New Therapies on the Horizon

Themos Dassopoulos, M.D. Director, Baylor Scott and White Center for IBD Adjunct Professor of Medicine, Texas A&M University [email protected] Tel: 469-800-7189; Cell: 314-686-2623 IBD Pathogenesis Neurath Nature Reviews. 2014

Cytokines in pathogenesis of IBD

Neurath Nature Reviews. 2014

Cytokine signaling in IBD

Neurath Nature Reviews. 2014

IL-12 and IL-23, their receptors and downstream signaling pathways

Anti-P19------Ustekinumab ---Ustekinumab

Teng Nature Med. 2015 Abrilumab

Lobaton. Aliment Pharamcol Ther 2014 Etrolizumab, anti-β7 mAb, Selectively Blocks T Cell Trafficking and Retention

E-cadherin

αEβ7

propria

Etrolizumab Lamina

Extravasation αE β7 α4 β1 α4 β7 MAdCAM-1 VCAM-1

α4β7 α4β1

Gut-homing T cells

Adapted from Marsal J, Agace WW. J Int Med. 2012;272(5):411-429; Vermeire S et al. Lancet. 2014;384(9940):309-318. UNITI: Phase III UST Development Program in CD

UNITI-1 Evaluate the safety/efficacy of ustekinumab induction therapy in subjects with moderately-to-severely active Crohn's disease who have failed or are intolerant to aTNF therapy

UNITI-2 Evaluate the safety/efficacy of ustekinumab induction therapy in subjects with moderately-to-severely active Crohn's disease who have failed or are intolerant to corticosteroids or immunosuppresants or are dependent on corticosteroid medications

IM-UNITI Evaluate the safety/efficacy of ustekinumab maintenance therapy in subjects with moderately-to-severely active Crohn’s disease that responded to induction

Feagan et al. N Engl J Med 2016; 375: 1946-1960 UST Achieves Superior Clinical Outcomes after Single IV Dose in anti-TNF & Conventional Failures

UNITI-1 UNITI-2 aTNF Failures Conventional Failures 100 100 PBO (n = 247) PBO (n = 209) UST 130 mg (n = 245) UST 130 mg (n = 209) 80 80 UST ~6 mg/kg (n = 249) UST ~6 mg/kg (n = 209) * 60 60 52 * 56 40* 40 34 * 34* 40 ** 29 31 22 * 21 * 20 20 16 20 7

Primary Endpoint Primary Endpoint Fraction of patients (%) patients of Fraction 0 0 Wk 6 CR-100 Wk 8 Rem Wk 6 CR-100 Wk 8 Rem

• UNITI-1 (N=741): median CDAI ~317, CD dx ~10.1 yrs; all pts failed aTNF (1º or 2º LOR): 1+ (100%), 2+ (51%), 3 (10%)

• UNITI-2 (N = 628): median CDAI ~292 despite conv. therapy; CD dx ~6.4 yrs, CS (~39%), IS (~35%), aTNF-exposed (~31%) *p < 0.005 any UST vs. PBO; ** p=0.009 CR: Clinical Response Feagan et al. N Engl J Med 2016; 375: 1946-1960 UST SC Maintains Clinical Remission and Response

Clinical Outcomes at Week 52 100 PBO Maintenance (n = 131) UST 90 mg SC q12w (n = 129) 80 UST 90 mg SC q8w (n = 128)

58 * 59 * 60 53** 49* 47 (*) 44 43 (*) 40 36 30

20

Fraction of patients (%) patients of Fraction Primary Endpoint 0 Clinical Remission Clinical Response Steroid Free (CR-100) Remission

• Phase III, multicentre, prospective RCT, N = 397 UST week 8 responders randomized from UNITI-1 and UNITI-2 induction trials • Mod-to-sev CD (med. BL CDAI ~311), CD dx ~7.6 yrs, aTNF-refractory (~45%)

*p < 0.05; **p<0.005; (*), (**) nominal; Any UST vs. induction only Feagan et al. N Engl J Med 2016; 375: 1946-1960 Rates of Clinical Outcomes Appear Higher in Bio-Naïve Patients

UNITI-1 UNITI-2 aTNF Failures aTNF-Naïve **

100 100

PBO (n = 247) PBO (n = 135) 80 UST ~6 mg/kg (n = 249) 80 UST ~6 mg/kg (n = 144) ∆ 23% * 60 60 56 ∆ 12% 40 34 * 40 33 22

