Brian G Feagan MD Professor of Medicine, Epidemiology and Biostatistics Senior Scientific Director, Robarts Clinical Trials Western University

16/06/2016

Beyond TNF Antagonists

Relevant Disclosures

I have received consulting fees and grant support from both Takeda Pharma and Janssen Inc

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VEDOLIZUMAB

Therapeutic Targets

Leucocyte Adhesion CD 11a/CD18 NATALIZUMAB VEDOLIZUMAB LEUCOCYTE

41 47 (VLA-4) CCX282-B ISIS-2302

CCR9 MAdCAM mAb rhuMA (PF-547659) b Beta 7 CCL- ICAM-1 MadCAM-1 VCAM-1 25

ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS

Adapted from Danese S Gut 2011;60:998-1008

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Vedolizumab: Background

Alpha 4 Beta 7 • Ligand for 47 is MAdCAM MAdCAM -1 ACT -1 • Animal models show that ACT- 1 selectively blocks trafficking of 47 positive lymphocytes to the gut • Raises possibility of gut specific immune modulation • Striking benefit in cotton-top tamarin model

Hesterberg PE et al. Gastroenterology 1996;111:1373‐80 Podolsky et al. JCI 1993;92:372‐80

Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks

50 47.1 P<0.0001 P=0.0010 45 Placebo 40.9 Vedolizumab 40 35 30 25.5 24.8 % 25 P=0.0010 20 16.9 15 10 5.4 5 0 Clinical Response Clinical Remission Mucosal Healing  21.7  11.5  16.1 95% CI: 11.6, 31.7 4.7, 18.3 6.4, 25.9

Feagan BG et al New Eng J Med 2013;369(8):699‐710

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Primary and Secondary Outcomes : 52 Weeks

*** *** 60 56.6 56.0 *** *** 52.0 51.6 Placebo VDZ Q8Wks 50 *** *** *** 44.8 VDZ Q4Wks 45.2 41.8 40 * % 31.4 30 ** 23.8 ** 24.0 19.8 20.5 20 15.9 13.9 10 8.7

0 Clinical Remission Durable Clinical Mucosal Healing Durable Clinical CS‐Free Remission Response Remission n: 72 70 73 26.1 29.1 32.8 28.5 32.0 36.3 11.8 15.3 17.6 31.4 *P<0.05. **P<0.01. ***P<0.0001

Feagan BG et al New Eng J Med 2013;369(8):699‐710

Vedolizumab for CD Induction and Maintenance

Induction Phase Maintenance Phase Week 0 – Week 6 Week 6 – Week 52

Cohort 1 Placebo Placebo Blinded N=148 N=148 Induction N=368 VDZ No VDZ N=220 N=506 No Placebo Week 6: N=153 Responder? Week 52 Assessments Screening, Cohort 1 complete? VDZ Enrollment Yes Q8 wks N=154

Yes VDZ Q4 wks N=154 Cohort 2 Open‐Label VDZ Corticosteroid Tapering* Induction N=747 N=747

*Responders began tapering regimen at 6 weeks; others, as soon as a clinical response was achieved.

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Clinical Remission and CDAI-100 Response at Week 6

P=0.23

35 PBO 31.4 30 VDZ 25.7 25 P=0.02 20 14.5 15 Patients, % 10 6.8 5 0 Clinical Remission CDAI-100 Response

Mean % vs PBO (95% CI) 7.8 (1.2, 14.3) 5.7 (–3.6, 15.0)

Sandborn WJ. et al. New Eng J Med 2013;369(8):711‐21.

Primary and Secondary Outcomes at 52 Weeks

Primary Secondary Outcomes 50 Outcome † ‡ 45.5 43.5 VDZ/PBO 39.0† 40 36.4† VDZ/VDZ Q8W 31.7‡ VDZ/VDZ Q4W 30.1 ‡ 30 28.8 21.6 21.4 20 15.9 16.2

Patients, % 14.4 10

0 Clinical Remission CDAI-100 Response CS-Free Remission§ Durable Remission

Mean % vs VDZ/PBO 17.4 14.7 13.4 15.3 15.9 12.9 7.2 2.0

†P<0.01 vs placebo; ‡P<0.05 vs placebo §

Sandborn WJ. et al. New Eng J Med 2013;369(8):711‐21.

