1

Optimizing Management of IBD: Beyond Anti-TNFs

Remo Panaccione, MD, FRCPC Director, Inflammatory Bowel Disease Clinic

Professor of Medicine University of Calgary

2

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

3

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

4

Managing IBD in 2016: An evolution in IBD care

5-ASA Steroids Azathioprine1 Anti-TNFs for CD

Vedolizumab for CD5

Surgery

1995 2000 2005 2010 2015/16

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 infliximab for Crohn's Disease https://www.nice.org.uk/guidance/ta40. 4. National Institute for Health and Care Excellence technology appraisal guidance [TA329]: Infliximab, adalimumab and golimumab 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.

5-ASA Steroids Azathioprine, Cyclosporin1,2

Anti-TNFs for UC

Crohn’s disease (CD)

Vedolizumab for UC5 Anti-TNFs for CD Initial report Biosimilars

Ulcerative Colitis (UC)

5

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. 2. Sandborn WJ, et al. N Engl J Med 2007;357:228–38. 3. Hanauer SB, et al. Gastroenterology 2006;130:323–33. 4. Targan SR, et al. N Engl J Med 1997;337:1029–35.

. 1. Schreiber S, et al. N Engl J Med 2007;357:239–50. 2. Hanauer SB, et al. Lancet 2002;359:1541–9. 3. Colombel JF, et al. Gastroenterology 2007;132:52–65. 4. Sandborn WJ, et al. N Engl J Med 2007;357:228–38.

6

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

7

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)

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

Moran, Panaccione et al. Clin Gastroenterol Hepatol 2014 Mar;12(3):434-42

Cu

mu

lati

ve p

rob

abili

ty o

f m

ajo

r ab

do

min

al s

urg

ery

(%

)

Follow-up in years 0

0 1 2 3 4 5

0.1

0.2

0.3

0.4

0.5

B2 B2L1

B3

B1

8

0

Khanna R, et al. Lancet 2015

Time to first hospitalisation, surgery or complication

CM ECI

0 0 3 6 9 12 15 18 21 24

10

20

30

40

Time (months)

Ho

spit

alis

atio

n,

surg

ery

or

com

pli

cati

on

s (%

)

HR (95% CI) = 0.73 (0.62, 0.86), p<0.001

Baseline

20

40

60

80

100

Month 6 Month 12 Month 18 Month 24

p=0.790 p=0.498 p=0.389 p=0.250

Pat

ien

ts (

%)

Conventional management Early combined immunosuppression

Symptomatic remission (HBI≤4 and no corticosteroids)

20 practices 20 practices

60 patients per practice

Accelerated care treatment algorithm Usual care

REACT cluster randomisation: 898 CD in conventional management vs 1094 CD in early combined immunosuppression

Randomised Evaluation of an Algorithm for Crohn’s Treatment (REACT 1)

34.7% 27.4%

8

9

Temporal trend analysis of colectomy rates: stratified by emergent vs. elective colectomy

Colectomy rates in adults hospitalised for a flare of UC

UC, ulcerative colitis. Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates. Kaplan GG, et al. Am J Gastro 2012; 107:1879–87.

0 1997

1

2

3

4

5

6

Inci

denc

e pe

r 100

,000

pop

ulat

ion

Total

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Elective Emergent

10

Real Life vs. Clinical Trials: The example of ADA and IFX in UC

Sandborn et al. Curr Med Res Opin. 2016 Mar 30:1-9

11

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.

