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1 Corporate Presentation The treatment of perianal December fistula 2015in Crohn s disease patients Key Opinion Leader Event 8 th May 2017

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 statements 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 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

4 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

5 Epidemiology of Crohn s Disease Fistulas *Enterovesical and entero-intra-abdominal fistulas Schwartz et al. Gastroenterology

6 Epidemiology of Crohn s Disease Fistulas Schwartz et al. Gastroenterology

7 Parks Classification of Perianal Fistulas Primary tracts Superficial Intersphinteric Transsphincteric Suprasphincteric Extrasphincteric Secondary tracts Infralevator Supralevator Horseshoe Parks et al. Br J Surg

8 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

9 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

10 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

11 Current Management Strategies: the FACTS Antibiotics Study Patients Intervention Comparison Duration Outcome Thia et al Maeda et al 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 Dewint et al 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

12 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 Tacrolimus (p.o.) Placebo 10w Response: 43% vs. 8% placebo, p=0.004 Remission: ns. Hart et al Tacrolimus (ointment) Placebo 12w Response: ns. 8

13 Current Management Strategies: the FACTS Anti-TNF Study Patients Intervention Comparison Duration Outcome Present et al Sands et al 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

14 Current Management Strategies: the FACTS Others Study Patients Intervention Comparison Duration Outcome Fukuda et al Reinisch et al 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

15 Current Management Strategies: the FACTS Surgery Study Patients Intervention Comparison Duration Outcome Lindsey et al 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 Fibrin glue Placebo 8w Remission: 38% fibrin glue vs. 16% placebo, p=0.04 Senejoux et al Seton removal + Fistula plug Seton removal 12w Remission: 31% fistula plug vs. 23% seton removal, p=

16 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

17 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

18 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):

19 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

20 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 % 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 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: ; 4. Present DH, et al. N Engl J Med. 1999;340: ; 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: ; 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:

21 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: ; 2. MRI, magnetic resonance imaging 3

22 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

23 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

24 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) (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) (31.6) (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: ;supplementary appendix.. 6

25 Primary endpoint: Combined remission (Week 24) mitt population, n=204 p= (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:

26 Clinical remission & response (Week 24) mitt population, n=204 mitt Population (N=204) Clinical Remission P= (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:

27 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 ( )) 9

28 Combined remission at Week 52 mitt population, n=204 Week 24 Week 52 p= (97.5%CI) Δ= 15.8 percent points p= (95%CI) Δ= 17.7 percent points 51.5 % 35.6 % 56.3 % 38.6 % Cx601 Placebo Cx601 Placebo 28 10

29 Patients with no relapse at Week 52 Patients in Combined Remission at Week 24 and with no Relapse* at Week % 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

30 Clinical remission up to Week 52 mitt population, n=204 Week 24 Week 52 P= (95%CI) Δ= 12.8 percent points p= (95%CI) Δ= 17.6 percent points 55.3 % 42.6 % 59.2% 41.6% Cx601 Control Cx601 Control 30 12

31 Clinical case Cx601 in CD perianal fistula Baseline Week 24 Week 52 13

32 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

33 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:

34 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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