A Randomized, Double-Blind, Placebo-Controlled Induction

Trial of an Oral S1P Receptor Modulator Ozanimod

(RPC1063) in Moderate to Severe Ulcerative Colitis:

Results of the TOUCHSTONE Study

William Sandborn, MD

21 February 2015

Barcelona, Spain

W.

Sandborn¹,

B.

Feagan²,

D.

Wolf³,

G.

D'Haens

4

,

S.

Vermeire

5

,

S.

Hanauer

6

,

S. Ghosh

7

, H. Smith

8

, M. Cravets

8

, P. Frohna

8

, S. Gujrathi

8

, A. Olson

8

1

University of California San Diego, Division of Gastroenterology, La Jolla, United States

2

University of Western Ontario, Department of Gastroenterology, London, Canada

3

Atlanta Gastroenterology Associates, Emory Saint Joseph's, Atlanta, United States

4

Academic Medical Centre, Inflammatory Bowel Disease Centre, Amsterdam, Netherlands

5

University Hospital Leuven, Department of Gastroenterology, Leuven, Belgium

6

Northwestern University Feinberg School of Medicine, Digestive Health Center, Chicago, United States

7

University of Calgary, Department of Gastroenterology, Alberta, Canada

8

Receptos, Inc., Clinical Development, San Diego, United States

Conflict of Interest Statements

•

W Sandborn-

Financial support for research: Receptos, Jansen, Abbvie, Prometheus

Laboratories, Pfizer, Amgen, Genentech, Takeda. Consultancy: Receptos, Jansen, Abbvie, UCB

Pharma, Shire, Salix, Actavis, Prometheus Laboratories, Pfizer, Amgen, Genentech, Takeda

•

B Feagan-

Consultancy: AbbVie, Actogenix, Albireo, Amgen, AstraZeneca, Avaxia Biologics,

Baxter, Biogen Idec, Boehringer-Ingelheim, BMS, Calypso, Celgene, Elan, EnGene, Ferring

Pharma, Roche/Genentech, GiCare, Gilead, Given Imaging, GSK, Ironwood, Janssen, JnJ,

Lexicon, Lilly, Merck, Millennium, Nektar, Novonordisk, Pfizer, Prometheus, Protagonist,

Receptos, Sanofi, UCB. Directorship: Robarts Clinical Trials

•

D Wolf-

Financial support for research: AbbVie, Amgen, Elan, Given Imaging, Genentech,

Janssen, Millennium, Pfizer, Prometheus, Receptos, UCB. Lecture fees: AbbVie, Janssen,

Prometheus, Santarus, Salix, Takeda, UCB. Consultancy: AbbVie, Genentech, Given Imaging,

Janssen, Prometheus, Salix, Takeda, UCB

•

G D’Haens-

Consultancy: Abbvie, Ablynx, Actogenix, Amgen, AM Pharma, AstraZeneca,

Boerhinger Ingelheim, Cosmo, Elan, Ferring, DrFALK Pharma, Celgene, Celltrion, Janssen,

Engene,

Galapagos,

Giuliani,

GivenImaging,

GSK,

Hospira,

Takeda,

Mitsubishi

Pharma,

MSD,

Mundipharma,

Novonordisk,

Norgine,

Otsuka,

Pfizer,

Photopill,

PDL,

Prometheus,

Receptos,

Robarts, Salix, Sandoz, Setpoint, Shire, TEVA, Tigenix, Tillotts, UCB, Versant, Vifor

•

S Vermeire-

Financial support for research: Abbvie, MSD, Centocor. Consultancy: Abbvie, MSD,

Takeda,

Pfizer,

Genentech/Roche,Ferring,

Mundipharma,

Receptos

•

S Hanauer-

Consultancy: Receptos, AbbVie, Janssen, UCB, Shire, Actavis, Salix, BMS, Merck,

Pfizer, Boehringer-Ingelheim, Sanofi-Aventis, Ferring, Celgene, Caremark

•

S Ghosh-

Financial support for research: Abbvie. Lecture fees: Abbvie, MSD. Consultancy:

Pfizer, Novo Nordisk BMS , Janssen, Abbvie, Receptos

•

H Smith,

M

Cravets,

P

Frohna,

S

Gujrathi,

and

A

Olson

are

full-time

employees

of

Receptos

•

S1P

1R

signaling on CCR7+

lymphocytes (central

memory T cells) facilitate

their exit from lymph nodes 

along an S1P gradient

•

Ozanimod induces S1P

1R

internalization so

lymphocytes do not respond

to S1P and are retained in

the lymph node

•

Protective immunity is

generally preserved since

CCR7-

lymphocytes (effector

memory T cells) do not

circulate through the lymph

nodes

S1P

1R

Modulation Results in Sequestration

of Select Lymphocyte Subsets

S1P

1R

Modulators

•

Fingolimod

is

the

first

S1P

receptor

modulator

(S1P

1,3,4,5R

)

and

oral

agent approved in 2010 for the treatment of Relapsing Multiple

Sclerosis (RMS)

•

Well established efficacy and safety profile

•

Over 100,000 patients have been treated with Fingolimod

•

No increase in serious infections, opportunistic infections, TB,

PML or malignancies over time

•

Warnings and Precautions include first dose cardiac effects (HR

reduction and cardiac conduction abnormalities), LFT elevations,

and macular edema

•

Ozanimod

(RPC1063)

is

a

next

generation

oral

S1P

receptor

modulator

•

Increased

selectivity

for

the

S1P

1R

and

S1P

5R

•

Improved pharmaceutic properties that allow for enhanced tissue

penetration and faster clearance

•

Demonstrated efficacy in a Phase 2 trial in RMS patients

•

Clinical trial experience to date has demonstrated an improved

cardiovascular

profile,

reduced

LFT

elevations,

no

macular

edema

and rapid lymphocyte recovery

Patient Population: Key Inclusion/Exclusion

Criteria

•

Inclusion:

•

Adults with moderate to severe UC defined by a Mayo score of 6-

12 inclusive with endoscopic subscore

2 by central read

•

Receiving treatment with oral aminosalicylates and/or prednisone

•

Patients were allowed to receive MTX, 6-MP or AZA until the day

of dosing with Ozanimod

•

Exclusion:

•

Treatment with biologics within 5 half-lives

•

History of clinically relevant cardiovascular disease

•

Resting heart rate

55 bpm

Study Design

Induction Period

Maintenance Period

Randomization

Placebo (N=65)

Ozanimod 0.5 mg (N=65)

Ozanimod 1 mg (N=67)

Mayo Responders

Open-Label

Primary

Endpoint:

Induction

Disease

Relapse

Week 32

Maintenance

Endpoint

1 Week Dose

Titration

8 Weeks

Treatment

24 Weeks

Treatment

•

Conducted at 57 sites in 13 countries

•

Induction period completion rate: 95%

Study Endpoints and Methods

•

Primary Efficacy Endpoint

•

Proportion of patients in clinical remission at Week 8,

defined as a Mayo score

2 points with no subscore > 1

point

•

Key Secondary Efficacy Endpoints

•

Proportion of patients with clinical response at Week 8

•

Change from Baseline in Mayo score at Week 8

•

Proportion of patients with mucosal improvement/mucosal

healing (endoscopic subscore

1)

•

Methods

•

All endoscopies were read centrally by a blinded evaluator

for both eligibility confirmation and endpoint scoring

•

Subjects with different central and local endoscopic sub-

scores had an additional central read and adjudication

Patient Demographics and UC Disease History

Placebo

(N=65)

Ozanimod 0.5 mg

(N=65)

Ozanimod 1 mg

(N=67)

Demographics

Male –

n (%)

35 (53.8)

32 (49.2)

48 (71.6)

Age (years)

–

mean (SD)

41.9 (12.3)

38.8 (12.1)

41.8 (11.0)

UC Disease History

Years

since

UC

diagnosis

–

mean

(SD)

6.1 (5.5)

5.9 (5.4)

6.7 (6.8)

Mayo

Score

by

central

read

–

mean

(SD)

8.6 (1.5)

8.3 (1.5)

8.5 (1.6)

Prior anti-TNF medication –

n (%)

