Corporate Presentation The treatment of perianal December fistula 2015in Crohn s disease patients Key Opinion Leader Event 8 th May 2017
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Agenda & Speakers Dr. Marie Paule Richard Chief Medical Officer TiGenix Dr. William Sandborn Professor of Medicine and Adjunct Professor of Surgery Chief, Division of Gastroenterology Vice Chair for Clin.Ops., Department of Medicine Director, UCSD IBD Center University of California San Diego and UC San Diego Health System Dr. Julian Panés Head of Gastroenterology Department at Hospital Clinic Barcelona (Spain) and of the Inflammatory Bowel Disease IDIBAPS research team, President of the European Crohn s and Colitis Organization Uthra Sundaram VP, GI Therapeutic Area Global Commercial Leader at Takeda Pharmaceuticals 3
Complex Perianal Fistulas In Crohns Patients: The Unmet Medical Need And Current Management Strategies William J. Sandborn MD Professor and Chief, Division of Gastroenterology Director, UCSD IBD Center
Epidemiology of Crohn s Disease Fistulas *Enterovesical and entero-intra-abdominal fistulas Schwartz et al. Gastroenterology 2002 1
Epidemiology of Crohn s Disease Fistulas Schwartz et al. Gastroenterology 2002 2
Parks Classification of Perianal Fistulas Primary tracts Superficial Intersphinteric Transsphincteric Suprasphincteric Extrasphincteric Secondary tracts Infralevator Supralevator Horseshoe Parks et al. Br J Surg 1976 3
AGA Classification of Perianal Fistulas Simple Fistulas Low tract* Single external opening Not associated with abscess, rectovaginal fistula stricture With/without proctitis Complex Fistulas High tract May have multiple external openings May be associated to pain suggestive of abscess May be associated with rectovaginal fistula or stricture With/without proctitis Durable remission rate: 67% simple vs. 37% complex fistulas (p<0.001) * A low fistula tract runs through the lower one third of the external anal sphincter. AGA Technical Review, Gastroenterology 2003; Molendik et al. Inflamm Bowel Dis 2014 4
Fistula Drainage Assessment Response: a reduction of 50% or more in the number of draining fistulas on at least two consecutives visits. Remission: the absence of any draining fistulas on two consecutive visits. Open: actively draining. Closed: no longer drains despite gentle finger compression. Present et al. N Eng J Med. 1999 5
Van Assche Score Anatomical Components Active Inflammation Number of tracts None 0 Single, unbranched 1 Single, branched 2 Multiple 3 Location Extra- or intersphincteric 1 Transsphincteric 2 Suprasphincteric 3 Extension Infralevatoric 1 Supralevatoric 2 Hyperintensity on T2-wighted images Absent 0 Mild 4 Pronounced 8 Collections Absent 0 Present 4 Rectal wall involvement Normal 0 Thickened 2 Van Assche et al. Am J Gastroenterol 2003 6
Current Management Strategies: the FACTS Antibiotics Study Patients Intervention Comparison Duration Outcome Thia et al. 2009 Maeda et al. 2010 25 74 Cipro Metro Metro (ointment) Placebo 10w Remission FDA: 30% ciprofloxacin 0% metronidazole 12.5% placebo, ns. Placebo 4w Reduction in PDAI: ns. West et al. 2004 Dewint et al. 2014 24 Cipro + IFX IFX 18w 76 Cipro + ADA ADA 24w Response FDA at w18: 73% Cipro + IFX 39% IFX alone, p=0.12, ns. Response FDA at w12: 71% Cipro + ADA 47% ADA, p=0.047 Response at w24: ns. FDA: Fistula Drainage Assessment 7
Current Management Strategies: the FACTS Immunosuppresives Thiopurines no RCTs assessing fistulas as the primary endpoint MTX no relevant trial data Cyclosporin A no relevant trial data Tacrolimus Study Patients Intervention Comparison Duration Outcome Sandborn et al. 2003 48 Tacrolimus (p.o.) Placebo 10w Response: 43% vs. 8% placebo, p=0.004 Remission: ns. Hart et al. 2007 12 Tacrolimus (ointment) Placebo 12w Response: ns. 8
