing Crohn s with allogeneic local product (Cx601) 4 IIS study in rectovaginal fistulas with allogeneic local product (Cx601) Phase IIa study in Rheumatoid Arthritis with allogeneic i.v. product (Cx611) as well as by third party publications Woo Yong Lee et al, 2013, Stem Cells: Phase II data with Cupistem in complex perianal fistulas Tan J. et al, JAMA, 2012 Mar 21: Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial Wang L, et all, Stem Cells Dev Dec 15: Human umbilical cord mesenchymal stem cell therapy for patients with active Rheumatoid Arthritis: Safety and efficacy (1) García Olmo, et al., Diseases of the Colon & Rectum (2) García Olmo, et al., Diseases of the Colon & Rectum (3) Herreros, et al., Diseases of the Colon & Rectum (4) de la Portilla, F. et al., Int. Journal of Colorectal Disease 16

17 Reproducibility Manufacturing procedures designed to ensure product consistency and process reproducibility Tissue source: healthy, consenting adult donors no tissue type matching needed stringent sourcing requirements and acceptance criteria Tissue dissociation and isolation of cells according to defined protocol: preservation of functional integrity of the cells and effectiveness of the isolation Expansion through a standardised cell culture process: no pooling of cells > 600 procedures produced in-house to date Banking system with master and working cell banks possibility of long term storage of product in frozen form (stability data of cell banks for up to 2.5 years) 17

18 easc Manufacturing Schematic manufacturing overview Cellular expansion Isolation of Stromal Vascular Fraction (SVF) Freezing Cell Banks 18

19 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 Master cell bank (cryo) Finished product units at current doses (clinical trials): 2,400 doses of Cx601 1 Frozen Drug Substance (FDS) 4,000 doses of Cx611 2 Finished Product 1 Based on ADMIRE CD trial (120M cells per patient) 2 Assumes 1 million eascs/ Kg, weight average 80Kgs 19

20 Targeting a rising patient population CROHN S DISEASE Chronic inflammatory condition of the digestive tract Diagnosed in adults and children Currently affects more than a million Europeans and Americans 1 Incidence rising significantly in Asia Can occur anywhere in the digestive tract but most commonly affects the lower part of the small intestine Incurable, but treatments available to relieve symptoms Complications include the appearance of fistulas 1 Roughly 50% on each side of the Atlantic 20

21 Perianal fistulas: a common severe complication Fistulas: sores or ulcers that tunnel through the affected area into surrounding tissues 12% of Crohn s patients are affected by perianal fistulas 1 80% of these are complex Large intestine affect anal sphincters present multiple tracts are recurrent are often associated with perianal abscess Fistula > Crohn s patients suffer from complex perianal fistulas every year in Europe and the US alone => compromised QoL, pain, depression, risk of anal epithelial carcinoma 1 Source: >60 publications (including Schwartz 2002, Lapidus 2006), the European Federation of Crohn s and Colitis Associations, US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics 21

22 Current treatments don t offer a long term cure Pharmaceutical treatment alternatives: Antibiotics: safety concerns with prolonged use of antibiotics; no long-term healing data supporting the use of antibiotics 1 Immunosuppresors: low healing rates + relapse on drug cessation 2 Biologics: > 67% of patients receive biologics at some point in time 3. BUT: Low efficacy: - Infliximab: remission of 23% (fistula closure at consecutive visits four or more weeks apart) 4 - Humira: remission (56 weeks): 33% 5 High rate of relapse 6 - >20% of patients require a dose increase 2 Safety remains a concern with long term use of biologics Surgical treatment is also an option. BUT: High risk of anal incontinence ( 12% 7 ) High proportion of recurrence % recurrence within 4 months of cessation of treatment (Bnernstein LH et al. (1980). Gastroenterology 79: ) 2 Pearson DC et al. (1995) Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 123: IMS study on the epidemiology, management and burden of the disease in 11 hospitals in Spain 4 ACCENT II clinical trial 5 CHARM clinical trial 6 54% for infliximab after 1 year (Sands BE et al. (2004). N Engl J Med 350: A. Soltani, A. Kaiser, Diseases of the Colon & Rectum vol.53:4 (2010) 8 Schouten at al, Mizrahi et al, Sonoda et al, van der Hagen et al 22

