Optimizing Management of IBD: Beyond Anti-TNFs

Remo Panaccione, MD, FRCPC Director, Inflammatory Bowel Disease Clinic Professor of Medicine University of Calgary

1 Disclosures: R. Panaccione

 Consultant for: AbbVie, ActoGeniX, AGI Therapeutics, Alba Therapeutics Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Aptalis, Astellas, Athersys, Atlantic Healthcare, BioBalance, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek, Cellerix, Cerimon, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle, Eisai Medical Research, Elan, EnGene, Eli Lilly, Enteromedics, Exagen Diagnostics, Ferring, Flexion Therapeutics, Funxional Therapeutics, Genentech, Genzyme, Gilead, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood, Janssen, KaloBios, Lexicon, Lycera, Meda, Merck & Co., Merck Research Laboratories, MerckSerono, Millennium, Nisshin Kyorin, Novo Nordisk, NPS Pharmaceuticals, Optimer, Orexigen, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb, Purgenesis Technologies, Receptos, Relypsa, Salient, Salix, Santarus, Shire Pharmaceuticals, Sigmoid Pharma, Sirtris (a GSK company), S.L.A. Pharma (UK), Targacept, Teva, Therakos, Tillotts, TxCell SA, UCB Pharma, Vascular Biogenics, Viamet and Warner Chilcott UK.

 Speaker’s fees for: Abbvie, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire, Takeda

 Advisory Board for: Abbvie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Biogen Idec, Eisai, Ferring, Genentech, Janssen, Merck, Shire, Elan, Glaxo-Smith Kline, Hospira, Pfizer, Bristol-Myers Squibb, Takeda, Cubist, Celgene, Salix

 Research/Educational Support from: Abbvie, Ferring, Janssen, Shire Takeda

2 Objectives

 1. Discuss new treatment targets in IBD – Where we were – Where we are – Where we are going  2. Review the latest data that will impact your clinical practice in 2016 and beyond

 3. Discuss positioning of new therapies in IBD

3 Managing IBD in 2016: An evolution in IBD care

Crohn’s disease (CD) 5-ASA Steroids Anti-TNFs for CD for UC5 Azathioprine1 Initial report Anti-TNFs for CD Biosimilars

1995 2000 2005 2010 2015/16

5-ASA Steroids Azathioprine, Anti-TNFs for UC Vedolizumab for CD5 Cyclosporin1,2 Ulcerative Colitis (UC) Surgery

1. Mulder DJ, et.al. A tale of two diseases: The history of inflammatory bowel disease. J Crohn Colitis 2013; 8:341–348 2. Botoman AV, et al. Management of Inflammatory Bowel Disease. Am Fam Physician 1998;57:57–68 3. National Institute for Health and Care Excellence technology appraisal guidance [TA40]: The clinical effectiveness and cost effectiveness of for Crohn's Disease https://www.nice.org.uk/guidance/ta40. 4. National Institute for Health and Care Excellence technology appraisal guidance [TA329]: Infliximab, and for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): http://www.nice.org.uk/guidance/ta329/chapter/about-this-guidance. 5. National Institute for Health and Care Excellence technology appraisal guidance [TA342] - Vedolizumab for treating moderately to severely active ulcerative colitis. June 2015. http://www.nice.org.uk/guidance/ta342. Last accessed June 2015. 4 Introducing Biological Therapy: Where we were  The biologic revolution began over 15 years ago with the approval of infliximab for the treatment of moderate to severe CD1.

 Despite the development and approval of “newer” anti TNFs, the overall induction of remission in RCTs was ~30-50%2-5 and maintenance of remission was ~20-40%.6-10

 Therefore there is a need to develop new agents for the treatment of IBD.

. 1. Schreiber S, et al. Gastroenterology 2005;129:807–18. 1. Schreiber S, et al. N Engl J Med 2007;357:239–50. 2. Sandborn WJ, et al. N Engl J Med 2007;357:228–38. 2. Hanauer SB, et al. Lancet 2002;359:1541–9. 3. Hanauer SB, et al. Gastroenterology 2006;130:323–33. 3. Colombel JF, et al. Gastroenterology 2007;132:52–65. 4. Targan SR, et al. N Engl J Med 1997;337:1029–35. 4. Sandborn WJ, et al. N Engl J Med 2007;357:228–38.