20 20

Fraction Fraction of patients (%) Fraction Fraction of patients (%) 0 0 Wk 6 CR-100 Wk 6 CR-100

• Data sets suggest that absolute rates of clinical outcomes appear higher in bio-naïve pts • Prior Bx exposure may be a marker for treatment resistant disease and may impact efficacy of subsequent therapy CR: Clinical Response *p<0.005; **69% of UNITI-2 population Feagan et al. N Engl J Med 2016; 375: 1946-1960; Janssen, data on File UST Reduces Endoscopic Activity at Weeks 8 and 52

SES-CD Reduction >3 (wk 8) SES-CD reduction ≥50% (wk 52)

100 100 PBO maintenance UST 90 mg q12w 80 80 UST 90 mg q8w 60 P = 0.005 60 ∆ 20% 48 ∆ 20% P=0.012 P=0.043 40 30 40 34 24 17 20 20 14

4 6 Fraction Fraction of patients (%) Fraction Fraction of patients (%) 0 0 PBO Combined IV UST n = 24 17 29 51 47 74 (n = 97) (n = 155) Primary Randomized Pooled Population Population • Endoscopic sub-study of the prospective ph III RCTs UNITI-1, 2 & IM-UNITI • Endoscopies at wk 0, wk 8, and wk 52 • Eligible subjects (aTNF-failures, experienced, bio-naïve included) must have lesions at wk 0 • Central reader blindly scored all video endoscopies and SES-CD SES-CD reduction ≥3 from induction BL SES-CD reduction ≥50% from induction BL Rutgeerts et al. UEGW 2016, Abstract OP104 Proportion of patients with CD experiencing loss of response to ustekinumab maintenance therapy

Ma, C Inflamm Bowel Dis 2017;23:833–839 PSOLAR: Psoriasis Longitudinal Assessment and Registry Cumulative Incidence Rates of Malignancy (Excluding NMSC) in PsO

Rates of Malignancy (Excluding NMSC) per 100 PY*

5 4 UST IFX Non-Sponsor Bx Non-Bx Total 3 2 0.79 0.84 1 0.48 0.73 0.68

Risk of PY SI/100 Risk PY 12742 5176 15991 6749 40388 0 UST IFX Non-Sponsor Non-Bx Total Bx • PSOLAR is a multicentre observational registry of 12,093 PsO pts treated with all therapies, med f/u = ~3.4 yrs/pt, the overall prevalence of IBD is 2.3% • BL characteristics were comparable, though IFX used in more sev PsO • Events attributed to UST first, IFX second, all other Bx 3rd, then non-Bx • Multivariate analyses: UST is not associated with increased risk of malignancy, major adverse CV events, serious infections or mortality * within 91 days of Bx Administration (NMSC:non-melanoma skin cancer) Papp et al. J Drugs Dermatol 2015;14:706-14 PSOLAR Incidence of Serious Infections in patients with PsO and prevalent IBD

Rates of Serious Infections per 100 PY*

10 IBD subset Full PSOLAR population 8 5.75 6 4.32 3.47 3.81 4 2.91 1.91 1.60 Risk of PY SI/100 Risk 1.38 1.43 2 0.93 0 PY 218 7944 226 3301 301 12823 173 16322 918 40389 UST IFX Non-Sponsor Bx Non-Bx Total

• PSOLAR is a multicentre observational registry of 12,093 PsO pts treated with all therapies, med f/u = ~3.4 yrs/pt, the overall prevalence of IBD is 2.3% • BL characteristics were comparable, though IFX used in more sev PsO • Events attributed to UST first, IFX second, all other Bx 3rd, then non-Bx

* within 91 days of Bx Administration (SI= Serious Infection) Loftus et al. ECCO 2016 Abstract P626 The Race to Develop IL 23 (p19) Antibodies

• Brazikumab (AstraZeneca/Medimmune/Amgen, now Allergan) • Risankizumab (Boehringer Ingelheim, now Abbvie) • Geslekumab (Janssen) • LY3074828 (Lilly) • MK 3222 (Merck) Binding of cytokine receptors by cytokines activates JAK pathways signaling Consequence of Janus kinase (JAK) inhibition on signaling by key immunoregulatory cytokines