12

The IBD therapeutic pipeline

Registration

Launched

Phase III

Phase II

Phase I Chemokine receptors

Immunomodulators

JAK3 inhibitors

IL inhibitors

CAM inhibitors

TNF-α inhibitors Stem cell therapies

Tofacitinib Pfizer

NN8555 Novo Nordisk

laquinimod Teva / Active Biotech Rifaximin EIR AlphaWessermann

RDP 58 Genzyme

ZP1848 Zealand

CCX-025 GSK

CCX282-B GSK

TNFK-005 Neovacs

C326 QPharm

Vidofludimus 4SC

PF-04236921 Pfizer

AMG 827 Amgen

PF 05230900 Pfizer

AIN 457 Novartis

GSK 1070806 GSK

QAX576 Novartis

SCH-900222 Merck & Co

Ustekinumab Centocor

ELND-004 Elan/Biogen Idec

PF-547659 Pfizer

AJM-300 Ajinomoto

Natalizumab Elan/Biogen Idec

Vedolizumab Millenium / Takeda

HMPL-004 Hutchinson

Ozoralizumab Pfizer

Debiaerse Neovacs

Adalimumab AbbVie

Infliximab Centocor

Certolizumab pegol UCB

Remestemcel-L Osiris

PDA-001 Celgene Cellular

Cellerix

OvaSave TXCell

Adapted from Danese S. Gut 2012;61:918–32.

13

Emerging therapies in IBD

Leukocyte Trafficking inhibitors

– Vedolizumab

– Etrolizumab

– Anti-MAdCAM

Anti IL-12/23

– Ustekinumab

– Briakinumab

– Rizankinumab

Jak inhibitors

– Tofacitinib

Anti S1 P1

– Ozanimod

Anti-SMAD 7

– Mongersen

14

Lymphocytes Preferentially Migrate to Particular Tissues Throughout the Body

Salmi M, Jalkanen S. Immunol Rev. 2005;206:100-113. Agace W. Nat Rev Immunol. 2006;6:682-692.

• 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

15

α4β7 Integrin–MAdCAM-1 is One of the Interactions That Contributes to Chronic Inflammation in UC and CD

Briskin M, et al. Am J Pathol. 1997;151:97-110.

α4β7−MAdCAM-1 interaction has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC

and CD

MAdCAM-1

α4β7 integrin

Memory T lymphocyte

MAdCAM-1

β7 subunit

α4 subunit

Accumulation of excess infiltrating lymphocytes in the gastrointestinal

tissue

MAdCAM-1=mucosal addressin cell adhesion molecule-1

16

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, monoclonal antibody ; VCAM-1, vascular cell adhesion molecule-1 . 1. Soler D, et al. J Pharmacol Exp Ther 2009;330:864–75;.

17

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

AE, adverse event; CS, corticosteroid; IS, immunosuppressant; RCT, randomised controlled trial Feagan et al, N Engl J Med. 2013 Aug 22;369(8):699-710.

25 5

25 47

17

41

Response Remission Mucosal healing0

20406080

100

Pat

ien

ts (

%)

PBO (n=149) VDZ 300 mg (n=225)

All p<0.0001 VDZ vs. PBO

Week 6 outcomes after 2-dose induction

Primary endpoint

18

GEMINI I: vedolizumab in UC maintenance

15.9 23.8 19.8

41.8

56.6 51.6

44.8 52 56

Clinical remission at 52 weeks

Durable clinicalresponse

(at 6 and 52 weeks)

Mucosal healingat 52 weeks

0

20

40

60

80

100

Pat

ien

ts (

%)

Placebo (n=126)

VDZ 300 mg every 8 weeks (n=122)

VDZ 300 mg every 4 weeks (n=125)

Feagan BG et al, N Engl J Med. 2013 Aug 22;369(8):699-710.

Primary and secondary efficacy endpoints

p<0.0001

p<0.001

p<0.001

19

GEMINI I: vedolizumab in UC maintenance

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

Steroid-free clinical remission

Durable clinical remission

13.9

31.4 45.2

PlaceboN=72

VDZ300 mg q8w

N=70

VDZ300 mg q4w

N=73

0

20

40

60

80

100

Perc

ent o

f sub

ject

s

8.7 20.5 24.0

PlaceboN=126

VDZ300 mg q8w

N=122

VDZ300 mg q4w

N=125

* *

** ***

Feagan BG et al, N Engl J Med. 2013 Aug 22;369(8):699-710.

