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

Themistocles.Dassopoulos@BSWHealth.org

Tel: 469-800-7189; Cell: 314-686-2623

Neurath Nature Reviews. 2014

IBD Pathogenesis

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

Teng Nature Med. 2015

---Ustekinumab---UstekinumabAnti-P19---

Lobaton. Aliment Pharamcol Ther 2014

Abrilumab

MAdCAM-1 VCAM-1

α4β1 α4β7

Lam

ina

pro

pri

a

Extravasation

Gut-homing T cells

E-cadherin

αEβ7

αE β7 α4 β7 α4 β1

Etrolizumab

Adapted from Marsal J, Agace WW. J Int Med. 2012;272(5):411-429; Vermeire S et al. Lancet. 2014;384(9940):309-318.

Etrolizumab, anti-β7 mAb, Selectively Blocks

T Cell Trafficking and Retention

UNITI: Phase III UST Development Program in CD

Feagan et al. N Engl J Med 2016; 375: 1946-1960

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

UST Achieves Superior Clinical Outcomes after Single IV Dose in anti-TNF & Conventional Failures

UNITI-1 aTNF Failures

UNITI-2 Conventional Failures

22

7

34

16

34

21

0

20

40

60

80

100

Wk 6 CR-100 Wk 8 Rem

PBO (n = 247)UST 130 mg (n = 245)UST ~6 mg/kg (n = 249)

Fra

cti

on

of

pati

en

ts (

%)

*

* 29

20

52

31

56

40

0

20

40

60

80

100

Wk 6 CR-100 Wk 8 Rem

PBO (n = 209)UST 130 mg (n = 209)UST ~6 mg/kg (n = 209)

*

*

*p < 0.005 any UST vs. PBO; ** p=0.009

CR: Clinical Response

Primary Endpoint

*

*

*

**

Primary Endpoint

• 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%)

Feagan et al. N Engl J Med 2016; 375: 1946-1960

UST SC Maintains Clinical Remission and Response

36

44

30

49

58

43

53 59

47

0

20

40

60

80

100

Clinical Remission Clinical Response(CR-100)

Steroid FreeRemission

PBO Maintenance (n = 131)UST 90 mg SC q12w (n = 129)UST 90 mg SC q8w (n = 128)

Clinical Outcomes at Week 52 F

racti

on

of

pati

en

ts (

%)

*p < 0.05; **p<0.005; (*), (**) nominal; Any UST vs. induction only

Primary Endpoint

* **

* *

(*) (*)

• 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%)

Feagan et al. N Engl J Med 2016; 375: 1946-1960

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

Rates of Clinical Outcomes Appear Higher in Bio-Naïve Patients

22

34

0

20

40

60

80

100

Wk 6 CR-100

PBO (n = 247)

UST ~6 mg/kg (n = 249)

33

56

0

20

40

60

80

100

Wk 6 CR-100

PBO (n = 135)

UST ~6 mg/kg (n = 144)

*

UNITI-1

aTNF Failures

UNITI-2

aTNF-Naïve **

• 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

Fra

cti

on

of

pati

en

ts (

%)

Fra

cti

on

of

pati

en

ts (

%)

∆ 23%

∆ 12% *

SES-CD reduction ≥3 from induction BL

SES-CD reduction ≥50% from induction BL Rutgeerts et al. UEGW 2016, Abstract OP104

UST Reduces Endoscopic Activity at Weeks 8 and 52

• 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

30

48

0

20

40

60

80

100F

racti

on

of

pati

en

ts (

%)

PBO

(n = 97)

Combined IV UST

(n = 155)

P = 0.005

SES-CD Reduction >3 (wk 8)

4

14 6

17 24

34

0

20

40

60

80

100PBO maintenanceUST 90 mg q12wUST 90 mg q8w

∆ 20%

P=0.012 ∆ 20%

P=0.043

SES-CD reduction ≥50% (wk 52)

Primary Randomized

Population Pooled

Population

Fra

cti

on

of

pati

en

ts (

%)

n = 24 17 29 51 47 74

Ma, C Inflamm Bowel Dis 2017;23:833–839

Proportion of patients with CD experiencing loss of response to ustekinumab maintenance therapy