23 Developing a new treatment paradigm Cx401 (autologous) Phase I I 5 patients 1 centre Phase II 50 patients 3 centres Phase III (FATT 1) patients 19 centres Cx601 (allogeneic) Phase II Phase I/II, IIS 2 (ALOREVA,) 34 patients 6 centres 10 patients 1 centre Phase III (ADMIRE-CD) 278 patients 52 centres 1 Fistula Advanced Therapy Trial complex perianal fistulas in non Crohn s patients 2 Investigator Initiated Study in rectovaginal fistulas Note: Patient data refers to number of patients recruited 23

24 Clinical evidence supporting Cx601 Cx401 Autologous Perianal fistula Phase I (1), II (2), III (3) 22 centers patients recruited* 152 patients received Cx401* Efficacy 40-75% Cx601 Allogeneic Perianal fistula Phase II (4) 6 centers patients recruited 24 patients received Cx601 Efficacy 56% Cx601 Allogeneic Rectovaginal fistula IIS 1 center patients recruited and treated with Cx601 Efficacy 57% Cupistem Autologous Perianal fistula Phase II (5) 5 centers patients recruited 43 patients received Cupistem Efficacy (6) 4 82% 1 García Olmo, et al., Diseases of the Colon & Rectum 2 García Olmo, et al., Diseases of the Colon & Rectum 3 Herreros, et al., Diseases of the Colon & Rectum 4 de la Portilla, F. et al., Int. Journal of Colorectal Disease 5 Woo Yong Lee et al, 2013, Stem Cells 6 Efficacy at 8 weeks based on modified PP population; * Only includes patients in completed trials 24

25 Cx401: autologous development Phase II: statistically significant superior efficacy Efficacy results at 8 weeks (primary endpoint) 100% 80% 60% (p-value <0.001) 40% 70.8% 20% 0% Cx401 + Fibrin Glue 16.0% Fibrin glue Cx401 + fibrin glue is an effective treatment for complex fistula: more than four times higher efficacy than fibrin glue in phase II (statistically significant results) Cx401 is safe: no serious adverse events related to Cx401 recorded until now Quality of Life: physical and emotional functions improve in patients treated with Cx401 + fibrin glue Long term effect: at 1 year follow-up, the recurrence rate in Cx401 + fibrin glue treated patients was 17.6%. No patient experienced recurrence until at least 7 months after treatment 25

26 Cx601: allogeneic development Phase II: the switch to an allogeneic therapy TRIAL SUMMARY Start June 2009 Completion September 2010 Conditions Study design Enrolment Complex perianal fistula in Crohn s patients Single arm Non-controlled Safety/Efficacy Study One fistula/tract treated. Maximum of 2 doses patients PATIENT SELECTION Older than 18 years: both genders Complex perianal fistula fulfilling some of the following conditions: associated faecal incontinence risk factors of anal incontinence at least 1 previous operation for a fistulous disorder recto-vaginal fistula Crohn s disease Controlled No # of centres 6 in Spain Primary endpoint Secondary endpoint Incidence of treatment emergent adverse-events Closure of external openings (clinically and MRI) Reduction nr. draining fistulas Efficacy 56% 1 First dose of 20M cells; Second dose of 40M cells injected if fistula has not closed after 12 weeks 26

27 Cx601 phase II Safety of allogeneic cells confirmed Immune system tolerated repeated treatment with allogeneic eascs Controlled number of adverse events related to study treatment Overview of adverse events. Full analysis set (n=24) Patients with at least one TEAE1 during the study: 13 (54.2%) Patients with at least one TEAE possibly related to eascs during the study 5 (20.8%) Serious adverse events reported leading to withdrawal 2 (8.3%) (Events considered to be possibly related to the study treatment; no clinically relevant abnormalities found during physical examination or in the vital signs) 27

28 Cx601 phase II Allogeneic eascs confirm efficacy of autologous cells Closure of external openings of treated perianal fistula tracts 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 38,1% After 12 weeks (N=21) 56,3% After 24 weeks (N=16) Reduction in number of draining fistulas Nº fistulas: 1 2 (only 1 dose received) (week 26 if 2 doses received) (only 1 dose received) (week 26 if 2 doses received) Superior efficacy in closure of treated fistula tracts Reduction of drainage in treated fistulas that have not achieved complete closure Positive effect on adjacent fistula tracts that have not directly been treated 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 50,0% 10,0% After 12 weeks (N=21) 61,5% 7,7% After 24 weeks (N=16) N= Patients with available information. Missing data not included in percentage calculations 28