Current Management Strategies: the FACTS Anti-TNF Study Patients Intervention Comparison Duration Outcome Present et al. 1999 Sands et al. 2004 94 IFX Placebo 18w 195 IFX Placebo 54w Response FDA: 62% IFX vs. 26% placebo, p=0.002 Remission FDA: 46% IFX vs. 13% placebo, p=0.001 Time to LOR: 40w IFX vs. 14w placebo p<0.001 Remission FDA: 36% IFX vs. 19% placebo p=0.009 FDA: Fistula Drainage Assessment 9
Current Management Strategies: the FACTS Others Study Patients Intervention Comparison Duration Outcome Fukuda et al. 2008 Reinisch et al. 2014 57 AST-120* Placebo 8w 249 AST-120* Placebo 8w Response: 37.0% AST-120 vs. 10.0% placebo, p=0.025 Remission: 29.6% AST-120 vs. 6.7% placebo, p=0.035 Response: 27.0 vs. 34.6%, ns. *Spherical carbon adsorbent 10
Current Management Strategies: the FACTS Surgery Study Patients Intervention Comparison Duration Outcome Lindsey et al. 2002 42 Fibrin glue Conventional treatment (fistulotomy in simple and seton +/- advancement flap in complex fistulas) 8w Remission: simple: 50% fistula plug vs. 100% fistulotomy, p=0.06 complex: 69% fibrin glue vs. 13% conventional, p=0.003 Grimaud et al. 2010 77 Fibrin glue Placebo 8w Remission: 38% fibrin glue vs. 16% placebo, p=0.04 Senejoux et al. 2015 106 Seton removal + Fistula plug Seton removal 12w Remission: 31% fistula plug vs. 23% seton removal, p=0.19 11
Current Management Strategies: the GAPS Outcome measures Validated tool to evaluate response to treatment PROM? Treatment repertoire Little progress in the past decade Limited long-term efficacy Quality of evidence: RCTs with fistula healing as the primary endpoint are scarce 12
Conclusions Fistulising disease is common and incidence increases with disease duration Optimal, multidisciplinary management remains challenging Validated clinical trial endpoints are needed New treatment modalities are needed 13
Thank You With thanks to Krisztina Gécse & co-authors for A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn s disease. Gut, 2014, 63(9):1381-92. 14
Cx601 ADMIRE-CD Trial Week-24 and Week-52 Results Prof. Julián Panés, M.D. Head of Gastroenterology Department at Hospital Clinic, Barcelona, Spain President of the European Crohn s and Colitis Organization Inflammatory Bowel Disease IDIBAPS research team
Background Crohn s disease (CD) is complicated by perianal fistulas in 30 50% of patients 1 Perianal fistulas in Crohn s disease are difficult to treat with currently available therapies and often leads to pain, swelling, infection and incontinence 70 80% of perianal fistulas are classified as complex 2,3 Most challenging to treat Often refractory to conventional treatment and anti- TNF agents 4-8 60 70% of patients relapse after stopping treatment and few achieve long-term remission 9-14 Cx601 is a suspension of 120 x 10 6 allogeneic or donorderived expanded adipose-derived stem cells (eascs) administered locally, which has shown to be efficacious and well tolerated in CD patients with complex perianal fistulas 15 1. Schwartz DA, et al. Gastroenterology. 2002;122:875-80; 2. Eglinton TW, et al. Dis Colon Rectum. 2012;55:773-7; 3. Bell SJ, et al Aliment Pharmacol Ther. 2003;17:1145-51; 4. Present DH, et al. N Engl J Med. 1999;340:1398-405; 5. Sands BE, et al. N Engl J Med. 2004;350:876-85; 6. Pearson DC, et al. Ann Intern Med. 1995;123:132-42; 7. Thia KT, et al. Inflamm Bowel Dis. 2009;15:17-24; 8. Present DH, N Engl J Med. 1980;302:981-7; 9. Domenech E, et al. Aliment Pharmacol Ther. 2005;22:1107-13; 10. Goldstein ES, et al. Inflamm Bowel Dis. 2004;10: 79-84; 11. Korelitz BI, Present DH. Dig Dis Sci. 1985;30:58-64; 12. Brandt LJ, et al. Gastroenterology. 1982;83:383-7; 13. Solomon MJ, et al. Can J Gastroenterol. 1993;7:571-3; 14. Molendijk I, et al. Inflamm Bowel Dis. 2014;20:2022-8; 15. Panés J, et al. Lancet. 2016;388:1281-90. 2