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Vedolizumab Induction Trial II in CD CDAI-100 Response

ITT Population

Anti-TNFα Failure Population Overall Population PBO 60 (n=315) (n=416) VDZ 50 46.8† 47.8† 39.2* 39.2‡ 40

30 24.8 22.3 22.7 24.2 Patients, % 20

0 Week 6 Week 10 Week 6 Week 10 CDAI-100 Response

*P=0.0011 vs placebo; †P<0.0001 vs placebo; ‡P=0.0002 vs placebo

Sands et al, Gastroenterology 2015

Ustekinumab in CD

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Ustekinumab (UST)

• The cytokines IL-12 and IL-23 have been implicated in CD IL-12 IL‐12 IL-23IL‐23 pathogenesis

p40 • They are structurally related p35 p19 p40 heterodimers with a common 40 kD subunit (p40) ustekinumab • UST is a fully human IgG1κ monoclonal antibody that binds the p40 subunit of human IL-12/23 • Prevents IL-12 and IL-23 from NK or T cell binding IL-12Rβ1 membrane • Reduces IL-12 and IL-23 mediated signaling, cellular activation, and cytokine production No IL-12 or IL-23 • Proven effective for psoriasis and No Intracellular Signal: Jak2, Tyk2, STAT3 psoriatic arthritis

1. Torti DC, Feldman SR. J Am Acad Dermatol. 2007;57(6):1059-68. 2. Trinchieri G. Nat Rev Immunol. 2003;3(2):133-46.

UST Clinical Development Program in CD

Phase 3

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Phase 3 Crohn’s Disease Program Induction (8 wks) + Maintenance (44 wks) = 52 wks

Two Induction Studies One Maintenance Study UNITI-1: αTNF Failure Population

Placebo IV (N=225)* IM-UNITI Randomized Withdrawal R UST 130 mg IV Maintenance Study (N=225)* UST ~6 mg/kg† IV Responders (N=225)* 90 mg SC q8 wks Maintenance UNITI-2: Failed Convent. Therapy R 90 mg SC q12 wks study: Followed by (up to) 3 yr UST 130 mg IV Placebo SC LTE (N=200)* Responders † R UST ~6 mg/kg IV (N=200)*

† Placebo IV (N=200)* Weight-based UST IV doses ~ 6 mg/kg • UST 260 mg (weight ≤55 kg) • UST 390 mg (weight >55 kg and ≤85 kg) • UST 520 mg (weight >85 kg)

UNITI-2

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UNITI-2 UNITI-2 Study Design: Single-Dose IV Induction

Patients enter maintenance study Week 0 3 6 8 Primary Screening R Endpoint

UNITI-2 Study Enrolled: • Patients with mod-to-severe CD (CDAI score 220-450) of > 3 months duration who had NOT previously demonstrated inadequate response or intolerance to 1 or more TNF antagonist therapies • Active CD confirmed by either elevated CRP, fecal calprotectin > 250 mg/kg, or endoscopic evidence of active inflammation • Required prior inadequate response or failure to tolerate CS or IS

R = Randomization = Study Agent Administration Feagan et al. UEGW 2015, Abstract OP054

UNITI-2 Key Study Endpoints

Primary Endpoint: • Clinical Response at Week 6, defined as a reduction from baseline in the CDAI score of ≥100 points

Major Secondary Endpoints: • Clinical Remission (CDAI <150) at Week 8 • Clinical Response (CR-100) at Week 8 • 70-point CDAI response at Week 6 • 70-point CDAI response at Week 3

Feagan et al. UEGW 2015, Abstract OP054

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UNITI-2 Baseline Demographic and Disease Characteristics

