Present Situation and Problems of Clinical Trials for Inflammatory Bowel Disease in Japan

PMDA Workshop Future Perspectives in the Development of Novel Medications for IBD (2015.2.4. Tokyo)

Present Situation and Problems of Clinical Trials for inflammatory bowel disease in Japan

Takayuki Matsumoto Division of Gastroenterology, Iwate Medical University Japan Available or Provisionally Applicable Biologics for the Treatment of Crohn’s Disease

IL inhibitors Chemokine receptors TNFK-005 Neovacs Phase I C326 QPharm SCH-900222 Merck & Co CCX282-B GSK Phase II Ustekinumab Centocor Vidofludimus 4SC CCX-025 GSK Immuno- Phase III PF-04236921 Pfizer Pfizer ZP1848 Zealand PF 05230900 modulators Registration QAX576 AMG 827 Amgen Novartis RDP 58 Genzyme GSK 1070806 GSK Rifaximin EIR Launched laquinimod Teva / AIN 457 Novartis AlphaWessermann Natalizumab Active Biotech ELND-004 Elan/Biogen Idec Elan/Biogen Idec PF-547659 Pfizer NN8555 Novo Nordisk CAM inhibitors Tofacitinib Pfizer Vedolizumab Adalimumab AbbVie Millenium / Takeda AJM-300 Ajinomoto Certolizumab pegol UCB Infliximab JAK3 inhibitors Centocor HMPL-004 Hutchinson Remestemcel-L Osiris Ozoralizumab Pfizer PDA-001 Celgene Cellular Cellerix Debiaerse OvaSave TXCell Neovacs

Stem cell therapies TNF-α inhibitors

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

Innate immunity Aquired immunity

LRRK2 IL23R IL12B CARD9 JAK2 TYK2 NOD2 STAT3 CCR6 ATG16L1 TNFSF15 IL2RA IRGM

No association in Jp Strong association in Jp No SNP in Jp Weak association in Jp Not enough power

Hirano A, Matsumoto T, et al. Inflammatory Bowel Dis 2013 Major Clinical Trials for Adalimumab in Crohn’s Disease Western countries CLASSIC I M02-403 Induction Infliximab naïve CHARM M02-404 Maintenance GAIN Infliximab naïve + failure M04-691 Induction Infliximab failure

Japan

M04-729 Induction Maintenance Infliximab naïve + failure M06-837 Results of Induction Trial

80 Placebo 80/40 mg 160/80 mg n=23 n=34 n=33 * 69.7

58.8 60 * 50.0 * 45.5 40 33.3 30.4

20 17.6 17.4

Percentage of Subjects 13.0

0 Clinical Clinical Response Clinical Response Remission ∆100 ∆70

*p<0.05 vs. placebo (FAS population) Watanabe M, et al. J Crohn’s Colitis 2012 Comparison between Induction Trials （Patients Naïve to Infliximab）

Western area（CLASSIC I） Japan（M04-729）

Placebo 80/40 mg 160/80 mg Placebo 80/40 mg 160/80 mg n=74 n=75 n=76 n=10 n=14 n=14 78.6 80 80 71.4 * * 59.5 58.6 57.1 60 * 60 50.0 50.0 42.9 * 40.0 40 35.5 36.8 40 28.6 24.0 25.0 20.0 20.0 20.0 20 20 12.2

0 0 Clinical Clinical Clinical Clinical Clinical Clinical Remission Response Response Remission Response Response ∆100 ∆70 ∆100 ∆70 *p<0.05 vs. placebo (FAS population) No statistical test was conducted. Comparison between Induction Trials （Patients with Prior Use of Infliximab）

Western area（GAIN） Japan（M04-729）

Placebo 160/80 mg Placebo 80/40 mg 160/80 mg 80 n=166 n=159 80 n=13 n=20 n=19

63.2 60 * 60 51.6 50.0 45.0 * 42.1 38.5 40 38.4 40 33.7 26.3 * 24.7 21.4 20 20 15.4 10.0 7.2 7.7 0 0 Clinical Clinical Clinical Clinical Clinical Clinical Remission Response Response Remission Response Response ∆100 ∆70 ∆100 ∆70