5 Where we are: Lessons learned during the anti-TNF era  Anti-TNFs are safe

 Antibodies are bad; adequate drug levels are good

 There is value in combination therapy

 Treating early is better

 We can treat beyond symptoms

 We can decrease surgical /hospitalization rates

 We do better in real life than in clinical trials

6 Phenotypic features of Crohn's disease associated with anti-TNF treatment failure

Retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry. Probability of surgery over time after anti-TNF prescription depending on phenotype at prescription (B1=inflammatory, B2=stricturing, B2L1=ileal stricturing , B3=penetrating)

0.5 B2 0.4 B2L1 0.3 B3 0.2 B1 0.1

Cumulative probability ofprobability Cumulative 0

major abdominal surgery major abdominal surgery (%) 0 1 2 3 4 5 Follow-up in years

7 Moran, Panaccione et al. Clin Gastroenterol Hepatol 2014 Mar;12(3):434-42 Randomised Evaluation of an Algorithm

for Crohn’s Treatment (REACT 1) 20 practices 20 practices

60 patients per practice

Symptomatic remission (HBI≤4 and no corticosteroids) Usual care Accelerated care treatment algorithm Conventional management 100 Early combined immunosuppression Time to first hospitalisation, surgery or complication 80 p=0.790 p=0.498 p=0.389 p=0.250 40 HR (95% CI) = 0.73 (0.62, 0.86), p<0.001 (%) (%) 60 34.7% 30 CM 27.4% ECI 40 20 Patients Patients 20 10

0 or complications 0 Baseline Month 6 Month 12 Month 18 Month 24 Hospitalisation, surgery 0 3 6 9 12 15 18 21 24 Time (months) REACT cluster randomisation: 898 CD in conventional management vs 1094 CD in early combined immunosuppression

8 Khanna R, et al. Lancet 2015 8 Temporal trend analysis of colectomy rates: stratified by emergent vs. elective colectomy

Colectomy rates in adults hospitalised for a flare of UC 6 Total 5 Elective Emergent 4

3

2

1

0 Incidence per 100,000 population population 100,000per Incidence 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

UC, ulcerative colitis. Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates.

9 Kaplan GG, et al. Am J Gastro 2012; 107:1879–87. Real Life vs. Clinical Trials: The example of ADA and IFX in UC

10 Sandborn et al. Curr Med Res Opin. 2016 Mar 30:1-9 Many biologic agents have failed in IBD

 Anti-IL-2 receptor – Basiliximab1 – Daclizumab2  Anti-CTLA-4 – Abatacept3  Anti-CD3 receptor – Visilizumab4

1. Sands BE, et al. Gastroenterology 2012 Aug;143:356–64. 2. Van Assche G, et al. Gut 2006;55:1568–74. 3. Sandborn WJ, et al. Gastroenterology 2012;143:62–69. 4. Sandborn WJ, et al. Gut 2010;59:1485–92.

11 The IBD therapeutic pipeline

TNFK-005 Neovacs IL inhibitors Phase I Chemokine receptors C326 QPharm SCH-900222 Merck & Co Phase II Centocor CCX282-B GSK Vidofludimus 4SC CCX-025 GSK Phase III PF-04236921 Pfizer Immunomodulators PF 05230900 Pfizer ZP1848 Zealand Registration QAX576 Novartis AMG 827 Amgen RDP 58 Genzyme GSK Launched GSK 1070806 AIN 457 Novartis Rifaximin EIR laquinimod Teva / Active Biotech AlphaWessermann ELND-004 Elan/Biogen Idec Elan/Biogen Idec PF-547659 Pfizer Novo Nordisk NN8555 CAM inhibitors Pfizer Vedolizumab Tofacitinib Adalimumab AbbVie Millenium / Takeda AJM-300 Ajinomoto UCB Infliximab HMPL-004 Hutchinson JAK3 inhibitors Centocor Remestemcel-L Osiris Ozoralizumab Pfizer PDA-001 Celgene Cellular Cellerix Debiaerse OvaSave TXCell Neovacs Stem cell therapies TNF-α inhibitors

Adapted from Danese S. Gut 2012;61:918–32. 12 Emerging therapies in IBD  Leukocyte Trafficking inhibitors  Anti S1 P1 – Vedolizumab – Ozanimod – – Anti-MAdCAM  Anti-SMAD 7  Anti IL-12/23 – Mongersen – Ustekinumab – – Rizankinumab  Jak inhibitors – Tofacitinib

13 Lymphocytes Preferentially Migrate to Particular Tissues Throughout the Body

• As part of the body’s adaptive immune response, lymphocytes are imprinted for migration to areas of inflammation in certain tissues • Lymphocytes become imprinted in certain lymphoid tissues in which they first encounter antigen • After this initial activating encounter, lymphocytes preferentially leave the blood in the same type of tissue in which they became activated

14 Salmi M, Jalkanen S. Immunol Rev. 2005;206:100-113. Agace W. Nat Rev Immunol. 2006;6:682-692. α4β7 Integrin–MAdCAM-1 is One of the Interactions That Contributes to Chronic Inflammation in UC and CD

MAdCAM-1 MAdCAM-1 Accumulation of excess infiltrating lymphocytes in the gastrointestinal tissue

Memory T lymphocyte

α4β7 α4 β7 integrin subunit subunit

α4β7−MAdCAM-1 interaction has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC MAdCAM-1=mucosal addressin cell adhesion molecule-1 and CD