10 (15.4)

12 (18.5)

15 (22.4)

Prior

use

of

AZA/6-MP/MTX

–

n

(%)

17 (26.2)

24 (36.9)

22 (32.8)

Baseline

use

of

corticosteroids

–

n

(%)

23 (35.4)

22 (33.8)

26 (38.8)

1°

Endpoint: Proportion of Patients in Remission at

Week 8 (Adjudicated Central Read)

p = 0.1422

p = 0.0482

6.2%

13.8%

16.4%

0%

5%

10%

15%

20%

Treatment Group

Placebo (N=65)

Ozanimod 0.5 mg (N=65)

Ozanimod 1 mg (N=67)

p = 0.0698

p = 0.0114

p = 0.1422

p = 0.0482

Comparison of 1°

Endpoint: Original Central Read vs.

Adjudicated Central Read

4.6%

6.2%

13.8%

13.8%

17.9%

16.4%

0%

5%

10%

15%

20%

Original Central Read

Adjudicated Central Read

Placebo (N=65)

Ozanimod 0.5 mg (N=65)

Ozanimod 1 mg (N=67)

2°

Endpoint: Proportion of Patients in Clinical Response

at Week 8 (Adjudicated Central Read)

p = 0.0648

p = 0.0140

36.9%

53.8%

58.2%

0%

10%

20%

30%

40%

50%

60%

70%

Treatment Group

Placebo (N=65)

Ozanimod 0.5 mg (N=65)

Ozanimod 1 mg (N=67)

2°

Endpoint:

Proportion

of

Patients

With

Mucosal

Improvement/Mucosal

Healing

(Endoscopy

score

of

1

at

Week

8,

Adjudicated

Central

Read)

p = 0.0348

p = 0.0023

12.3%

27.7%

34.3%

0%

10%

20%

30%

40%

Treatment Group

Placebo (N=65)

Ozanimod 0.5 mg (N=65)

Ozanimod 1 mg (N=67)

Safety: Treatment Emergent Adverse Events

Number of Subjects

Placebo

(N=65)

Ozanimod 0.5 mg

(N=65)

Ozanimod 1 mg

(N=67)

1 TEAE

22 (33.8)

23 (35.4)

19 (28.4)

Most Common TEAEs

Placebo

Ozanimod 0.5 mg

Ozanimod 1 mg

Anemia / Decreased HgB

4 (6.2)

4 (4.6)

0

Worsening of UC

3 (4.6)

2 (3.1)

1 (1.5)

Serious TEAEs

Placebo

Ozanimod 0.5 mg

Ozanimod 1 mg

Number of Subjects with

1 Serious TEAE

4 (6.2)

1 (1.5)

1 (1.5)

Colitis ulcerative

2 (3.1)

0

1 (1.5)

Hyperpyrexia

0

1 (1.5)

0

Iron deficiency anemia

1 (1.5)

0

0

Jaundice (due to cholestasis)

1 (1.5)

0

0

No notable cardiac, ophthalmologic, or infectious TEAEs observed

24-hr Holter Monitoring Findings

Placebo

(n=65)

Ozanimod 0.25 mg

(n=132)

Subjects with 2

Degree AVB

0

0

Subjects with Sinus Pause

0

0

Safety: Holter Monitoring and Transaminase

Elevations

ALT elevation > 3xULN

Placebo

(n=65)

Ozanimod 0.5 mg

(n=65)

Ozanimod 1 mg

(n=67)

ALT elevation

0

2 (3.1)

1 (1.6)

ALT

elevations

were

asymptomatic,

transient,

not

associated

with

elevations

in

bilirubin

and

improved

while receiving Ozanimod

nd

Conclusions

•

Ozanimod

1

mg

induced

clinical

remission

at

Week

8

(1

°

EP)

•

All 3 secondary endpoints were met for Ozanimod 1 mg at Week 8

•

Proportion of patients with a clinical response

•

Change from baseline in Mayo score

•

Proportion of patients with mucosal improvement

•

A dose response relationship was observed for all primary and key

secondary efficacy endpoints

•

Ozanimod was well tolerated with a favorable benefit-risk profile