20

GEMINI II: vedolizumab in CD induction

45 40 35 30 25 20 15 10

5 0

Patie

nts

(%)

Clinical remission CDAI-100 response Clinical remission CDAI-100 response

Placebo

VDZ

4.3

10.5

22.9 23.8

9.0

18.3

28.2

38.3

95% CI: -9.1, 21.3 6.2 1.0

-11.8, 13.7 9.3

-0.2, 18.8 10.1

-3.3, 23.4

Induction ITT population Patients with prior anti-TNF failure

(n=175) Patients without prior anti-TNF failure

(n=193)

Sandborn W et al N Engl J Med. 2013 Aug 22;369(8):711-21

21

GEMINI II: vedolizumab in CD maintenance

45 40 35 30 25 20 15 10

5 0

Patie

nts

(%)

Clinical remission CDAI-100 response CS-free remission†

Placebo

VDZ Q8wk

21.6

30.1

*p<0.05, 17.4 15.3 15.9

Maintenance ITT population

50

15.9

* 31.7 *

28.8

14.4

21.4

16.2

** 45.5 *

43.5 **

36.4

** 39.0

VDZ Q4wk

†CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.

14.7 **p<0.01

13.4 12.9 Durable remission

7.2 2.0

Sandborn W et al N Engl J Med. 2013 Aug 22;369(8):711-21

22

Is there a better way forward with vedolizumab?

Bridging: co-induction with steroids?

CS, corticosteroid; IMM, immunomodulator; VDZ, vedolizumab. Colombel JF, et al. J Crohns Colitis 2015;9;S344. Abstract P528.

7.7

4.4

8.0 7.7 12.1

20.9

8.1

18.4

0

5

10

15

20

25

30

VDZ CS only and VDZ IMM only and VDZ CS and IMM and VDZ

PBO (n=148)

VDZ (n=220)

GEMINI II: Clinical Remission at Week 6 By Concomitant Medication Use at Week 0

Patie

nts,

%

23

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

*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. Sandborn WJ, et al. J Crohns Colitis 2014;8;S274-275. Abstract P497.

7.2 11.6 11.6

8.7 7.2

13.2 21.7 23.1 23.9 25.4

0

10

20

30

Week 10 Week 14 Week 18 Week 22 Week 52

PBO (n=69) VDZ (n=351)

GEMINI II: CDAI-100 Response Among Week 6 Non-responders*

Patie

nts,

%

Is there a better way forward with vedolizumab?

24

0

20

40

60

80

100

Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years

Vedolizumab and Infections: Exposure-Adjusted Incidence Rates in CD

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.

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

Nu

mb

er o

f p

atie

nts

w

ith

eve

nt

/10

0 P

Y (9

5%

CI)

89.7

68.6

37.2

29.5

7.7 9.7 6.9

6.5 3.8

5.2 4.6 3.9 3.8 3.6 6.1

3.6 5.3

3.0 0.8 2.1 1.5 2.1 4.6

2.2 0.8 1.5 2.3 0.8 0.8 0.8 0 0.6

1.5 0.7 0 0.9

0.8 0.4

0.8 0.3

PBO (n=355)a

VDZ (n=1723)b

25

0

1

2

3

4

5

6

7

Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years

Vedolizumab and Serious Infections: Exposure-Adjusted Incidence Rates in CD

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.

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

Nu

mb

er o

f p

atie

nts

wit

h

even

t /1

00

PY

(95

% C

I)

3.0 5.6

0

0.5

0.8 2.4

0

0.3

0

0.1

0

0.1

0

<0.1

0

<0.1

0

<0.1

0.8

0.3

PBO (n=355)a VDZ (n=1723)b

26

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.

27

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

• 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.