15 Briskin M, et al. Am J Pathol. 1997;151:97-110. Vedolizumab is a novel gut-selective anti-inflammatory biologic

 Humanized mAb that binds exclusively to the α4β7 integrin heterodimer – Does not bind to α4β1 or αEβ7 integrin1  Selective antagonist of α4β7 integrin – Inhibits adhesion to MAdCAM-1 and fibronectin, but not VCAM-11  Contains a mutated Fc region, preventing elicitation of2 – Complement-mediated cytotoxicity – Antibody-dependent cellular cytotoxicity – Cytokine release

Fc, fragment crystallisable; mAb, ; VCAM-1, vascular cell adhesion molecule-1

. 16 1. Soler D, et al. J Pharmacol Exp Ther 2009;330:864–75;. GEMINI I: vedolizumab induction therapy for UC

 Phase 3, multicentre, prospective, RCT (N=374) – Randomised 3:2, patients received VDZ 300mg (IV) or PBO on days 1 & 15  Mod-to-severe active UC (Mayo 8.6, mean), despite conventional therapy – UC diagnosis ~6.4 yrs, CS (~54%), IS (~31%) and anti-TNF failures (~39%)  Rates of AEs and serious AEs were similar between VDZ and PBO groups Week 6 outcomes after 2-dose induction All p<0.0001 VDZ vs. PBO Primary endpoint 100 PBO (n=149) VDZ 300 mg (n=225) 80

60 47 41 40 25 17 25 20 5 0

Patients (%) Patients Response Remission Mucosal healing

AE, adverse event; CS, corticosteroid; IS, immunosuppressant; RCT, randomised controlled trial

17 Feagan et al, N Engl J Med. 2013 Aug 22;369(8):699-710. GEMINI I: vedolizumab in UC maintenance

Primary and secondary efficacy endpoints 100 Placebo (n=126) VDZ 300 mg every 8 weeks (n=122) 80 VDZ 300 mg every 4 weeks (n=125) p<0.001 56.6 p<0.001 56 60 p<0.0001 52 51.6 41.8 44.8 40 23.8 19.8 20 15.9 Patients (%) Patients 0 Clinical remission Durable clinical Mucosal healing at 52 weeks response at 52 weeks (at 6 and 52 weeks) 18 Feagan BG et al, N Engl J Med. 2013 Aug 22;369(8):699-710. GEMINI I: vedolizumab in UC maintenance

100 Steroid-free Durable clinical remission clinical remission 80

* 60 * 45.2 40 31.4 ** *** 20.5 24.0 20 13.9 8.7

Percent of subjects of Percent 0 Placebo VDZ VDZ Placebo VDZ VDZ N=72 300 mg q8w 300 mg q4w N=126 300 mg q8w 300 mg q4w N=70 N=73 N=122 N=125

*p<0.0001, **p=0.0079, ***p=0.0009 vs placebo.

19 Feagan BG et al, N Engl J Med. 2013 Aug 22;369(8):699-710. GEMINI II: vedolizumab in CD induction

Induction ITT population Patients with prior anti-TNF failure Patients without prior anti-TNF failure 45 (n=175) (n=193) Placebo 40 38.3 VDZ 35 30 28.2 23.8 25 22.9 20 18.3 15 Patients (%) Patients (%) 10.5 9.0 10 4.3 5 0 Clinical remission CDAI-100 response Clinical remission CDAI-100 response 6.2 1.0 9.3 10.1 95% CI: -9.1, 21.3 -11.8, 13.7 -0.2, 18.8 -3.3, 23.4

20 Sandborn W et al N Engl J Med. 2013 Aug 22;369(8):711-21 GEMINI II: vedolizumab in CD maintenance

Maintenance ITT population ** * 50 45.5 43.5 45 ** Placebo 39.0 ** 40 36.4 VDZ Q8wk * VDZ Q4wk 35 30.1 31.7 * 28.8 30 25 21.6 21.4 15.9 16.2 20 14.4

Patients (%) Patients (%) 15 10 5 0 Clinical remission CDAI-100 response CS-free remission† Durable remission 17.4 14.7 13.4 15.3 15.9 12.9 7.2 2.0 *p<0.05,**p<0.01 †CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.

21 Sandborn W et al N Engl J Med. 2013 Aug 22;369(8):711-21 Is there a better way forward with vedolizumab?

Bridging: co-induction with steroids? GEMINI II: Clinical Remission at Week 6 By Concomitant Use at Week 0 30 PBO (n=148) 25 VDZ (n=220) 20.9 20 18.4 15 12.1 10 7.7 8.0 8.1 7.7 Patients, % Patients, % 4.4 5 0 VDZ CS only and VDZ IMM only and VDZ CS and IMM and VDZ

CS, corticosteroid; IMM, immunomodulator; VDZ, vedolizumab.