ADMIRE-CD 1 study design/objective Phase 3, randomized, double blind, placebo-controlled, multicenter study 2 Objective: determine the efficacy and safety of a single administration of Cx601 for the treatment of complex perianal fistulas in CD patients at 24 weeks as well as over the long term (at 52 weeks) *Standard of care (SOC): antibiotics, immunosuppressants, and/or anti-tnf therapies; Fistula preparation visit, including examination under anaesthesia, fistula curettage, and seton placement as clinically indicated at least 2 weeks before investigational product administration; At treatment administration visit, patients had the seton(s) removed if present. MRI, magnetic resonance imaging. 1. Panés J, et al. Lancet. 2016;388:1281-90; 2. MRI, magnetic resonance imaging 3
ADMIRE-CD study key selection criteria/endpoints Key selection criteria CD diagnosed 6 mo earlier and with non-/mildly active luminal disease at inclusion (CDAI 220) Patients with complex perianal fistulas with 2 internal and 3 external openings Fistula draining 6 weeks before inclusion Patients with inadequate response to at 1: antibiotics, immunosuppressants and / or anti-tnfs 1 Absence of proctitis Primary endpoint Combined remission at Week 24: clinical assessment of closure* of all treated external openings that were draining at baseline, and absence of collections >2 cm of treated perianal fistulas, confirmed by blinded centrally read MRI 2 Secondary endpoints included: Key secondary endpoints: clinical remission and response at Week 24 Combined remission, clinical remission, relapse and response at Week 52 Safety *Defined as absence of draining despite gentle finger compression; Defined as closure of all treated external openings that were draining at baseline despite gentle finger compression; Defined as closure of at least 50% of all treated external opening that were draining at baseline.; 1. TNF, tumor necrosis factor; 2. MRI, magnetic resonance imaging 4
Patient disposition up to Week 52 *ITT (intention-to-treat population): all randomized patients; mitt (modified intention-to-treat): patients randomized, treated, and with 1 post-baseline assessment; Patients who received study treatment. ICF, informed consent form. Efficacy was assessed in the m- ITT population; safety was assessed in the safety population 5
Baseline patient and disease characteristics mitt population, n=204 Cx601 n=103 Control n=101 Mean age, y (SD) 38.9 (13.1) 37.7 (13.3) Men, n (%) 57 (55.3) 53 (52.5) Caucasian, n (%) 96 (93.2) 92 (91.1) Mean CD duration, y (SD) 11.8 (9.8) 11.4 (9.0) Mean PDAI score (SD) 6.7 (2.5) 6.5 (2.8) Fistula internal openings (safety population) 0 0 1 (1.0%) 1 82 (79.6%) 89 (88.1%) 2 21 (20.4%) 11 (10.9%) Fistula external openings (safety population) 1 58 (56.3%) 72 (71.3%) 2 37 (35.9%) 25 (24.8%) 3 8 (7.8%) 4 (4.0%) Mean CDAI score (SD) 87.8 (48.3) 93.3 (55.0) Mean IBDQ score (SD) 173.5 (31.6) 169.4 (36.1) CDAI, Crohn s Disease Activity Index; IBDQ, Inflammatory Bowel Disease Questionnaire; mitt, modified intention-to-treat; PDAI, Perianal Disease Activity Index; SD, standard deviation; CD, Crohn s Disease; Panés J, et al. Lancet. 2016;388:1281-90;supplementary appendix.. 6
Primary endpoint: Combined remission (Week 24) mitt population, n=204 p= 0.021 (97.5%CI) Δ= 15.8 percent points 51.5 % 35.6 % Cx601 Placebo Combined Remission: clinical assessment of closure at week 24 of all treated external openings that were draining at baseline, despite gentle finger compression, and absence of collections > 2 cm of the treated perianal fistulas confirmed by centrally blinded MRI assessment by week 24 (α=0.025; β=0.20; power=80%) 1. Panés J, et al. Lancet. 2016;388:1281-90. 25 7