Week 10 clinical and endoscopic outcomes (all comers)

0 0 15

27 21 10 26 33

10 8

21 31 15 9

23 21

020406080

100

Remission EndoscopicRemission

Mucosal Healing Clinical Response

PBO (n = 41) ETZ 100 (n = 39) ETZ LD + 300 (n = 39) ETZ Pooled (n = 78)

**

Frac

tion

of p

ts (%

)

** *

*p < 0.05 **p < 0.01 vs. PBO Primary endpoint

Vermiere S et al. Lancet. 2014 Jul 26;384(9940):309-18

28

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

• 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

Vermeire et al. ECCO 2015, Abstract OP021

.

Primary and Secondary Endpoints at Week 12

3

29

8 11

38

16 17

54

28 16

45

25

6

50

14

0

20

40

60

80

100

Clinical Remission Clinical Response Mucosal Healing

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)

Frac

tio

n o

f P

ts (

%)

* *

*P < 0.05 vs. PBO

* * Primary Endpoint

TURANDOT

29

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

59

23 14

62

27 37

65

28 24

58

29 39

0

20

40

60

80

100

Response(CDAI-70)

Remission Remission(BL CRP > 18)

PBO (n = 63) PF 22.5 mg (n = 67) PF 75 mg (n = 64) PF 225 mg (n = 68)

• 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.

Primary and Secondary Endpoints at Week 12

Frac

tio

n o

f P

ts (

%)

Primary Endpoint

All P = NS

OPERA

30

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

Nielsen OH et al. Exp Opin Invest Drugs. 2016: doi.

S1P S1P1 Internalised S1P S1P modulators Degraded S1P

Endothelium Lymphocyte egression

Internalisation and degradation

Lymph node (low S1P concentration)

Lymphocyte egression blocked

Signalling

Lymphocyte

Signalling

Lymph (high S1P concentration)

S1P receptor modulation

31

Phase II Trial of Ozanimod (S1P1 Receptor Modulator) in Mod-Sev UC

Sandborn et al. NEJM May 2016

*P<0.05 vs placebo; **P<0.01 vs placebo

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

13.8

26.2

53.8

35.4

27.7

33.8

16.4 20.9

58.2

50.7

34.3 32.8

6.2 6.2

36.9

20

12.3 12.3

0

25

50

75

100

Week 8 Week 32 Week 8 Week 32 Week 8 Week 32

Pat

ien

ts (

%)

Low dose (N=65) High dose (N=67) Placebo (N=65)

* *

**

Mucosal Improvement (endoscopy score ≤1)

*

**

* ** ** **

Clinical Response Clinical Remission

TOUCHSTONE

32

Biology and site of action of interleukins 12 and 23

Ustekinumab and risankizumab 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

33

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

Feagan et al. NEJM in press

N=741 N=648

34

-0.18 1.03

-0.14

-4.76 -5.97

-3.97

-8.61 -8.41 -8.56

-10

-8

-6

-4

-2

0

2

4

0 1 2 3 4 5 6 7 8Weeks

PBOUST 130 mgUST ~6 mg/kg

Ustekinumab Reduces CRP at Weeks 3, 6 and 8

Mean CRP Concentration Change by Week 8 M

ean

Ch

ange

fro

m

Bas

elin

e C

RP

(m

g/L)

all p<0.001 vs. PBO

UNITI-2

Feagan et al. UEGW 2015, Abstract OP054

Subjects who had insufficient data at the designated analysis time point had their last value carried forward

Feagan et al. NEJM in press

35

Ustekinumab for Maintenance in CD: Results of Phase III

Feagan et al. NEJM in press

36

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

27 15

25

10

49

27

46 42

0

20

40

60

80

100

Clinical Effect Clinical Remission Clinical Response Clinical +Biomarkers*

PBO (n = 60) MEDI2070 (n = 59)

Frac

tio

n o

f P

ts (

%)

Primary Endpoint

Efficacy Outcomes at Week 8

• 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

Sands et al. ECCO 2015, Abstract OP025

Clinical Effect: CDAI-100 response or CDAI <150) Clinical + Biomarkers: Clinical Effect & ≥50% reduction in BL CRP or FC