22 Colombel JF, et al. J Crohns Colitis 2015;9;S344. Abstract P528. Is there a better way forward with vedolizumab? Define timeline for response? – Appropriate induction therapy / maintenance therapy for responders – Role of combination therapy is being defined – Allow 10-14 weeks for maximal induction response GEMINI II: CDAI-100 Response Among Week 6 Non-responders* 30 PBO (n=69) 23.9 25.4 VDZ (n=351) 21.7 23.1 20 13.2 11.6 11.6 10 7.2 8.7 7.2

Patients, Patients, % 0 Week 10 Week 14 Week 18 Week 22 Week 52

*In GEMINI II, 31.4% patients in the vedolizumab and 25.7% of patients in the placebo group had a CDAI-100 response at week 6. This is a post-hoc analysis; therefore P values are not reported.

23 Sandborn WJ, et al. J Crohns Colitis 2014;8;S274-275. Abstract P497. Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years Vedolizumab and Infections: Exposure-Adjusted Incidence Rates in CD

89.7 100 PBO (n=355)a VDZ (n=1723)b 80 68.6 60 37.2 40 (95% CI) 29.5 20 9.7 6.9 with event /100 PY /100PY event with Number of patients patients of Number 7.7 6.5 5.2 6.1 5.3 4.6 3.8 4.6 3.9 3.8 3.6 2.1 2.1 2.2 2.3 1.5 0.8 0.8 0 3.6 3.0 0.8 1.5 0.8 1.5 0.8 0.8 0.8 0 0.6 0.7 0 0.9 0.4 0.3

Data shown for patients with any infection and common infections (defined as ≥0.5 patient events/100 PY in any patient group). aGEMINI 2 and 3 studies. bStudies C13004, GEMINI 2 and 3, and GEMINI LTS. cMedDRA PTs listed under ‘infections and infestations’ system organ class. dMedDRA high-level terms Candida infections, fungal infections NEC, tinea infections. eMedDRA PTs listed under ‘sepsis, bacteremia, viremia and fungemia NEC’ high-level term. CD, Crohn’s disease; GI, gastrointestinal; CI, confidence interval; LTS, long-term safety; MedDRA, Medical Dictionary for Regulatory Activities; NEC, not elsewhere classified; PBO, placebo; PT, preferred term; PY, person-year; VDZ, vedolizumab.

 24 Colombel J-F, et al. Gut 2016;0:1–13. doi:10.1136/gutjnl-2015-311079. Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years Vedolizumab and Serious Infections: Exposure-Adjusted Incidence Rates in CD

7 5.6 PBO (n=355)a 3.0 6 VDZ (n=1723)b 5 4 2.4 3 0 0.8 0 0 0.8 0 0 0 0 2 1 0.5 0.3 0.3 <0.1

event /100 PY /100PY (95% event CI) 0.1 0.1 <0.1 <0.1 Number of patients with ofpatients Number 0

AGEMINI 2 and 3 studies. bStudies C13004, GEMINI 2 and 3, and GEMINI LTS. cMedDRA PTs listed under ‘infections and infestations’ system organ class. dMedDRA PTs anal abscess, perirectal abscess, rectal abscess, rectovaginal septum abscess, abdominal abscess, abscess intestinal, abscess, perineal abscess, pelvic abscess. eMedDRA high-level terms Candida infections, fungal infections NEC, tinea infections. fMedDRA PTs under ‘sepsis, bacteremia, viremia and fungemia NEC’ high-level term. CD, Crohn’s disease; CI, confidence interval; LTS, long-term safety; MedDRA, Medical Dictionary of Regulatory Activities; NEC, not elsewhere classified; PBO, placebo; PT, preferred term, PY, person-year; VDZ, vedolizumab.

 25 Colombel J-F, et al. Gut 2016;0:1–13. doi:10.1136/gutjnl-2015-311079. Etrolizumab

 Etrolizumab is a humanized mAB that targets the integrin receptors that regulate trafficking and retention of leukocyte/lymphocyte subsets in the intestinal mucosa signals

 Etrolizumab differs from vedolizumab by blocking αEβ7 as well as α4β7

 Etrolizumab is GI specific and targets β7 not α4β1, therefore risk PML thought to be low.