29 Cx601: investigator-initiated study ALOREVA Therapeutic effect of eascs also confirmed in extremely tough condition TRIAL SUMMARY Start September 2009 Completion December 2011 Conditions Study design Enrolment Rectovaginal fistulas Open label Non-controlled Safety and efficacy study 10 patients # of centres 1 in Madrid Primary endpoint Secondary endpoint Efficacy Closure of the external opening of the treated RV fistula Quality of life (SF-36) Number of adverse events Clinically relevant variations in laboratory test 57% (1 year) PATIENT SELECTION and RESULTS PATIENT SELECTION and RESULTS Women of a childbearing age (>18) Rectovaginal fistula Patients with Crohn s disease diagnosed at least 12 months earlier with either one previous surgery for fistulous disease or a physical status which discourage liposuction 7 patients completed the study 4 out of these showed complete closure of the fistula ALL 10 patients avoided the previously indicated colostomy 29

30 Cx601: Phase III ADMIRE-CD trial Efficacy results from Cx401 Safety of allogeneic approach confirmed in Cx601 phase II Efficacy confirmed in Cx601 phase II and IIS Advice from international panel of experts EMA Scientific Advice pre-phase III (March 2011) Pre-clinical package sufficient for MA filing Proposed phase III qualifies as a single pivotal trial 30

31 Cx601 Phase III ADMIRE-CD trial International Advisory Board Steering Committee Dr. J Panés, Head Inflammatory Disease Unit, Hospital Clínic Barcelona, Spain Dr. FD Colombel, Professor of Hepato-Gastroenterology, Centre Hospitalier Universitaire (CHU) de Lille, France Dr. W. Reinisch, University Professor at the Medical University of Vienna, Austria Dr. G. Van Assche, Consultant Gastroenterologist, Division of Gastroenterology, University Hospital Leuven, Belgium Dr. S. Danese, Head, IBD Center, Division of Gastroenterology, Istituto Clinico Humanvisitas, Milan, Italy Dr. D Baumgart, Charité Medical School, Virchow Hospital Department of Medicine, Division of Gastroenterology & Hepatology, Berlin, Germany 31

32 Cx601 Phase III ADMIRE-CD trial Robust Phase III designed to qualify as a pivotal study TRIAL SUMMARY Start July 2012 Completion Condition Study design Enrolment Ongoing Complex perianal fistula in Crohn s patients Randomized, double blind, placebo controlled trial All tracts treated. Fixed single dose patients screened 208 patients randomized # of centres 52 centres in 8 countries Primary endpoint Secondary endpoint Remission 1 at week 24 Response 2 Time to remission/ time to response PDAI score and QoL assessment (IBDQ) PATIENT SELECTION PATIENT SELECTION Older than 18 years: both genders Patients with perianal fistulising Crohn s disease refractory to antibiotics, immunosuppressants and/or anti-tnf Exclusion of naïve patients Limit of patients refractory to antibiotics to <25% of total recruited patients 2 internal openings (fistulas) and 3 external openings (tracts) Non active luminal CD (CDAI 220) CD diagnosed for 6 months; Fistula draining < 6 weeks prior to inclusion Concomitant treatments allowed without modification of treatment dose or regimen 1 Closure of all draining tracts at baseline despite gentle finger compression confirmed by MRI (no collections >2cm) 2 Closure of 50% draining tracts at baseline despite gentle finger compression confirmed by MRI (no collections >2cm) million cells 32

33 Poised to deliver results in 2015 Status Trial ongoing in 8 countries: Austria, Belgium, France, Germany, Israel, Italy, the Netherlands and Spain 52 centers initiated Close to 90% of patients recruited Anticipated filing calendar in Europe Last patient in expected 2014 Study results (24 week follow-up) expected 3Q 2015 Study results (1 year follow-up) expected 1Q 2016 Filing for EMA approval 1H