Papp et al. J Drugs Dermatol 2015;14:706-14 * within 91 days of Bx Administration (NMSC:non-melanoma skin cancer)

Cumulative Incidence Rates of

Malignancy (Excluding NMSC) in PsO

PSOLAR: Psoriasis Longitudinal Assessment and Registry

Rates of Malignancy (Excluding NMSC) per 100 PY* R

isk o

f S

I/100 P

Y

• 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

0.48 0.79 0.73 0.84 0.68

0

1

2

3

4

5

UST IFX Non-SponsorBx

Non-Bx Total

UST IFX Non-Sponsor Bx Non-Bx Total

PY 12742 5176 15991 6749 40388

Loftus et al. ECCO 2016 Abstract P626 * within 91 days of Bx Administration (SI= Serious Infection)

Incidence of Serious Infections in

patients with PsO and prevalent IBD Rates of Serious Infections per 100 PY*

Ris

k o

f S

I/100 P

Y

• 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

1.38

5.75

4.32 3.47 3.81

0.93

2.91 1.91

1.43 1.60

0

2

4

6

8

10

UST IFX Non-Sponsor Bx Non-Bx Total

IBD subset Full PSOLAR population

PY 218 7944 226 3301 301 12823 173 16322 918 40389

PSOLAR

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

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

Tofactinib Jak 1>3

Filgotinib/

Upadacitinib Jak 1

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

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

10mgBIDb

5mgBIDb

10mgBID

Placebo

5mgBID

10mgBID

Placebo

Completers&TreatmentFailures

A3921139Open-labelextension

Enrollm

ent

Assessm

ent

OCTAVESustain

52weeksa

Re-randomization

Assessmen

t

OCTAVEInduction1

10mgBID

Placebo

8weeksa

Ran

domization

Assessm

ent

Non-responders

Responders

OCTAVEInduction2

8weeksa

Ran

domization

Assessm

ent

Responders

Non-responders

Demographics and Baseline Characteristics

21

OCTAVE Induction 1 OCTAVE Induction 2

Placebo

N=122

Tofacitinib 10 mg BID

N=476

Placebo

N=112

Tofacitinib 10 mg BID

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)

Tofacitinib Efficacy by TNF inhibitor exposure

1.5

15.812.6

25.2

0

20

40

60

Yes No

Pe

rce

nt o

f p

ati

en

ts w

ith

re

mis

sio

n

Prior TNFi exposure

0

8.512.0

22.1

0

20

40

60

Yes No

Pe

rce

nt o

f p

ati

en

ts w

ith

re

mis

sio

n

Prior TNFi exposure

6.2

26.324.0

39.6

0

20

40

60

Yes No

Pe

rce

nt o

f p

ati

en

ts w

ith

mu

co

sa

l h

ea

lin

g

Prior TNFi exposure

6.2

19.121.8

36.4

0

20

40

60

Yes No

Pe

rce

nt o

f p

ati

en

ts w

ith

mu

co

sa

l h

ea

lin

g

Prior TNFi exposure

OCTAVE Induction 1 OCTAVE Induction 2

∆=11.1

∆=9.4

∆=12.0

∆=13.5

∆=15.6

∆= 17.3

∆=17.9

∆=13.3

Remission Remission

Mucosal healing Mucosal healing

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

Mucosal healing

23

Sandborn New England J Med in press

13.1

37.4 45.7

0

10

20

30

40

50

60

70

80

90

100

Mucosal healing at Week 52

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID

n/N 26/198 74/198 90/197

Diff.fromplacebo(95%CI)

- 24.2(16.0,32.5)

32.6(24.2,41.0)

p<0.001

p<0.001

∆=32.6

∆=24.2

Proportionofpatients(%)

Sustained Corticosteroid -free Remission

24

Sandborn et al New Eg J Med in press

5.1

35.4

47.3

0

10

20

30

40

50

60

70

80

90

100

Sustained steroid-free remission at Weeks 24 & 52, among remitters at baseline

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID

n/N 3/59 23/65 26/55

Diff.fromplacebo(95%CI)