Ustekinumab Characteristics PBO 130 mg ~6 mg/kg Combined Total Subjects randomized 210 209 209 418 628 Age (years)* 39.0 37.0 36.0 36.0 37.0 Male (%) 46.9 49.8 43.1 46.4 46.6 Weight (kg)* 70.0 70.5 71.7 70.9 70.8 CDAI score* 289.5 294.0 286.0 293.0 292.5 CD duration (years)* 8.28 5.61 6.21 5.82 6.40 CRP (mg/L)* 8.50 7.38 7.82 7.71 8.05 Abnormal CRP (%) 76.5 75.1 78.9 77.0 76.9 Previously adequately treated with & failed** n (%) Corticosteroids 174 (82.9%) 163 (78.0%) 171 (81.8%) 508 (80.9%)

Immunosuppressants 152 (72.4%) 140 (67.0%) 132 (63.2%) 424 (67.5%)

Exposed but not failed aTNF 75 (35.7%) 57 (27.3%) 65 (31.1%) 197 (31.4)

aTNF naïve 135 (64.3%) 152 (73.4%) 144 (68.9%) 431 (68.6%)

* Median ** Pts who failed to respond, became intolerant to CS or IS; or dependent on CS Feagan et al. UEGW 2015, Abstract OP054

UNITI-2 Clinical Response (CR-100) at Week 6

Clinical Response at Week 6 (≥ 100 Point CDAI Reduction) 100 Primary Endpoint *p<0.001 vs. PBO 80

55.5 * * 60 51.7* 53.6

40 28.7

20 Fraction of patients (%) of patients Fraction 0 PBO UST 130 mg UST ~6 mg/kg Combined (n = 209) (n = 209) (n = 209) (n = 416)

Feagan et al. UEGW 2015, Abstract OP054

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UNITI-2 Clinical Remission at Week 8

Clinical Remission at Week 8 (CDAI < 150) 100 Major Secondary Endpoint *p<0.001 vs. PBO †p=0.009 vs. PBO 80

60 * 40.2 * 40 † 35.4 30.6 19.6 20 Fraction of patients (%) of patients Fraction 0 PBO UST 130 mg UST ~6 mg/kg Combined (n = 209) (n = 209) (n = 209) (n = 416)

Feagan et al. UEGW 2015, Abstract OP054

UNITI-2 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 -4.76 -5.97 -6 PBO Mean Change from Change Mean Baseline CRP (mg/L)Baseline CRP UST 130 mg -8.61 -8.41 -8.56 -8 UST ~6 mg/kg -10 012345678 Weeks • Mod-to-sev active CD pts (mean CDAI ~293), 69% are bio-naïve (31% exposed to anti-TNF but not failed), received single-dose IV induction

Feagan et al. UEGW 2015, Abstract OP054

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UNITI-1

UNITI-1 and UNITI-2 Clinical Response (CR-100)

Clinical Response* (≥ 100 Point CDAI Reduction) UNITI-1 UNITI-2 TNF Failures Non-TNF-Failures 100 100 PBO PBO 80 UST 130 mg 80 UST 130 mg UST ~6 mg/kg UST ~6 mg/kg 57.9 60 60 55.5

37.8 38.8 51.7 33.7 47.4 40 30.1 40 33.5 32.5 34.3 32.1 20 25.3 20 28.7 Fraction of patients (%) of patients Fraction 21.5 (%) of patients Fraction 21.5 17.8 20.2 0 0 012345678 012345678 Weeks Weeks Sandborn et al. CCFA 2015, Abstract O-001 *All p-values < 0.05 Feagan et al. UEGW 2015, Abstract OP054

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UNITI-1 and UNITI-2 Clinical Remission Through Week 8

Clinical Remission** (CDAI < 150) UNITI-1 UNITI-2 TNF Failures Non-TNF-Failures 100 100 PBO PBO 80 UST 130 mg 80 UST 130 mg UST ~6 mg/kg UST ~6 mg/kg 60 60