34 US strategy and partnering Homework done; clear strategy defined End-of-Phase II meeting held with FDA in December 2013 Affirmative feedback received regarding adequacy of the existing non-clinical package to support an IND 1 filing for a US-based phase III trial phase III trial design acceptability of using data from the ongoing ADMIRE-CD phase III study in Europe to support a biologic license application (BLA) Development plan for the US now clarified: selection of contract manufacturing organization for technology transfer (3Q 2014) application for special protocol assessment (submission 4Q 2014) IND 1 to be filed as soon as technology transfer finalised Partnering discussions re-opened 1 Investigational New Drug 34

35 Clinical Development of Cx611 Selecting the right indication Key criteria Scientific Advisory Board Medical need Current and future treatment options Mechanism of action of eascs Early Rheumatoid Arthritis (RA) Severe Sepsis Induce and maintain low disease activity target acute & inflammatory disease state indication of activity evidenced in refractory patients in phase ii clinical trial reduce high mortality despite current treatments focus on both pro- and antiinflammatory response robust evidence of therapeutic efficacy in experimental animal models 35

36 Cx611 in early rheumatoid arthritis 36

37 Disease & pathogenesis Key underlying processes in RA Multi-process disease Activation of dendritic cells (DCs), T cells, B cells and macrophages Dysregulated expression of cytokines Activation of effector cells, including neutrophils, mast cells, endothelial cells and synovial fibroblasts Clinical manifestations include inflammation, cartilage damage, synovial hyperplasia, angiogenesis Source: Iain B. McInnes & Georg Schett,

38 Current treatment algorithm for RA Source: Smolen et al., Annals Rheumatic Diseases,

39 The future management of RA Goal: induction of remission EULAR guidelines just published (Smolen et al., Annals Rheumatic Diseases, 2013) More risk profile-based aggressive induction remission schemes being proposed (COBRA, BEST, CareRA) Current treatments: results and shortfalls 60-70% remission in 4 months if aggressive induction/remission protocol is used (Verschueren, Westhovens et al, CareRA); otherwise with current clinical practice it could be as low as 25% Biologics started within 4-6 months but with significant challenges: Lack of adequate response 1,2 ; efficacy limited in time, switch to other biologic likely required 3,4 Once started, biologics are taken for long duration of time (health economic implications) If stopped, relapse in >50% of patients (first data sets being published) Safety concerns 5. Several carry black boxes and other warnings 6. High cost of side effects 7 Multiple molecular targets, but so far none leading to long-term remission 1 November 2012 investor note (Credit-Suisse) 2 Rendas Baum et al, Arthritis Research & Therapy Consumer Reports, 2010: Evaluating prescription drugs to treat the symptoms of RA: The biologics 4 University of Maryland Medical Center 5 Medscape Medical News 6 Humira and Enbrel 7 Medpagetoday, article on Enbrel (Dec. 6 th, 2012) 39

40 What is needed? Where could Cx611 potentially fit? eascs have broader immuno-modulatory properties and could better tackle a complex multipathway disease Use an alternative mechanism of action to induce and maintain low disease activity ahead of entering into treatment with biologicals is a real need 40

41 TNF (pg/ml) IL17 (pg/ml) α Mechanism of action of eascs in RA (CIA model) Potential effect in inflammatory and autoimmune indications 25 TNFα 14 IL Arthritic score after three i.v. doses of easc Treg cells * * Days after treatment Source: TiGenix data * p<

42 hasc FLS FLS + hasc eascs down-regulate the activation of synoviocytes from RA patients (in vitro) Fibroblast-like synoviocyte (FLS) -hasc +hasc LPS TNFα Co-culture of eascs with synoviocytes leads to a reduction of inflammation and a lower activity of enzymes involved in the destruction of cartilage and bone in RA patients Source: González-Rey et al. Ann. Rheum. Dis

43 % cytokine-secreting T cells % cytokine-secreting T cells % cytokine-secreting T cells eascs positively alter the T cell profile of cells from RA patients (in vitro) IFN -gamma TNF - alpha IL - 10 Source: González-Rey et al. Ann. Rheum. Dis

