Present Situation and Problems of Clinical Trials for inflammatory bowel

disease in Japan

Takayuki MatsumotoDivision of Gastroenterology, Iwate Medical University

Japan

PMDA WorkshopFuture Perspectives in the Development of Novel Medications for IBD

(2015.2.4. Tokyo)

Available or Provisionally Applicable Biologics for the Treatment of Crohn’s Disease

Registration

Launched

Phase III

Phase II

Phase IChemokine receptors

Immuno-modulators

JAK3 inhibitors

IL inhibitors

CAM inhibitors

TNF-α inhibitorsStem cell therapies

Tofacitinib Pfizer

NN8555 Novo Nordisk

laquinimod Teva / Active Biotech

Rifaximin EIRAlphaWessermann

RDP 58 Genzyme

ZP1848 Zealand

CCX-025 GSK

CCX282-B GSK

TNFK-005 NeovacsC326 QPharm

Vidofludimus 4SCPF-04236921 Pfizer

AMG 827 AmgenPF 05230900 Pfizer

AIN 457 NovartisGSK 1070806 GSK

QAX576Novartis

SCH-900222 Merck & CoUstekinumab Centocor

ELND-004 Elan/Biogen IdecPF-547659 Pfizer

AJM-300 Ajinomoto

NatalizumabElan/Biogen Idec

VedolizumabMillenium / Takeda

HMPL-004 Hutchinson

Ozoralizumab Pfizer

DebiaerseNeovacs

Adalimumab AbbVie

InfliximabCentocor

Certolizumab pegol UCB

Remestemcel-L Osiris

PDA-001 Celgene CellularCellerix

OvaSave TXCell

Danese S: Gut 2012

Present Situation and Problems of Efficacy Assessment in Biologics for Crohn’s Disease

1. Provisional differences in response to biologics between Western and Asian populations.

2. Differences in protocols and results of clinical trials between Western countries and Japan (i.e. Adalimumab for Crohn’s disease).

3. Problems in objective assessment of efficacy.

4. Problems in practical management of clinical trials(subject enrollment, global trials, etc.) including clinician-orientated clinical trials.

Genome-wide Association Study of Japanese Patients with Crohn’s Disease

Yamasaki K, Matsumoto T, et al. Gastroenterology 2013

Aquired immunityInnate immunity

IL23R

JAK2

STAT3

TNFSF15

Comparison of Crohn’s Disease-Associated Genes between Western and Japanese Population

IL12B

TYK2

CCR6

IL2RA

Strong association in Jp

Weak association in Jp

No association in Jp

No SNP in Jp

Not enough power

LRRK2

CARD9

NOD2

ATG16L1

IRGM

Hirano A, Matsumoto T, et al. Inflammatory Bowel Dis 2013

Major Clinical Trials for Adalimumab in Crohn’s Disease

Japan

Western countriesCLASSIC I

M02-403 InductionInfliximab naïve CHARM

M02-404 MaintenanceInfliximab naïve + failureGAIN

M04-691 InductionInfliximab failure

M06-837 MaintenanceM04-729 InductionInfliximab naïve + failure

Results of Induction Trial

*p<0.05 vs. placebo (FAS population)

Clinical Remission

Clinical Response∆100

Clinical Response ∆70

Per

cent

age

of S

ubje

cts

n=23 n=34 n=33

13.0 17.6

33.3

*

**

17.4

50.0 45.5

30.4

58.8

69.7

0

20

40

60

80 Placebo 80/40 mg 160/80 mg

Watanabe M, et al. J Crohn’s Colitis 2012

Comparison between Induction Trials（Patients Naïve to Infliximab）

Western area（CLASSIC I）

*p<0.05 vs. placebo (FAS population)

*

*

* *

12.2

25.0

36.8

24.0

40.0

58.6

35.5

50.0

59.5

0

20

40

60

80

Placebo 80/40 mg 160/80 mg

20.0

28.6

42.9

20.0

57.1

50.0

20.0

71.4 78.6

n=74 n=75 n=76

Clinical Remission

Clinical Response

∆100

Clinical Response

∆70

Japan（M04-729）

No statistical test was conducted.

0

20

40

60

80

Placebo 80/40 mg 160/80 mgn=10 n=14 n=14

Clinical Remission

Clinical Response

∆100

Clinical Response

∆70

Western area（GAIN）

*p<0.05 vs. placebo (FAS population)

n=166 n=159

*

*

*

7.2

24.7

33.7

21.4

38.4

51.6

0

20

40

60

80Placebo 160/80 mg

7.710.0

26.3

15.4

45.0 42.138.5

50.0

63.2

Clinical Remission

Clinical Response

∆100

Clinical Response

∆70

Japan（M04-729）

No statistical test was conducted.

n=13 n=19n=20

0

20

40

60

80Placebo 80/40 mg 160/80 mg

Clinical Remission

Clinical Response

∆100

Clinical Response

∆70

Comparison between Induction Trials（Patients with Prior Use of Infliximab）

Comparison between Maintenance Trials

Japan（M06-837）

Pat

ient

s in

Rem

issi

on (%

) *

*

**

42.4

17.111.8

47.1

39.5 36.0

*40.9

18.2

9.1

38.1 33.3

38.1 38.9

46.5 41.4

0

10

20

30

40

50

Week 4 Week 26 Week 56 Week 0x Week 24x Week 52x

Placebo 40 mg EOW 40 mg Weekly

NRI ( Non-responder imputation)*p<0.05 vs. placebo (FAS population)