*p<0.05 vs. placebo (FAS population) No statistical test was conducted. Comparison between Maintenance Trials

Western area（CHARM） Japan（M06-837）

Placebo 40 mg EOW 40 mg Weekly * 50 47.1 46.5 * 42.4 * 41.4 40.9 * 38.9 39.5 * 38.1 38.1 40 36.0 33.3 30

20 17.1 18.2 11.8 9.1 10 Patients in Remission (%)

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

NRI ( Non-responder imputation) *p<0.05 vs. placebo (FAS population) Current measures of Crohn’s disease activity

Clinical activity • CDAI Crohn’s disease activity index developed by the NCCDS • HBI Harvey–Bradshaw simple index Endoscopic 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 anastomosis Histologic 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 EvenExtent though of affected simplified, 1. It is surfaceextremely complicated to calculate, and Narrowing 2. It does（０～３） not take jejunal and ileal lesions into account.

Size of ulcer 0; none 1; 0.1~0.5cm 2; 0.5cm~2cm 3; >2cm Extent of ulcerative surface 0; nine 1; <10% 2; 10~30% 3; >30% Extent of affected surface 0; none 1; <50% 2; 50~75% 3; >75% Narrowing 0; none 1; single 2; multiple 3; scope not pass through Daperno M et al. Gastrointest Endosc 2004 Example of SES-CD

I: 3+2+1+0=6 A: 2+1+1+0=4 T: 0+0+0+0=0

SES-CD=20

D/S: 3+2+1+0=6 R: 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 (p=0.001) SES-CD (n.s.)

SES-CD≧16（n=22） Anal fistula +(n=13)

（） Anal fistula -(n=29) SES-CD<16 n=22

Fuyuno Y, Matsumoto T, et al.: Dig Endosc (under submission) The Lémann score for the assessment of digestive damage in Crohn’s disease

Segment (CD location based on patient Required evaluation) investigations

Upper MRI tract + Upper endoscopy

Small MRI or CTE Digestive Patient bowel Investi- damage inclusion gations evaluation Large MRI + colonoscopy bowel

MRI Anus + pelvic MRI + Clinical examination

Pariente B et al. Inflamm Bowel Dis 2011 Lémann Score: small bowel example

Severity assessment for each 20 cm segment

History of surgery or Stricturing lesions Penetrating lesions other interventional Grade (0–3) (0–3) procedure (0–3) Null (0) Normal Normal No procedure

Mild (1) Wall thickening <3 – Endoscopic dilatation mm without pre- stenotic dilatation Moderate Wall thickening ≥3 Transmural fissure By-pass diversion (2) mm without pre- with increased Stricturoplasty stenotic dilatation density in perienteric fat Severe (3) Stricture with Abscess or fistula Resection pre-stenotic dilatation 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 hyperenhancement Mural stratification

Takeuchi K, et al: Stomach Intestine 2012 Comb sign Number of Patients with CD at Kyushu University Hospital

Patients diagnosed during 1970-2011: N=403

Lost to follow-up or Under follow-up transferred elsewhere: N=296 N=107

Naïve to biologics Under biologics N=139 N=157例 (IFX :127 ADA:30) Clinician-oriented Clinical Trial for Crohn’s disease

Aim: To evaluate the efficacy of simultaneous AZA for active CD under ADA. Study protocol: Multicenter, open-labelled, prospective study.

0W 2W 4W 12W 26W 52W

Screening randomization

Adalimumab Active CD ・CDAI220-450 ・naïve to biologics ・naïve to AZA Adalimumab+Azathioprine 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

200 12 登録症例登録症例（累計）目標症例（累計）

180

10 160

140 8

120

100 6

4 60

40 2

0 0 Jul-11 Jul-12 Jul-13 Jan-12 Jan-13 Jan-14 Jun-11 Jun-12 Jun-13 Jun-14 Oct-11 Oct-12 Oct-13 Apr-12 Apr-13 Apr-14 Feb-12 Sep-11 Feb-13 Sep-12 Feb-14 Sep-13 Dec-11 Dec-12 Dec-13 Aug-11 Aug-12 Aug-13 Nov-11 Nov-12 Nov-13 Mar-12 Mar-13 Mar-14 May-12 May-13 May-14 …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.