40.2 40 40 34.9

20.9 23.0 18.5 28.7 30.6 Fraction of patients (%) of patients Fraction 20 12.9 20 15.8 16.3 19.6 10.6 15.9 17.7 8.9 11.5 0 5.7 7.3 0 012345678 012345678 Weeks Weeks Sandborn et al. CCFA 2015, Abstract O-001 **All p-values < 0.05 except 130 mg dose at Week 3 Feagan et al. UEGW 2015, Abstract OP054

UNITI-1 and UNITI-2

CRP at Weeks 3, 6 and 8

Mean CRP Concentration Change by Week 8* UNITI-1 UNITI-2 TNF Failures Non-TNF-Failures

4 PBO UST 130 mg UST ~6 mg/kg 1.03 2 3.30 2.37 2.74 -0.18 -0.14 0

-2 -3.97 -4.76 -4 -5.18 -5.70 -5.96 -5.97

Mean Change from Change Mean -6 Baseline CRP (mg/L)Baseline CRP -5.55 -5.66 -8.61 -8.41 -8.56 -8 -6.89 -10 012345678 012345678

*All p-values < 0.001 Weeks Subjects who had insufficient data at the designated analysis Sandborn et al. CCFA 2015, Abstract O-001 time point had their last value carried forward Feagan et al. UEGW 2015, Abstract OP054

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IM-UNITI Overall UNITI Phase 3 Crohn’s Program

Two Induction Studies One Maintenance Study

UNITI-1: anti-TNF Failure Population

Placebo IV* IM-UNITI Randomized Withdrawal R Stelara 130 mg IV* Maintenance Study

Stelara ~6 mg/kg IV* Responders

90 mg SC q8 wks 44 Week UNITI-2: Failed Convent. Therapy R 90 mg SC q12 wks maintenance study: Placebo SC Followed by Stelara 130 mg IV* (up to) 4 yr LTE Responders R Stelara ~6 mg/kg IV*

Placebo IV*

Sandborn W.J., et al. DDW 2016. Presentation 768.

IM-UNITI Key Endpoints

In the primary efficacy population (i.e., subjects in clinical response to IV ustekinumab in UNITI-1 or UNITI-2): • Primary Endpoint – Clinical remission at Week 44: CDAI score of <150 points • Major Secondary Endpoints – Clinical response at Week 44: reduction in the CDAI score of 100 points or clinical remission – Remission at Week 44 among subjects in clinical remission to ustekinumab induction (remission in remitters) – Corticosteroid-free remission at Week 44 – Clinical remission at Week 44 in patients refractory or intolerant to TNF antagonists (UNITI-1 subgroup)

Sandborn W.J., et al. DDW 2016. Presentation 768.

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IM-UNITI Induction Baseline Demographics: Randomized Maintenance Subjects

Ustekinumab Placebo 90 mg SC 90 mg SC SC* q12w q8w Combined Total Subjects randomized 133 132 132 264 397 Age (years)** 38.0 36.5 35.0 35.0 36.0 Male (%) 44.4 43.9 42.4 43.2 43.6 Weight (kg)** 70.50 66.10 70.0 67.50 69.0 CD duration (yrs)** 8.39 6.81 8.52 7.14 7.57 Abnormal CRP or Calprotectin >250 mg/kg 117 (89.3) 111 (86.0) 105 (82.0) 216 (84.0) 333 (85.8) at Induction BL

Sandborn WJ et al. DDW 2016. Presentation 768.

IM-UNITI Number of Subjects in Clinical Remission**,† at Week 44; Primary Endpoint: Clinical Remission at Week 44

100

80 p=0.040 p=0.005 ∆ 12.9% ∆ 17.2%

60 53.1 48.8

40 35.9

0 Proportion of Subjects (%) Placebo SC* 90 mg SC q12w 90 mg SC q8w (N=131) (N=129) (N=128) Ustekinumab

Sandborn W.J., et al. DDW 2016. Presentation 768.