26 Phase II: safety and efficacy of etrolizumab (humanized anti-beta7 mAb) for moderate-to-severe UC

100 Week 10 clinical and endoscopic outcomes (all comers) 80 *p < 0.05 **p < 0.01 vs. PBO 60 Primary endpoint 40 33 ** * ** 23 27 31 21 10 26 21 21 20 15 10 9 15 0 0 8 0 Remission Endoscopic Mucosal Healing Clinical Response Fraction of pts (%) (%) pts of Fraction Remission PBO (n = 41) ETZ 100 (n = 39) ETZ LD + 300 (n = 39) ETZ Pooled (n = 78)

• Phase 2, multicentre, prospective, RCT (N=119) • Randomised 1:1:1, patients received ETZ 100 mg/mo s.c. or 420 mg loading dose between Week 0 & 2 then 300 mg/mo s.c. or PBO for 3 doses • Moderate-to-severe active UC: Mayo ≥5, endoscopy subscore ≥ 2 and RBS ≥1 • UC diagnosis ~9 yrs, mean Mayo ~9, CS (~42%), IS (~38%), anti-TNF failures (~60%) • Rates of AEs were comparable between ETZ and PBO groups

ETZ, etrolizumab; RBS, rectal bleed severity. Clinical remission: Mayo score ≤ 2 with no individual score >1. Endoscopic remission: Mayo endoscopy subscore 0.

27 Vermiere S et al. Lancet. 2014 Jul 26;384(9940):309-18 Phase II: PF-00547659 (Anti-MAdCAM-1 mAb) for Mod-Sev UC TURANDOT Primary and Secondary Endpoints at Week 12 100 PBO (n = 83) PF 7.5 mg (n = 71) PF 22.5 mg (n = 70) 80 PF 75 mg (n = 73) PF 225 mg (n = 70) Primary Endpoint * * 60 54 50 *P < 0.05 vs. PBO 45 38 * 40 * 29 Fraction of Pts (%) of Fraction 28 25 20 17 16 16 14 11 6 8 3 0 Clinical Remission Clinical Response Mucosal Healing • Phase IIa: N = 357 mod-sev UC pts (total Mayo ≥ 6; endo subscore ≥ 2) were randomized to PBO, 7.5 mg, 22.5 mg, 75 mg or 225 mg PF- 00547659, q4w (s.c.) • BL mean Mayo (~8.4); anti-TNF failures (~43%) • PF-00547659 appears to be well-tolerated and not associated with increased rate of infection

28 Vermeire et al. ECCO 2015, Abstract OP021 . Phase II: PF-00547659 (Anti-MAdCAM-1 mAb) for Active Refractory, TNF-Experienced CD OPERA Primary and Secondary Endpoints at Week 12 100 PBO (n = 63) PF 22.5 mg (n = 67) PF 75 mg (n = 64) PF 225 mg (n = 68) 80 65 59 62 58 60 All P = NS 37 39 40 28 29 23 27 24 20 Primary Endpoint 14 Fraction of Pts (%) Fraction 0 Response Remission Remission (CDAI-70) (BL CRP > 18) • Phase IIa: N = 267 CD pts (CDAI 220-450) randomized to PBO, 22.5 mg, 75 mg or 225 mg PF-00547659, q4w (s.c.) • BL disease duration (~11 yrs); mean CDAI (~315); All pts were anti-TNF experienced with elevated hsCRP (> 3.0 mg/L) • Rates of AEs similar, higher numerical GI infections noted in PF vs. PBO

29 D’Haens et al. ECCO 2015, Abstract OP022. S1P Receptor Modulators and the S1P Signalling Pathway

 S1P receptor modulators prevent migration of lymphocytes from lymph nodes to sites of inflammation where they contribute to immune-mediate pathology

S1P receptor modulation

Lymph (high S1P concentration)

Endothelium Lymphocyte Lymphocyte egression egression blocked Lymph node (low S1P concentration) Internalisation and degradation Signalling Signalling

Lymphocyte

S1P S1P1 Internalised S1P Degraded S1P S1P modulators

30 Nielsen OH et al. Exp Opin Invest Drugs. 2016: doi. Phase II Trial of Ozanimod (S1P1 Receptor Modulator) in Mod-Sev UC TOUCHSTONE

Low dose (N=65) High dose (N=67) Placebo (N=65) 100 Clinical Remission Clinical Response Mucosal Improvement (endoscopy score ≤1)

75

* 58.2 53.8 ** 50.7 50 36.9 ** ** 35.4 34.3 33.8 **

Patients (%) Patients 32.8 ** * 26.2 27.7 * 25 20.9 20 16.4* 13.8 12.3 12.3 6.2 6.2

0 Week 8 Week 32 Week 8 Week 32 Week 8 Week 32 *P<0.05 vs placebo; **P<0.01 vs placebo

31 Sandborn et al. NEJM May 2016

Clinical Remission: Mayo Score ≤ 2, no subscore >1; Clinical Response: reduction ≥ 3 points and ≥ 30% of the Mayo score with a dec. RBS of ≥1 or RBS ≤1 Biology and site of action of 12 and 23