P = 0.010

P = 0.102

P = 0.017 P < 0.001

37

Efficacy and Safety of Risankizumab as Induction Therapy in CD

Feagan et al. DDW 2016, Abstract 812a

Frac

tio

n o

f P

atie

nts

(%

)

Summary of Key Clinical Outcomes at Week 12

• 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

15 21 3

13 24

37 15

27 37* 42* 20*

37*

020406080

100

Remission Response EndoscopicRemission

EndoscopicResponse

PBO (n = 39)RSK 200 mg (n = 41)RSK 600 mg (n = 41)

*p < 0.05 Primary Endpoint

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

38

Phase 2 Psoriasis: Risankizumab vs. ustekinumab PASI Results

39

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

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

• Dosing has potential to be the most patient friendly at once every 3 months

• Potential for durability above IL-12/23 and IL-17s at one year

?Best-in-class Biologic?

Sources: Humira (CHAMPION and REVEAL), Stelera (PHEONIX 1 and 2), COSENTYX (ERASURE and FIXTURE), Ixekizumab (UNCOVER 1, 2, 3), Tildrakizumab (Merck AAD 2013), Guselkumab (NEJM 2015), BI655066 (EADV 2015)

40

Tofacitinib is a JAK Inhibitor

40

JAK JAK

Cytokine

g b a

STA

T S

TAT

mRNA

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, interleukin; 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

Tofacitinib (CP-690,550) blocks phosphorylation of STAT and downstream activation

Cytokine Effects on the immune system

IL-2 Stimulate the proliferation and differentiation of Th, Tc, B, and NK cells

IL-4 Induce the differentiation of Th0 to Th2 Induce Ig switching

IL-7 Promote the development, proliferation and survival of T, B, and NK cells

IL-9 Stimulate intrathymic T cell development

IL-15 Promote the proliferation, cytotoxicity and cytokine production of NK cells

IL-21 Enhance T and B cell function

● Safety data showed no new or unexpected observations from results in tofacitinib studies in other populations

41

Efficacy and Safety of Tofacitinib in Phase 3 Moderate to Severe UC

Tofacitinib 10 mg BID (n=476) Placebo (n=122)

18.5

31.3

8.2 15.6

0102030405060

Overall Overall

Pat

ien

ts (

%)

Mucosal Healing Remission

OCTAVE Induction 1

16.6

28.4

3.6 11.6

0102030405060

Overall Overall

Pat

ien

ts (

%)

OCTAVE Induction 2 Mucosal Healing Remission

** ***

*** ***

Δ10.3

Δ15.7 Δ16.8

Δ13.0

Difference from placebo

12.6

25.2 24.0

39.6

1.5

15.8

6.2

26.3

0

10

20

30

40

50

60

TNFi-treated

TNFi-naive

TNFi-treated

TNFi-naive

Pat

ien

ts (

%)

Δ11.1

Δ9.4 Δ17.9

Δ13.3

12.0

22.1 21.8

36.4

0 8.5 6.2

19.1

0

10

20

30

40

50

60

TNFi-treated

TNFi-naive

TNFi-treated

TNFi-naive

Pat

ien

ts (

%)

Δ12.0

Δ13.5 Δ15.6

Δ17.3

Tofacitinib 10 mg BID (n=429) Placebo (n=112)

**P<0.01 vs placebo; ***P<0.001 vs placebo. BID=twice daily; TNFi=tumor necrosis factor inhibitor. Sandborn WJ et al. ECCO 2016. Abstract A-1213.

Onset of Action of Tofacitinib in Phase 3 OCTAVE Induction Studies

42

OCTAVE Induction 1 OCTAVE Induction 2

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Baseline Week 2 Week 4 Week 8

Me

an C

han

ge F

rom

Bas

elin

e

in P

arti

al M

ayo

Sco

re (

SE)

Placebo (N=122)Tofacitinib 10 mg BID (N=476)

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Baseline Week 2 Week 4 Week 8

Placebo (N=112)Tofacitinib 10 mg BID (N=429)

***

*** ***

***

*** ***

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.

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.

44

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.

