Anti-MAdCAM-1 antibody (PF-00547659) for active refractory Crohn's disease in Japanese and Korean patients: the OPERA study

Abstract

Background/aims: PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) that prevents the binding of α4β7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high affinity and selectivity, and is being developed for the treatment of Crohn's disease (CD).

Methods: OPERA is a randomized, multicenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 following subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein > 3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn's Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients.

Results: In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) defined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating β7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment.

Conclusions: In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509).

Keywords: Crohn disease; Japanese; Korean; MAdCAM; PF-00547659.

Fig. 1.

Comparison of (A, B) primary endpoint (CDAI-70 response rates at weeks 8 and 12) and (C, D) secondary endpoint (CDAI-100 response rates at weeks 8 and 12) between the (A, C) overall and (B, D) Asian (Japanese and Korean) populations. mITT, modified intent-to-treat population.

Fig. 2.

Comparison of secondary endpoint (CDAI remission rates at weeks 2, 4, 6, 8, 10, and 12) between the (A) overall and (B) Asian (Japanese and Korean) populations. mITT, modified intent-to-treat population.

Fig. 3.

Results of the post hoc analysis (CDAI remission rates at weeks 8 and 12) between the (A) overall and (B) Asian (Japanese and Korean) populations with baseline CRP >18.8 mg/L. The generalized linear mixed model (GLMM) contains fixed factors of treatment, the status of anti-TNF experience, the concomitant immunosuppressive therapy, baseline value, visit and treatment by visit, and a random effect of subject. mITT, modified intent-to-treat population.

Fig. 4.

Changes of hs-CRP at weeks 0, 4, 8, and 12 (A, B), percentage of β7⁺ central memory CD4⁺ T-lymphocytes*MESF at weeks 0, 8, and 12 (C, D), and changes of soluble MAdCAM at weeks 0, 2, 10, and 12 (E, F) in the (A, C, E) overall and (B, D, F) Asian (Japanese and Korean) populations. Error bars in the overall population denote 90% CIs. hs-CRP, high-sensitivity CRP; MESF, Molecules of Equivalent Soluble Fluorochrome; MAdCAM, mucosal addressin cell adhesion molecule; mITT, modified intent-to-treat population.