Tofactinib Jak 1>3 Filgotinib/ Upadacitinib Jak 1

O’Shea JJ, Plenge R. Immunity. 2012 Apr 20; 36(4): 542–550. Tofacitinib an oral JAK inhibitor

• Inhibits JAK1, JAK2, and JAK3 in vitro • Functional cellular specificity for JAK1 and JAK3 over JAK2 • Modulates signaling for an important subset of pro- inflammatory cytokines including IL-2, -4, -7, -9, -15, and -21

Sandborn W. N Engl J Med 2012;367:616-24. Phase 3 Program Design

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a R 8 weeksa Patients • ≥18 years old, moderately to severely active ulcerative colitis (Mayo score ≥6; rectal bleeding subscore ≥1; centrally read endoscopic subscore ≥2 (colonoscopy or flexible sigmoidoscopy) • Prior failure or intolerance to ≥1 of: corticosteroids, azathioprine, 6-MP or TNF inhibitors (TNFi) • Washout: TNFi, 8 weeks; immunosuppressants, 2 weeks • Concomitant corticosteroids: max dose 25 mg/day; stable during the study 20 Demographics and Baseline Characteristics

OCTAVE Induction 1 OCTAVE Induction 2 Placebo Tofacitinib Placebo Tofacitinib 10 mg BID 10 mg BID N=122 N=476 N=112 N=429 Gender, % female 36.9 41.8 50.9 39.6 Age, yearsa 41.8 (15.3) 41.3 (14.1) 40.4 (13.2) 41.1 (13.5) Geographic region, % Europe 59.0 59.9 56.3 58.0 North America 24.6 21.4 20.5 19.8 Other 16.4 18.7 23.2 22.1 Disease duration, yearsa 8.4 (7.6) 8.3 (7.1) 7.7 (6.3) 8.0 (6.9) Total Mayo scorea 9.1 (1.4) 9.0 (1.4) 8.9 (1.5) 9.0 (1.5) Extent of disease, % Proctosigmoiditis 15.6 13.7 14.4 15.7 Left-sided colitis 30.3 33.3 35.1 34.8 Extensive colitis or pancolitis 54.1 53.1 50.5 49.3 Prior TNFi treatment, % 53.3 53.4 58.0 54.5 Prior TNFi failure, % 52.5 51.1 53.6 51.7 Prior immunosuppressant failure, % 68.0 75.6 67.0 70.2 Prior corticosteroid failure, % 80.3 73.5 74.1 70.6 Oral corticosteroid use, % 47.5 45.0 49.1 46.2 aMean (standard deviation) 21 Tofacitinib Efficacy by TNF inhibitor exposure OCTAVE Induction 1 OCTAVE Induction 2 Remission Remission 60 60

∆=9.4 40 40 ∆=13.5 ∆=11.1 ∆=12.0 25.2 22.1 20 15.8 20 12.6 12.0 8.5

1.5 0 Percent of remissionof withPercent patients Percent of remissionwithof patients Percent 0 0 Yes No Yes No Prior TNFi exposure Prior TNFi exposure Mucosal healing Mucosal healing 60 ∆=13.3 60 ∆= 17.3

∆=17.9 39.6 ∆=15.6 40 40 36.4

26.3 24.0

21.8 healing healing 19.1 20 20

6.2 6.2 Percent of patients with mucosal with of patients Percent Percent of patients with mucosal with of patients Percent 0 0 Yes No Yes No Prior TNFi exposure Prior TNFi exposure

Sands B, et al. Am J Gastroenterol 2016;111(S1):S261. Mucosal healing

100

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Sandborn New England J Med in press

23 Sustained Corticosteroid -free Remission

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Sandborn et al New Eg J Med in press

24 Results of the OCTAVE maintenance trial of tofacitinib in ulcerative colitis

Sandborn WJ, Sands BE, Danese S, et al. Efficacy and safety of oral tofacitinib as maintenance therapy in patients with ulcerative colitis: Results from a phase 3 randomized controlled trial. DDW. 2017:1080 Incidence rates of herpes zoster and herpes simplex associated with anti-TNF and tofacitinib in RA

Person- Incidence Adjusted HR♮ Events Years Rate* (95% CI) Adalimumab 330 6832.8 4.83 (4.34-5.38) 0.89 (0.77-1.03) Certolizumab 161 2940.7 5.47 (4.69-6.39) 1.00 (0.83-1.19) Golimumab 89 1670.8 5.33 (4.33-6.56) 1.01 (0.80-1.27) Infliximab 492 8201.4 6.00 (5.49-6.55) 1.06 (0.93-1.21) Tofacitinib 74 972.9 7.61 (6.06-9.55) 1.40 (1.09-1.81) *Per 100 person-years. ♮Adjusted for age, sex, baseline glucocorticoid use, methotrexate, number of biologics used, hospitalization, hospitalized infection, outpatient infection and zoster vaccination.