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IM-UNITI Major SecondaryNumber Endpoint: of Subjects in Clinical Clinical ResponseResponse at Week 44**,† at Week 44

100 p=0.033 p=0.018 80 ∆ 13.8% ∆ 15.1%

58.1 59.4 60 44.3 40

0 Proportion of Subjects (%) Placebo SC* 90 mg SC q12w 90 mg SC q8w (N=131) (N=129) (N=128) Ustekinumab

Sandborn W.J., et al. DDW 2016. Presentation 768.

IM-UNITI Number of Subjects in Clinical Remission**,† at Week 44 Major Secondary Endpoint:Among Clinical Patients Remission at Week 44 Among Subjectsin Remission in Remission at Week at 0 Week 0

100 p=0.189 p=0.007 80 ∆ 10.8% ∆ 21.1% 66.7 60 56.4 45.6 40

Proportion of Subjects (%) 0 Placebo SC* 90 mg SC q12w 90 mg SC q8w (N=79) (N=78) (N=78) Ustekinumab

Sandborn WJ et al. DDW 2016. Presentation 768.

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IM-UNITI Number of Subjects in Clinical Remission**,†,‡ at Week 44 and Major SecondaryNot Endpoint: Receiving Clinical Corticosteroids Remission at at Week 44 and Not ReceivingWeek Corticosteroids 44

100

80 p=0.035 p=0.004 ∆ 12.8% ∆ 17.1% 60 46.9 42.6 40 29.8

0 Proportion of Subjects (%) Placebo SC* 90 mg SC q12w 90 mg SC q8w (N=131) (N=129) (N=128) Ustekinumab

Sandborn WJ et al. DDW 2016. Presentation 768.

IM-UNITI 34 ChangeMedian in CDAI ThroughChange Week From 44: Baseline in RandomizedCDAI Population Through Week 44**,†

100

0 + + + ++ ++

Change in CDAI (Median) Change -20 ++ ++ 0 4 8 12 16 20 24 28 32 36 40 44 Weeks Placebo SC* 90 mg SC q12w Ustekinumab 90 mg SC q8w Ustekinumab + p<0.05 + p<0.05

Sandborn WJ et al. DDW 2016. Presentation 768.

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IM-UNITI 35 Change from Baseline in CRP Concentration Through Week 44

Summary of Median Change from Baseline in CRP Concentration (mg/L) a,b 5 Through Week 44

Median Change from Change Median 0 Baseline in CRP (mg/L) BaselineCRP in

-1 0 4 8 121620242832364044 Weeks Placebo SCc 90 mg SC q12w 90 mg SC q8w ustekinumab ustekinumab

35 Sandborn WJ et al. DDW 2016. Presentation 768.

IM-UNITI 36 Summary of Key Safety Events Through Week 44 in the Randomized Population

Ustekinumab Placebo SC* 90 mg SC q12w 90 mg SC q8w Combined Treated subjects who were 133 132 131 263 randomized (n)

Avg. duration of follow-up 32.0 36.6 35.2 35.9 (weeks) Subjects with (%) Death 0% 0% 0% 0% AEs 83.5% 80.3% 81.7% 81.0% SAEs 15.0% 12.1% 9.9% 11.0% Infections 49.6% 46.2% 48.1% 47.1% Serious infections 2.3% 5.3% 2.3% 3.8% Discontinuation due to 6.0% 7.6% 3.1% 5.3% AE Malignancies 0.8% 0% 0.8% 0% MACE 0% 0% 0% 0%

36 Sandborn WJ et al. DDW 2016. Presentation 768.

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PSOLAR Risk of Adverse Events Observed In Ustekinumab-Treated Psoriasis Patients

Independent Predictors of Time to First Event: Ustekinumab-Treated vs. Non-Biologic-Treated 10

1 1.17 1.06 1.08 0.76

Malignancy Major adverse Serious Mortality

Adjusted HR [95%CI] HR Adjusted cardiovascular event infection 0.1

Papp K, et al. J Drugs Dermatol. 2015;14(7):706-714.