 Ustekinumab and are fully human monoclonal IgG1 antibodies

 Ustekinumab bind the p40 subunit of IL-12/23

 Risankizumab is a selective blocker of the IL23 p19 subunit

 Ustekinumab is approved for the treatment of PsA and plaque psoriasis

32 Ustekinumab for induction Therapy in CD: Results of Phase 3 UNITI 1 and UNITI 2: Clinical Remission (CDAI<150)

N=741 N=648

33 Feagan et al. NEJM in press UNITI-2 Ustekinumab Reduces CRP at Weeks 3, 6 and 8 Mean CRP Concentration Change by Week 8 4 all p<0.001 vs. PBO 2 1.03 -0.18 -0.14 0 -2 -3.97 -4.76 -4 -5.97 -6 PBO

Mean Change from from Change Mean UST 130 mg Baseline CRP CRP (mg/L)Baseline -8.61 -8.41 -8.56 -8 UST ~6 mg/kg -10 0 1 2 3 4 5 6 7 8 Weeks Subjects who had insufficient data at the designated analysis time point had their last value carried forward Feagan et al. UEGW 2015, Abstract OP054

34 Feagan et al. NEJM in press Ustekinumab for Maintenance in CD: Results of Phase III

35 Feagan et al. NEJM in press Phase IIa: Induction Study of MEDI2070 (Anti-p19 mAb) for Active, anti-TNF-refractory CD Efficacy Outcomes at Week 8 100 PBO (n = 60) MEDI2070 (n = 59) 80 Primary Endpoint 60 P = 0.010 49 46 P = 0.017 P < 0.001 42 40 27 P = 0.102 27 25 20 15 10 0 Fraction of(%) Pts Fraction Clinical Effect Clinical Remission Clinical Response Clinical + Biomarkers* • Phase II: N = 121 mod-sev CD pts (CDAI 220-450), Randomized to PBO or MEDI2070 700 mg IV at weeks 0 and 4 • BL CDAI ~320; dis. duration (~12 yrs); prior surg. (~45%); 31/58/11% failed 1/2/3 anti-TNF’s • MEDI2070, demonstrated clinical effect and favorable safety profile over 12wks Clinical Effect: CDAI-100 response or CDAI <150) Clinical + Biomarkers: Clinical Effect & ≥50% reduction in BL CRP or FC

36 Sands et al. ECCO 2015, Abstract OP025 Efficacy and Safety of Risankizumab as Induction Therapy in CD Summary of Key Clinical Outcomes at Week 12 100 *p < 0.05 PBO (n = 39) 80 Primary Endpoint RSK 200 mg (n = 41) 60 RSK 600 mg (n = 41) 42* (%) (%) 37* 37 37* 40 27 24 21 20* 15 15 13 20 3

Fraction of Patients of Patients Fraction 0 Remission Response Endoscopic Endoscopic Remission Response • Phase IIb, multicentre, RCT of risankizumab (humanized anti-IL-23p19 mAb) • N=121 randomized to receive i.v. q4w of RSK 200 mg, 600 mg or PBO • Mod-to-sev CD (mean CDAI ~298), CD dx (~13 yrs), aTNF-experienced (94%) • AE rates were similar between RSK and PBO & no dose-related associations Clinical Remission: CDAI of <150 points from BL Clinical Response: CDAI of <150 points or a CDAI reduction from BL of ≥100 points Endoscopic Remission: CDEIS of ≤4 Endoscopic Response: defines as a >50% CDEIS reduction from BL 37 Feagan et al. DDW 2016, Abstract 812a Phase 2 Psoriasis: Risankizumab vs. ustekinumab PASI Results

38 The anti-IL-23 and anti-IL-17 wars in psoriasis

?Best-in-class • Dosing has potential to be the most patient friendly at once every 3 months Biologic? • Potential for durability above IL-12/23 and IL-17s at one year

Comparison of PASI90 Scores at 12 wks Comparison of PASI100 Scores at 12 wks

39 Sources: Humira (CHAMPION and REVEAL), Stelera (PHEONIX 1 and 2), COSENTYX (ERASURE and FIXTURE), (UNCOVER 1, 2, 3), (Merck AAD 2013), (NEJM 2015), BI655066 (EADV 2015) Tofacitinib is a JAK Inhibitor Tofacitinib (CP-690,550) blocks phosphorylation of STAT and downstream activation Cytokine Cytokine Effects on the immune system Stimulate the proliferation and differentiation of Th, Tc, b g IL-2 a B, and NK cells Induce the differentiation of Th0 to Th2 IL-4 Induce Ig switching JAK JAK Promote the development, proliferation and survival of IL-7 T, B, and NK cells IL-9 Stimulate intrathymic T cell development

STAT Promote the proliferation, cytotoxicity and cytokine IL-15 production of NK cells STAT STAT mRNA IL-21 Enhance T and B cell function

 Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor that is being investigated as a targeted immunomodulator for several inflammatory diseases including ulcerative colitis  Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3 over JAK2. Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -21 Ig, immunoglobulin; IL, ; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; Th, T helper; Tc , cytotoxic T cell 1ADIS. Drugs 2010; 10(4): 271-274; 2Coombs J et al. Ann Rheum Dis 2007; 66: 257; 3Li X et al. Presented at the 15th IIRA Conference, Chantilly, Virginia, September 21-24, 2008; 4Rochman Y et al. Nat Rev Immunol 2009; 9(7): 480-490 4040 Efficacy and Safety of Tofacitinib in Phase 3 Moderate to Severe UC

Tofacitinib 10 mg BID (n=476) Placebo (n=122) Tofacitinib 10 mg BID (n=429) Placebo (n=112) OCTAVE Induction 1 OCTAVE Induction 2 60 Remission Mucosal Healing 60 Remission Mucosal Healing Δ15.7 50 *** 50 Difference from placebo ***Δ 16.8 ** 40 Δ10.3 31.3 40 ***Δ 13.0 28.4 30 30 18.5 15.6 16.6 20 8.2 20 11.6 10 10 3.6 Patients (%) Patients Patients (%) Patients 0 0 Overall Overall Overall Overall 60 Δ13.3 60

50 50 Δ17.3 39.6 Δ9.4 36.4 40 Δ17.9 40 Δ13.5 Δ15.6 25.2 26.3 30 Δ11.1 24.0 30 Δ12.0 22.1 21.8 15.8 19.1 20 12.6 20 12.0 6.2 8.5 6.2 Patients (%) Patients Patients (%) Patients 10 1.5 10 0 0 0 TNFi- TNFi- TNFi- TNFi- TNFi- TNFi- TNFi- TNFi- treated naive treated naive treated naive treated naive ● Safety data showed no new or unexpected observations from results in tofacitinib studies in other populations **P<0.01 vs placebo; ***P<0.001 vs placebo. BID=twice daily; TNFi= inhibitor.

Sandborn WJ et al. ECCO 2016. Abstract A-1213. 41 Onset of Action of Tofacitinib in Phase 3 OCTAVE Induction Studies

OCTAVE Induction 1 OCTAVE Induction 2 Baseline Week 2 Week 4 Week 8 Baseline Week 2 Week 4 Week 8 0.0 0.0

-0.5 -0.5

-1.0 -1.0

-1.5 -1.5

-2.0 -2.0 *** *** -2.5 -2.5

-3.0 *** -3.0 *** *** *** -3.5 Placebo (N=122) -3.5 Placebo (N=112) in Partial Mayo Score (SE) Score Mayo Partial in

Mean Change From Baseline From Change Mean Tofacitinib 10 mg BID (N=476) Tofacitinib 10 mg BID (N=429) -4.0 -4.0 Rapid and significant improvements in partial Mayo score were observed as early as Week 2

***P<0.001 vs placebo (linear mixed-effects model). BID=twice daily. BID=twice daily; SE=standard error.

42 Tofacitinib for Maintenance Treatment of Ulcerative Colitis

Pfizer press release July 28, 2016

“Pfizer Inc. announced today top-line results from Oral Clinical Trials for tofAcitinib in ulceratiVE colitis (OCTAVE) Sustain, the third Phase 3 study of tofacitinib citrate being investigated in patients with moderately to severely active ulcerative colitis (UC).

Top-line results from the OCTAVE Sustain study showed that the proportion of patients in remission at Week 52, the primary efficacy endpoint, was significantly greater in both the tofacitinib 5 and 10 mg BID groups compared to placebo. No new or unexpected safety findings for tofacitinib were observed in the study.”

BID=twice daily. Pfizer press release. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_positive_top_line_results_from_pivotal_ phase_3_maintenance_trial_of_oral_xeljanz_tofacitinib_citrate_in_ulcerative_colitis. July 28, 2016. Inhibition of IL-6

 IL-6's role as an anti- inflammatory cytokine is mediated through its inhibitory effects on TNF- alpha and IL-1, and activation of IL-1ra and IL- 10.

 PF-04236921 is a fully human antibody that binds to and neutralizes the IL-6 ligand.

44 Anti-IL-6 Antibody (PF-04236921) in Subjects with CD Who Are Anti-TNF Inadequate Responders: Week 12

n=249

2 doses sc @ week 0 and 4 p=0.04

p- = ns p= 0.04

p-= ns

45 Danese, Panaccione et al. Submitted NEJM Anti-IL-6 Antibody (PF-04236921) in Subjects with Crohn’s Disease

CDAI 70 CDAI 100

CDAI Remission CDAI Change from Baseline

46 * 1Danese,-sided p Panaccionevalue < 0.05. et al. Submitted NEJM Anti-IL-6 Antibody (PF-04236921) in Subjects with Crohn’s Disease: Suppression of CRP

47 Danese, Panaccione et al. Submitted NEJM SMAD7 Inhibition and the TGF- β/SMAD Pathway  Inhibition of SMAD7 restores SMAD2/3 activity and TGF-β-mediated signaling, thereby suppressing the production of proinflammatory cytokines1

 Mongersen Phase 2 study in UC is ongoing2 TGF-βI

P TGF-βRII TGF-βRI P SMAD2 SMAD7 SMAD3

Mongersen SMAD4 Cytoplasm

SMAD3 P e.g. SMAD7 SMAD4 SMAD2 Nucleus  Image adapted from Nielsen et al. Exp Opin Invest Drugs. 2016: doi 10.1517/13543784.2016.1165204.