45

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

p- = ns

p=0.04

p-= ns

p= 0.04

Danese, Panaccione et al. Submitted NEJM

n=249 2 doses sc @ week 0 and 4

46

Anti-IL-6 Antibody (PF-04236921) in Subjects with Crohn’s Disease

* 1-sided p value < 0.05.

CDAI 70 CDAI 100

CDAI Remission CDAI Change from Baseline

Danese, Panaccione et al. Submitted NEJM

47 Danese, Panaccione et al. Submitted NEJM

Anti-IL-6 Antibody (PF-04236921) in Subjects with Crohn’s Disease: Suppression of CRP

48

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

Image adapted from Nielsen et al. Exp Opin Invest Drugs. 2016: doi 10.1517/13543784.2016.1165204.

1. Nielsen et al. Exp Opin Invest Drugs. 2016: doi 10.1517/13543784.2016.1165204. 2. ClinicalTrials.gov NCT02601300.

Nucleus

Cytoplasm

SMAD3

SMAD2 SMAD4 P

e.g. SMAD7

TGF-βRII TGF-βRI

TGF-βI

SMAD7 SMAD3

SMAD2 P

SMAD4 Mongersen

P

48

49

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

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

50

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

21 14

21 15

29 29

58

70 63

67 72

67

0

20

40

60

80

100

Day 15 Day 28 Day 84

PBO MNG 10 mg/d MNG 40 mg/d MNG 160 mg/d

• 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

Monteleone et al. NEJM 2015.

CDAI Remission Over 3 Months

*Clinical Remission (CDAI ˂ 150 at day 15 and maintained for ≥ 2 wks)

Frac

tio

n o

f P

ts (

%)

*P < 0.0001 vs. PBO #P ≤ 0.0008 vs. PBO

# # * * * *

9/42 6/41 23/40 29/43 6/42 12/41 28/40 31/43 9/42 12/41 25/40 29/43

51

-160

-140

-120

-100

-80

-60

-40

-20

0

Me

an C

han

ge F

rom

Bas

elin

e

in C

DA

I Sco

re†

Phase IIb: Mongersen Endoscopic and Clinical Outcomes Study ΔCDAI Mean Change From Baseline Through Week 12

Data From All Treatment Groups

63 56 62 44 21 n=

Study Week

8 12 2 4

-133

* *

*

*

*P<0.0001

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

Feagan et al. UEGW 2016

Pooled analysis of 3 dosing groups GED 301 160mg X 4 weeks GED 301 160 mg X 8 weeks GED 301 160 mg X12 weeks

52

53 44

67

0102030405060708090

100

GED-0301 Treatment Group

4 Weeks 8 Weeks 12 Weeks (N=19) (N=23) (N=21)

Pat

ien

ts A

chie

vin

g C

linic

al

Re

spo

nse

* (%

)

Clinical response week 12

32 35

48

0102030405060708090

100

GED-0301 Treatment Group

4 Weeks 8 Weeks 12 Weeks

(N=19) (N=23) (N=21)

Pat

ien

ts A

chie

vin

g C

linic

al

Re

mis

sio

n*

(%)

Clinical remission week 12

Phase IIb: Mongersen Endoscopic and Clinical Outcomes Study

Feagan et al. UEGW 2016

53

Phase Iib: Mongersen Endoscopic Response at Week 12: SES-CD Reduction by ≥25% and ≥50%

53

*Data as observed.

SES-CD Reduction by ≥25%

All Evaluable Patients

Baseline SES-CD >12

37

63

0

20

40

60

80

100

Pat

ien

ts A

chie

vin

g En

do

sco

pic

R

esp

on

se*

(%)

19/52 10/16

15

31

0

20

40

60

80

100

8/52 5/16 n/N=

SES-CD Reduction by ≥50%

All Evaluable Patients

Baseline SES-CD >12

Pat

ien

ts A

chie

vin

g En

do

sco

pic

R

esp

on

se*

(%)

Feagan et al. UEGW 2016

54

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