IM-UNITI Ustekinumab: Conclusions 38

• Ustekinumab induction and maintenance studies achieved statistical significance for both regimens for primary and multiple secondary endpoint • New agent for both TNF antagonist naïve and failure patients • No notable safety issues identified, in either induction or maintenance- generally consistent with favorable psoriasis safety experience

Sandborn WJ et al. DDW 2016. Presentation 768.

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Beyond TNF Antagonists: Conclusions

• Vedolizumab and ustekinumab are highly effective new agents for treatment of IBD

• Key advantages are efficacy in patients who have failed TNF antagonists and SAFETY

• It is highly unlikely that in five years TNF antagonists will be optimal first therapy for IBD

Feagan et al. UEGW 2015, Abstract OP054

Additional Slides Dermatology Experience With Ustekinumab

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Other New MOAs on the Horizon in IBD Phase 2 Trials

TURANDOT Phase II: PF-00547659 (Anti-MAdCAM-1 mAb) for Mod-Sev UC

Primary and Secondary Endpoints at Week 12 100

80 PBO (n = 83) PF 7.5 mg (n = 71) PF 22.5 mg (n = 70) PF 75 mg (n = 73) PF 225 mg (n = 70)

Primary Endpoint 54 * 60 50* 45 *P < 0.05 vs. PBO 40 38 29 28 * 25 17 16* 16 20 11 14

Fraction of Pts (%) of Pts Fraction 8 3 6 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

Clinical Remission wk 12: f Mayo 0-2; Clinical Response wk 12: fMayo dec. ≥3 and ≥30% from BL ; MH wk 12: (Mayo 0 or 1) Vermeire et al. ECCO 2015, Abstract OP021

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OPERA Phase II: PF-00547659 (Anti-MAdCAM-1 mAb) for Active Refractory, TNF-Experienced CD

Primary and Secondary Endpoints at Week 12 100 PBO (n = 63) PF 22.5 mg (n = 67) 80 65 PF 75 mg (n = 64) PF 225 mg (n = 68) 59 62 58 60 All P = NS 37 39 40 28 29 23 27 24 20 Primary Endpoint 14 Fraction of Pts (%) 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

D’Haens et al. ECCO 2015, Abstract OP022.

TOUCHSTONE Phase II: RPC1063 (S1P Receptor Modulator) in Mod-Sev UC Outcomes at Week 8 Outcomes at Week 32 100 PBO (n = 65) PBO (n = 65) 80 0.5 mg OZM (n = 65) 0.5 mg OZM (n = 65) 1.0 mg OZM (n = 67) 1.0 mg OZM (n = 67) 60 P = 0.0046 Primary Endpoint P = 0.002 P =0.011 P = 0.0064 P = 0.035 40 P =0.048 34 P = 0.0021 32 33 P = 0.14 28 26 21 16

Fraction of Pts (%) 20 14 12 12 6 6 0 Remission MH* Remission MH*

• Phase IIa: N = 197 UC pts (Mayo 6-12), randomized to PBO, 0.5 mg, 1 mg qd. • Oral RPC1063 (OZM) inhibits S1P-1R and -5R • BL Mayo ~8.5; Dis. duration ~6.3 yrs; prior anti-TNF experienced ~18% • Well tolerated, only modest effects on heart rate, consistent with profile in MS • Positive efficacy and the safety/tolerability results from this study suggest a favorable risk-benefit profile that supports a Phase 3 UC program *Central read

Sandborn et al. UEGW 2015, Abstract OP004

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Phase IIa: Induction Study of MEDI2070 (Anti-p19 mAb) for Active, anti-TNF-refractory CD

Efficacy Outcomes at Week 8 100 Primary Endpoint PBO (n = 60) MEDI2070 (n = 59) 80 P = 0.010 P = 0.017 60 49 P < 0.001 46 42 40 P = 0.102 27 27 25 15 20 10

Fraction of Pts (%) 0 Clinical Effect Clinical Clinical Response Clinical + Remission 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