44 Phase IIa trial First randomised trial with eascs in refractory RA patients TRIAL SUMMARY Start March 2011 Completion January 2013 Condition Study design Enrolment Patients with RA refractory to at least two biologics Dose escalation, single blind, placebo-controlled (Cx611+ DMARD 1 vs. placebo + DMARD) 53 patients # of centres 23 sites Primary endpoint Secondary endpoint Safety (tolerability and treatmentemergent adverse events) Efficacy measured by: - ACR 2 remission (ACR 20, ACR50, ACR 70) - EULAR 3 (DAS 4 28, VSG 5 ) - Imaging (RAMRIS) - Quality of life (SF-36) PATIENT SELECTION Heterogeneous patient population: Median range of diagnoses 5 69 years Patients with severe grade of RA: Median DAS 28 score: 3,2-7,9 Patients refractory to at least two biologics Mean nº of previous DMARDs: 3.38 => 74% of patients received 3 or more DMARDs Mean nº of previous biologics: 2.92 => 45% of patients received 3 or more biologics 66% of patients had received Enbrel 64% of patients had received Humira 51% of patients had received Infliximab 1. DMARD: Disease-modifying anti-rheumatic drugs 2. American College of Rheumatology 3. European League Against Rheumatism 4. Disease Activity Score 5. Variable Surface Glycoprotein 44

45 Phase IIa trial Good safety profile of all three doses of Cx611 Safety profile Cx611+DMARD (N=46) Placebo+DMARD (N=7) Patients with any adverse events (AE) 38 (83%) 4 (57%) Patients with any related AE 22 (48%) 1 (14%) Patients with any grade 3-4 related AE 1 (2%) 1 (14%) Patients with any AE leading to discontinuation 1 (2%) 0 (0%) Only one patient experienced a serious adverse event leading to discontinuation of the treatment 1 All other side effects were mild and transient: most common related adverse events in the Cx611+DMARD group: fever (15%), headache (9%), asthenia (6%) 1 Lacunar infarction, which is defined as a type of stroke in the brain's deep structures 45

46 Phase IIa trial Encouraging activity in EULAR criteria endpoints % 43 % EULAR response Good + Moderate 0 0 M1 M2 M3 M6 (FV) Cx611 + DMARD Placebo + DMARD DAS 28 (CRP 1 ) <2.6 Remission M1 M2 M3 M6 FV(FV) Cx611 + DMARD Placebo + DMARD 9 Results shown are response rates in percentage M1, M2, M3 and M6 (FV) refers to month 1, 2, 3 and 6 (final visit) respectively For all graphs: N=46 for Cx611+DMARD cohort and N=7 for placebo + DMARD cohort 1 C Reactive Protein 46

47 Next steps in early RA Finalising design of next clinical trial Steering committee Professor Mark Genovese, Professor Immunology and Rheumatology, Stanford University, US Professor Paul Emery, Professor of Rheumatology, University of Leeds, UK Professor José María Alvaro-Gracia, Head of the Biological Therapies Unit at the Hospital Universitario de La Princesa, Madrid, Spain Goal of the trial Demonstrate potential of Cx611 in bringing early RA patients not responding to conventional regimens to remission (or very low disease activity) Key features of the upcoming clinical trial Condition: early RA (onset of RA < 1 year) Patient inclusion criteria: failure of MTX + CS ; CRP lower limit (t.b.d.), CCP 1 +/RF 2 +; >18 years Primary endpoint: Remission (DAS < 2.6) after 3 months Preliminary timelines First patient in: 3Q 2015 Study report: 1H Cyclic Citrullinated Peptide 2 Rheumatoid Factor 47

48 Cx611 in severe sepsis 48

49 Disease & pathogenesis Host response in severe sepsis Multi-process disease Simultaneous proinflammatory response (hyper-immune) & antiinflammatory response (hypo-immune) Pro-inflammatory responses lead to organ failure Coagulation leads to tissue hypo-perfusion and tissue injury Anti-inflammatory responses lead to susceptibility to infection Source: Angus et al.,

50 Disease & pathogenesis Staged progression Risk factors Chronic diseases Acquired immuno-deficiency syndrome Chronic Obstructive Pulmonary Disease Cancers Use of immunosuppressive agents Genetic composition Preexisting organ function General health status Age (higher in infants and elderly) Gender (higher in males) Ethnic background (higher in black people) Sepsis Systemic inflammatory response to infection Severe Sepsis Complicated by acute organ failure (incl. respiratory compromise, cardiovascular compromise, central nervous system dysfunction, acute kidney injury) Septic shock Complicated by hypotension refractory to fluid resuscitation or by hyperlactatemia (both associated with cardiovascular compromise) Mortality rates: 10% (sepsis), 30-35% (severe sepsis) and 45% (septic shock) (KOL interviews, Daniels 2011, Levy 2010) 50