48 1. Nielsen et al. Exp Opin Invest Drugs. 2016: doi 10.1517/13543784.2016.1165204. 2. ClinicalTrials.gov NCT02601300. 48 Smad7 Antisense Oligonucleotide Proposed Mechanism of Action

• In IBD, Smad7 appears over-expressed and this may result in decreased activity of TGF-β1 which is protective against an inflammatory state

• GED-0301 (Mongersen) is an oral antisense DNA oligonucleotide targeting Smad7 mRNA • In mouse models, knockout of Smad7 restores TGF-β1 activity, with the downstream effect of inhibiting inflammatory cytokine production

49 Monteleone et al. (2012) Mol Ther 20: 870-876. Phase IIa: Mongersen (GED-0301) in Active Crohn’s Disease

CDAI Remission Over 3 Months *P < 0.0001 vs. PBO 100 #P ≤ 0.0008 vs. PBO PBO MNG 10 mg/d MNG 40 mg/d MNG 160 mg/d 80 72* 67* 70 * # 67 * # 63 58 60

40 29 29 21 21 20 15 14 Fraction of Pts (%) Fraction 0 9/42 6/41 23/40 29/43 6/42 12/41 28/40 31/43 9/42 12/41 25/40 29/43 Day 15 Day 28 Day 84

• Phase IIa: N = 126 CD pts dosed for 14 days, with 3 mo f/u • CS-dependent/resistant mod-sev CD with ileal involvement (CDAI 220-400); no strictures/fistulae; CD dx ~10 yrs, median CDAI ~250, Con-IS (~32%) • Primary endpoint: Remission* achieved in 55% (40 mg/d) and 65% (160 mg/d) vs 9.5% PBO; P ˂ 0.0001 (no significant difference for 10 mg/d; 12.2%) • Rates of AEs and SAEs were similar across groups *Clinical Remission (CDAI ˂ 150 at day 15 and maintained for ≥ 2 wks) 50 Monteleone et al. NEJM 2015. Phase IIb: Mongersen Endoscopic and Clinical Outcomes Study ΔCDAI Mean Change From Baseline Through Week 12

Data From All Treatment Groups Study Week 0 2 4 8 12 -20

Pooled analysis of 3 dosing

-40 † * groups -60 P<0.0001 GED 301 160mg X 4 weeks GED 301 160 mg X 8 weeks -80 GED 301 160 mg X12 weeks -100 in CDAI Score CDAI in * -120 *

Mean Change From Baseline Baseline From Change Mean -140 * -133 -160 * n= 63 56 62 44 21

*CDAI mean change from baseline at Week 12 was determined in the ITT population using LOCF methodology.

51 Feagan et al. UEGW 2016 Phase IIb: Mongersen Endoscopic and Clinical Outcomes Study

Clinical response week 12 Clinical remission week 12

100 67 100 90 53 80 44 90 80 48 70 70 35 32 60 60 50 50 40 40

Response* (%) (%) Response* 30 30 20 (%) Remission* 20

Patients Achieving Clinical Achieving Patients 10 10 0 Clinical Achieving Patients 0

4 Weeks 8 Weeks 12 Weeks 4 Weeks 8 Weeks 12 Weeks (N=23) (N=19) (N=21) (N=19) (N=23) (N=21) GED-0301 Treatment GED-0301 Treatment Group Group

52 Feagan et al. UEGW 2016 Phase Iib: Mongersen Endoscopic Response at Week 12: SES-CD Reduction by ≥25% and ≥50%

SES-CD Reduction by ≥25% SES-CD Reduction by ≥50% 100 63 100

80 80 31 60 37 60

40 40 15 Response* (%) Response* Response* (%) Response* 20 20 Patients AchievingEndoscopic Patients 19/52 10/16 AchievingEndoscopic Patients 8/52 5/16 0 0 n/N= All Evaluable Baseline All Evaluable Baseline Patients SES-CD >12 Patients SES-CD >12

*Data as observed. 53 53 Feagan et al. UEGW 2016 Summary  Emerging strategies are defining improved ways of managing patients with IBD

 New therapies provide us with more choice and greater treatment flexibility

 Our task is to use the right treatment in the right patient at the right time – Explore the evidence base – Understand best practice – Optimise your first biologic – Tailor treatment to patient needs

54