Sands et al. ECCO 2015, Abstract OP025

Phase IIa: Safety and Efficacy of Eldelumab (anti-IP-10 mAb) for Patients with Mod-to-Sev CD

Clinical Outcomes at Week 11 100 100 Clinical Remission Clinical Response Endoscopic 80 73 Improvement All P = NS 65 60 48 46 40 41 42 38 40 35 29 29 30 30 29 29 24 26 25 20 23 23 23 23 20 22 20 14 Fraction of Pts (%) 7 0 All anti-TNF Failure Failure All Anti-TNF Failure Failure All Anti-TNF Failure Failure naive 1-2 ≥3 naive 1-2 ≥3 naive 1-2 ≥3 PBO (n = 40) ELD 10 mg/kg (n = 40) ELD 20 mg/kg (n = 41)

• N = 121 mod-sev CD pts (CDAI 220-450), randomized to either: PBO or eldelumab (ELD) 10 or 20 mg/kg IV on Days 1 and 8 and then eow • ELD showed trends towards clinical and endoscopic improvement endpoints • AEs were comparable across treatment groups; SAEs were more common in ELD 10 and 20 mg/kg grps (7.5% and 9.8%) vs. PBO (5.0%): infusion-related

Clinical Remission: CDAI <150 Clinical Response: reduction in CDAI ≥100 points from baseline or an absolute CDAI <150; Endoscopic improvement: 50% decrease from baseline Sandborn et al. DDW 2015, Abstract 827

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Smad7 Antisense Oligonucleotide Proposed Mechanism of Action

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• 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, knockdown of Smad7 restores TGF-β1 activity, with the downstream effect of inhibiting inflammatory cytokine production

Monteleone et al. (2012) Mol Ther 20: 870-876.

Phase IIa: Mongersen (GED-0301) in Active Crohn’s Disease

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

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

Monteleone et al. UEGW 2014, Abstract OP203.

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Placeholder for JAKs

Genome-wide Association Studies Identify 11 Shared Susceptibility Loci Between PsO And IBD

GRAIL: statistical genomics method Intracellular quantifying the degree of relatedness Signaling: between genes within 11 identified loci TYK2, Outer circle: lead SNPs from shared risk JAK2, loci STAT3

Inner circle: genes of the genomic regions around lead SNPs that were identified based on linkage disequilibrium properties

Lines: represent significant connections, thickness and redness inversely proportional to the probability to be seen IL-23R by chance IL-12B

• Meta-analysis of 5 published GWAS on PsO (2, 529 cases and 4, 955 controls) and CD (2,142 cases and 5,505 controls) identified 11 shared susceptibility loci, including IL23R and IL-12B • Gene relationships across implicated loci (GRAIL) analysis highlights number of nonrandom and evidence-based connections between genes in loci implicated in etiology of PsO /CD

Ellinghaus D . Am J Hum Genet. 2012 90(4):636-47

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PHOENIX 2 Long-Term Efficacy of Ustekinumab in PsO Through 5 Years of Therapy, With Dose Adjustment

UST 45 mg (n=606) UST 90 mg (n=606) 100 78.9% 78.6% 80 76.5% 60 71.4%

20 Achieving PASI 75 PASI Achieving

Percentage of Patients 0 0242 4 8 12 16 20 28 40 52 64 7688 100 112 128 140 152 164 176 188 200 212 224 236 244 Week

• PHOENIX 2 is an international, DB-RCT, of mod-sev PsO patients that have failed conventional therapies (~62%) or biologics (~38%) • Patients were dosed at weeks 0/4 then q12w; PBO group crossed-over at week 12; data is analyzed as ITT and presented as observed • 81% (979/1212) of pts completed the study, 63% (759/1212) achieved PASI75 at wk 244 (NRI), 28% of patients dose-adjusted

Dose adjustment was permitted during LTE at the discretion of the investigator

Adapted from Langley R, et al. Br. Journal of Dermatology, 2014