Western area（CHARM）

Current measures of Crohn’s disease activity

Clinical activity• CDAI Crohn’s disease activity index developed by the NCCDS• HBI Harvey–Bradshaw simple indexEndoscopic activity• CDEIS Crohn’s disease endoscopic index of severity developed

and validated by the GETAID for ileocolonic or colonic disease

• SES-CD Simplified version of CDEIS• Rutgeerts Score dedicated to endoscopic post-operative recurrence

in the neoterminal ileum after ileocolonic anastomosisHistologic activity• D’Haens, Geboes, et al. Scoring system for histological abnormalities

in Crohn’s disease mucosal biopsy specimens

Sandborn WJ, et al. Gastroenterology 2002

Simple endoscopic score for Crohn’s disease(SES-CD)

I A T D•S R total

Size of ulcer

Extent of ulcerative surface

Extent of affected surface

Narrowing（０～３）

Size of ulcer0; none 1; 0.1~0.5cm 2; 0.5cm~2cm 3; >2cm

Extent of ulcerative surface0; nine 1; <10% 2; 10~30% 3; >30%

Extent of affected surface0; none 1; <50% 2; 50~75% 3; >75%

Narrowing0; none 1; single 2; multiple 3; scope not pass through

Daperno M et al. Gastrointest Endosc 2004

Even though simplified, 1. It is extremely complicated to calculate, and2. It does not take jejunal and ileal lesions into account.

Example of SES-CD

I: 3+2+1+0=6 T: 0+0+0+0=0

D/S: 3+2+1+0=6 R: 2+1+1+0=4

SES-CD=20

A: 2+1+1+0=4

Is SES-CD predictive of clinical course of CD under infliximab?

Subjects: 44 patients with Crohn’s disease．Methods: The association between SES-CD and loss of response

to infliximab was retrospectively investigated.

Anal fistula +(n=13)

Anal fistula -(n=29) SES-CD<16（n=22）

SES-CD≧16（n=22）

SES-CD (n.s.)Anal fistula (p=0.001)

Fuyuno Y, Matsumoto T, et al.: Dig Endosc (under submission)

The Lémann score for the assessment of digestive damage in Crohn’s disease

Pariente B et al. Inflamm Bowel Dis 2011

Digestivedamage

evaluation

Patientinclusion

Investi-gations

Segment(CD locationbased onpatient evaluation)

Uppertract

Smallbowel

Largebowel

Anus

Requiredinvestigations

MRI+ Upper endoscopy

MRI or CTE

MRI + colonoscopy

MRI+ pelvic MRI

+ Clinical examination

Lémann Score: small bowel example

Severity assessment for each 20 cm segment

GradeStricturing lesions (0–3)

Penetrating lesions(0–3)

History of surgery or other interventional procedure (0–3)

Null (0) Normal Normal No procedure

Mild (1) Wall thickening <3 mm without pre-stenotic dilatation

– Endoscopic dilatation

Moderate (2)

Wall thickening ≥3 mm without pre-stenotic dilatation

Transmural fissure with increased density in perienteric fat

By-pass diversion Stricturoplasty

Severe (3) Stricture withpre-stenotic dilatation

Abscess or fistula Resection

Procedures for CT enterography

• By multidetector CT (MDCT), patients undergo CT examination in supine and prone positions.

• Positive or neutral contrast agent is administered transorally (enterography) or through duodenal tube (enteroclysis) for adequate luminal distension. Intravenous contrast material is administered for cases of positive contrat agent in the GI tract.

• Images are usually assessed under multiplanar reconstruction (MPR).

Hara AK, et al. Abdominal Imaging 2008

CTE findings of active CD

Mural hyperenhancementMural stratification

Comb signTakeuchi K, et al: Stomach Intestine 2012

Number of Patients with CD at Kyushu University Hospital

Patients diagnosed during

1970-2011: N=403

Lost to follow-up or

transferred elsewhere:

N=107

Naïve to biologicsN=139

Under biologicsN=157例(IFX :127 ADA:30)

Under follow-up

N=296

Clinician-oriented Clinical Trial for Crohn’s disease

0W

Active CD・CDAI220-450

・naïve to biologics

・naïve to AZA

Screening randomization

Adalimumab

Adalimumab+Azathioprine

12W 52W2W 26W4W

Aim: To evaluate the efficacy of simultaneous AZA for active CD under ADA.

Study protocol: Multicenter, open-labelled, prospective study.

Primary endpoint: Remission rate at 26 wks.Hypothesis: The combination of AZA and ADA is superior to ADA by an

15 points increase in remission rate.Sample size: 100 patients in each arm.

症例の登録状況（最終）

エントリー症例：177例

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登録症例 登録症例（累計） 目標症例（累計）

…and finally, Comments from Bedside-Claims from Clinical Research Associates-

Dose-escalation study of ADA for Crohn’s disease• Inclusion and exclusion criteria are difficult to interpret. • A certain proportion of candidates could not be enrolled because of minor

lack in clinical demographics. • Primary endpoint (efficacy at 8 wks) does not seem to be appropriate.

Induction and maintenance trial of ustekinumab• Extremely strict regulation and overload under global protocol. • This was especially the case for dropouts. • Both analogue and electronic CRFs were required.

In general• Many candidates could not be enrolled because of enteral nutrition. • Strict regulation under global protocol does not seem to conform to the

clinical management of CD in Japan. • IVRS does not seem to be appropriate for the clinical trial.

Conclusion

There seems to be following problems in clinical trials for Crohn’s disease in Japan.

1. Effects of biologics may be different between Western and Asian populations.

2. Assessment of disease activity may not be objective.3. There are difficulties in the assessment of actual

intestinal damages. 4. Less number of CD patients in Japan disturbs the

enrollment of study subjects. 5. Regulations in inclusion and exclusion are complicated.