Curtis JR, et al. Ann Rheum Dis 2016;75:1843–1847. Summary of adverse events

Placebo Tofacitinib Tofacitinib 5 mg BID 10 mg BID N=198 N=198 N=197 Adverse events, n (%) 149 (75.3) 143 (72.2) 156 (79.6) Most frequently occurring adverse events by preferred term (≥8%), n (%) Worsening ulcerative colitis 71 (35.9) 36 (18.2) 29 (14.8) Nasopharyngitis 11 (5.6) 19 (9.6) 27 (13.8) Arthralgia 19 (9.6) 17 (8.6) 17 (8.7) Headache 12 (6.1) 17 (8.6) 6 (3.1) Serious adverse events, n (%) 13 (6.6) 10 (5.1) 11 (5.6) Discontinuations 37 (18.7) 18 (9.1) 19 (9.7) Due to adverse events, n (%)a Insufficient clinical response, n (%)b 132 (66.7) 70 (35.4) 53 (27.0)

Sandborn New England J Med

27 Safety events of special interest

Placebo Tofacitinib Tofacitinib 5 mg BID 10 mg BID N=198 N=198 N=197 Infections, n (%) 48 (24.2) 71 (35.9) 78 (39.8) Serious infections, n (%)a 2 (1.0) 2 (1.0) 1 (0.5) Herpes zoster, n (%) 1 (0.5) 3 (1.5) 10 (5.1) All casesb Multidermatomal (non-adjacent or 1 (0.5) 2 (1.0) 4 (2.0) >2 adjacent dermatomes)c Disseminatedc 1 (0.5) 0 (0) 0 (0) Cardiovascular events, n (%)d 0 (0.0) 1 (0.5)e 1 (0.5)f Intestinal perforations, n (%)d,g 1 (0.5)h 0 (0.0) 0 (0.0) Malignancies, excluding NMSC, n (%)d 1 (0.5)i 0 (0.0) 0 (0.0) NMSC 1 (0.5) 0 (0.0) 3 (1.5) Death 0 (0) 0 (0) 0 (0)

Sandborn New England J Med \

28 Efficacy and Safety of Tofacitinib in Crohn’s Disease

8-Week Induction Study (N = 280) 100

PBO Tofa 5 mg BID Tofa 10 mg BID

80 71 * 69

60 Primary Endpoint 54 44 43 40 37

Fraction of patients (%) patients of Fraction 20 91 86 86 91 86 86 0 Remission wk 8 CR-100

aTNF-experienced (68%); CR: Clinical Response; *p<0.05

Panes et al. ECCO 2016, Abstract OP022 Efficacy and Safety of Filgotinib in Mod-Sev CD

Remission and Response Week 10 (N=275) Change in IBDQ at Week 10

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Vermeire et al. ECCO 2016, Abstract OP020 Modulation of S1P Receptors Results in Retention of Lymphocyte Subsets (CCR7+) in the Lymph Node

• Lymphocyte subsets (CCR7+ ) circulate through lymph nodes • Exit of these lymphocytes from the lymph

node is S1P1R dependent

• Ozanimod down modulates S1P1R, preventing these lymphocytes from exiting and contributing to tissue inflammation • Lymphocytes subsets (CCR7- ) important for viral and tumor surveillance continue to circulate Ozanimod : Study Design

Induction Period Maintenance Period

Primary Week 32 1 Week 8 Weeks Endpoint: 24 Weeks Maintenance Initial Doses Treatment Induction Treatment Endpoint

Placebo (N=65)

Mayo Responders Randomization Ozanimod 0.5 mg (N=65)

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30% p=0.140 p=0.048 p=0.002 p=0.010 26.2%

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10%

Patients (%) Patients 6.2% 6.2%

0% Week 8 Week 32 Placebo (N=65) Ozanimod 0.5 mg (N=65) Ozanimod 1 mg (N=67)

*Clinical remission defined as a Mayo Clinic Score ≤2, with no individual subscore >1 point