- 30.3(17.4,43.2)

42.2(27.9,56.5)

p<0.001

p<0.001

∆=42.2

∆=30.3

Proportionofpatients(%)

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

Results of the OCTAVE maintenance trial of tofacitinib in ulcerative colitis

Incidence rates of herpes zoster and herpes simplex associated with anti-TNF and tofacitinib in RA

Events

Person-Years

Incidence Rate*

Adjusted HR♮ (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

27

Sandborn New England J Med

Placebo

N=198

Tofacitinib5mgBIDN=198

Tofacitinib10mgBIDN=197

Adverseevents,n(%) 149(75.3) 143(72.2) 156(79.6)

Mostfrequentlyoccurringadverseeventsbypreferredterm(≥8%),n(%)

Worseningulcerativecolitis 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)

Seriousadverseevents,n(%) 13(6.6) 10(5.1) 11(5.6)

DiscontinuationsDuetoadverseevents,n(%)a

37(18.7) 18(9.1) 19(9.7)

Insufficientclinicalresponse,n(%)b 132(66.7) 70(35.4) 53(27.0)

Safety events of special interest

28

Sandborn New England J Med \

Placebo

N=198

Tofacitinib5mgBIDN=198

Tofacitinib10mgBIDN=197

Infections,n(%) 48(24.2) 71(35.9) 78(39.8)

Seriousinfections,n(%)a 2(1.0) 2(1.0) 1(0.5)

Herpeszoster,n(%)Allcasesb

1(0.5) 3(1.5) 10(5.1)

Multidermatomal(non-adjacentor>2adjacentdermatomes)c

1(0.5) 2(1.0) 4(2.0)

Disseminatedc 1(0.5) 0(0) 0(0)

Cardiovascularevents,n(%)d 0(0.0) 1(0.5)e 1(0.5)f

Intestinalperforations,n(%)d,g 1(0.5)h 0(0.0) 0(0.0)

Malignancies,excludingNMSC,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)

37

54

44

71

43

69

0

20

40

60

80

100

Remission wk 8 CR-100

PBO Tofa 5 mg BID Tofa 10 mg BID

Primary Endpoint

8-Week Induction Study (N = 280)

*

91 86 86 91 86 86

Efficacy and Safety of Tofacitinib in Crohn’s Disease

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

Panes et al. ECCO 2016, Abstract OP022

Frac

tio

n o

f p

atie

nts

(%

)

Efficacy and Safety of Filgotinib in Mod-Sev CD

18

34

0

20

40

60

80

100

ΔinIBDQ

23

4148

60

0

20

40

60

80

100

Remission CR-100

PBO 200mgFGN

RemissionandResponseWeek10(N=275) ChangeinIBDQatWeek10

Mean

Chan

gein

IBDQScore

PrimaryEndpoint

10/4461/12818/4477/128

*

**

**

Fractionofpatients(%)

aTNF-experienced(68%);CR:ClinicalResponse;*p<0.05;**p<0.01

Vermeireetal.ECCO2016,AbstractOP020

• 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

Modulation of S1P Receptors Results in Retention of Lymphocyte Subsets (CCR7+) in the Lymph Node

Ozanimod : Study Design

Induction Period Maintenance Period

Randomization

Placebo (N=65)

Ozanimod 0.5 mg (N=65)

Ozanimod 1 mg (N=67)

Mayo Responders

No

n-R

esp

on

ders

Open-Label Ozanimod 1 mg

Primary Endpoint: Induction

Disease Relapse

Week 32 Maintenance

Endpoint 1 Week

Initial Doses

8 Weeks Treatment

24 Weeks Treatment

Clinical Remission* at Week 8 and Week 32

6.2% 6.2%

13.8%

26.2%

16.4%

20.9%

0%

10%

20%

30%

Week 8 Week 32

Placebo (N=65) Ozanimod 0.5 mg (N=65) Ozanimod 1 mg (N=67)

Pat

ien

ts (

%)

p=0.002 p=0.010

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

p=0.140 p=0.048