51 Severe Sepsis A high unmet medical need Current treatments are insufficient and mainly symptomatic Only 17 first-in-class molecules are in clinical development 1 Infection control / symptom & supportive treatment Add-on Antibiotics Various broadspectrum antibiotics Low-dose corticosteroid treatment Focus on septic shock Vasopressor treatment Norepinephrine Dopamine Medical Devices Hemodialysis Mechanical ventilation Biologics are also used but in general with poor effect Product should optimally effect both the pro-inflammatory and anti-inflammatory pathways 1. Global Data

52 Severe sepsis Where could Cx611 potentially fit? Infection control / symptom & supportive treatment Add-on antimicrobial treatment fluid resuscitation * glycemic control * source control infection optimizing tissue oxydation * low-dose corticosteroid vasopressor treatment other organ function support ventilator treatment * blood transfusion 52

53 Severe sepsis Building on previous clinical trials Key learning points from previous trials Need to avoid a too heterogeneous target population Patient population not severe enough resulting in a control arm with low mortality No clear insights on mechanism of action (MoA) before start trial / or poor MoA Recommendations for clinical development in sepsis Focus on strictly defined & homogeneous target population to demonstrate efficacy Target severe patients: sustained organ failure ( 2 organ dysfunctions, >6 hours vasopressors) Perform study in healthy volunteers to optimise phase II design Leverage on a MoA which targets both the anti-inflammatory (including bacterial clearance) and pro-inflammatory responses Preclinical models with demonstrated clear efficacy 53

54 Why eascs could work in severe sepsis Cx611 reduces mortality in animal models LPS Model CLP Model Reduction in mortality LPS model: 60% survival vs. 0% after 96 hours< CLP model: 80% survival versus 20% after 10 days Decrease in pro-inflammatory mediators 1 anti-inflammatory mediators (IL-10) Antimicrobial effects Decrease infiltration of inflammatory cells in target organs 1 TNF, IL-6, IL1, IL12, IFN, RANTES, MIP-2 Source: Gonzalez-Rey,

55 Confirmed with other MSCs 1 Therapeutic effects of MSCs in sepsis models Reduction of mortality, inflammation and bacterial load (anti-microbial effects) So far, all publications indicate efficacy of MSC treatment Mechanism of action Anti-inflammatory monocyte/macrophages (IL10, increased phagocytosis) Neutrophils (increased phagocytosis) Anti-microbial peptides: LL-3 CLP model (Zhao et al. 2013) I.V. route after 1h; 1 dose CLP model (Hall et al. 2013) I.V. route after 2h, 24h and 48h 3 doses P. aeruginosa peritonitis mouse model (Krasnodembskaya et al. 2012) I.V. route after 1h; 1 dose 1 Mesenchymal Stem Cells 55

56 Next steps in severe sepsis Advisory Board Professor Pierre-François Laterre, Professor of Medicine and Head of Intensive Care, Saint Luc University Hospital, Brussels, Belgium Dr. Bruno François, Service de Réanimation Polyvalente,Centre Hospitalier Universitaire, Limoges, France Professor Sébastien Gibot, Service de Réanimation Médicale, Centre Hospitalier Universitaire, Nancy, France Professor Tom van der Poll, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands 56

57 Next steps in severe sepsis Clinical development path Proof of mechanism of action (MOA) in healthy volunteers, before starting a Phase II trial Indication: LPS (lipopolysaccharide, endotoxin) induced symptoms of inflammation Study trial design endorsed by leading KOLs Model to be used: LPS model with I.V. administration of Cx611 Dose-ranging study (3 doses) Estimated number of patients: 32 (24 treatment; 8 placebo) Follow-up: 2 days Total study duration: 10 months Endpoints: blood pressure, temperature, heart rate, symptom score, pro- and antiinflammatory cytokines, recruitment/activation of neutrophils, macrophages, T/B cells & endothelial cells, CRP, (anti-)coagulation activation / fibrinolysis, microarrays, etc. Preliminary timelines First patient in: January 2015 Study report: 3Q

58 R&D Media Briefing 30 June