Clinical remission & response (Week 24) mitt population, n=204 mitt Population (N=204) Clinical Remission P= 0.057 (95%CI) Δ= 12.8 percent points Response P=0.045 (95%CI) Δ= 13.5 percent points 68.9% 55.4% 55.3 % 42.6 % Cx601 Control Cx601 Control Clinical Remission: clinical assessment of closure at week 24 of all treated external openings that were draining at baseline, despite gentle finger compression 1. Panés J, et al. Lancet. 2016;388:1281-90. 26 8
Time to clinical remission ITT Population, n=212 50% of Cx601-treated patients achieved Clinical Remission after 6.7 weeks while this occurred in placebo-treated patients after 14.6 weeks (HR 95% CI 0.6 (0.4-0.8)) 9
Combined remission at Week 52 mitt population, n=204 Week 24 Week 52 p= 0.021 (97.5%CI) Δ= 15.8 percent points p= 0.010 (95%CI) Δ= 17.7 percent points 51.5 % 35.6 % 56.3 % 38.6 % Cx601 Placebo Cx601 Placebo 28 10
Patients with no relapse at Week 52 Patients in Combined Remission at Week 24 and with no Relapse* at Week 52 75.0% 55.9% Δ= 19.1 percent points Cx601 Control Relapse: reopening of any of the treated external openings with active drainage as clinically assessed, or development of a perianal collection > 2cm of the treated perianal fistulas confirmed by centrally blinded MRI assessment in patients with Clinical Remission at a previous visit 29 11
Clinical remission up to Week 52 mitt population, n=204 Week 24 Week 52 P= 0.057 (95%CI) Δ= 12.8 percent points p= 0.013 (95%CI) Δ= 17.6 percent points 55.3 % 42.6 % 59.2% 41.6% Cx601 Control Cx601 Control 30 12
Clinical case Cx601 in CD perianal fistula Baseline Week 24 Week 52 13
Safety profile up to Week 52 Safety Population, n=205 Week 24 Week 52 Patients, n (%) Cx601 n=103 Control n=102 Cx601 n=103 Control n=102 TEAEs 68 (66.0) 1 66 (64.7) 1 79 (76.7) 74 (72.5) Drug-related 18 (17.5) 1 30 (29.4) 1 21 (20.4) 27 (26.5) Withdrawn due to AEs 5 (4.9) 1 6 (5.9) 1 9 (8.7) 9 (8.8) TESAEs 18 (17.5) 1 14 (13.7) 1 25 (24.3) 21 (20.6) Drug-related 5 (4.9) 1 7 (6.9) 1 7 (6.8) 7 (6.9) Withdrawn due to SAEs 4 (3.9) 4 (3.9) 6 (5.8) 7 (6.9) TESAEs in 2.0% of patients* Anal abscess 9 (8.7) 1 7 (6.9) 1 14 (13.6) 8 (7.8) New anal fistula 1 (<1.0) 1 (<1.0) 4 (3.9) 1 (<1.0) Crohn s disease 0 1 (<1.0) 0 3 (2.9) No deaths occurred during the study *In either treatment group. TE(S)AEs, treatment emergent (serious) adverse events. 14
Conclusions Cx601 demonstrated significantly greater efficacy compared to control in achieving the primary endpoint, combined remission at Week 24, in the mitt (p= 0.021) population 1 A numerically higher proportion of patients treated with Cx601 met the key secondary endpoints Clinical Remission and Response at Week 24, in population Combined remission maintained at Week 52, with superiority of Cx601 vs. control (56.3% vs. 38.6%; p=0.010) with only a single administration of Cx601 Of those patients who achieved combined remission at Week 24, a numerically greater proportion of patients receiving Cx601 vs. control had no relapse at Week 52 (75.0% vs. 55.9%; p=0.052) Significantly more patients treated with Cx601 compared to the control group achieved clinical remission at Week 52 (59.2% vs. 41.6%; p=0.013) Favorable tolerability of Cx601 was maintained over long term 1. Panés J, et al. Lancet. 2016;388:1281-90 15
Q&A Dr. Marie Paule Richard Chief Medical Officer TiGenix Dr. William Sandborn Professor of Medicine and Adjunct Professor of Surgery Chief, Division of Gastroenterology Vice Chair for Clin.Ops., Department of Medicine Director, UCSD IBD Center University of California San Diego and UC San Diego Health System Dr. Julian Panés Head of Gastroenterology Department at Hospital Clinic Barcelona (Spain) and of the Inflammatory Bowel Disease IDIBAPS research team, President of the European Crohn s and Colitis Organization Uthra Sundaram VP, GI Therapeutic Area Global Commercial Leader at Takeda Pharmaceuticals 34
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