PF-00547659 for the treatment of Crohn’s disease and ulcerative colitis

ABSTRACT

Introduction: Gut-specific homing is mainly mediated by the expression of MAdCAM-1 on endothelial cells.

An increase in MAdCAM-1 expression has been shown in patients with inflammatory bowel disease (IBD).

Areas covered: PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. This review discusses the available data on effectiveness and safety of PF-00547659 in IBD.

Expert opinion: A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naïve and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn’s disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes. However, the time frame needed to evaluate clinical effectiveness of PF-00547659 may be longer in CD patients, given its transmural characteristic. In addition, it should be taken into consideration the possibility of incorporating new tools and more objective parameters in disease assessment that are proven to better correlate with inflammation. Future randomized-controlled trials are needed to confirm the efficacy of PF-00547659 in CD.

KEYWORDS:

• Anti-adhesion molecules
• Crohn’s disease
• inflammatory bowel disease
• MAdCAM-1
• PF-00547659
• ulcerative colitis

Article highlights

• Therapeutic armamentarium available for the treatment of IBD patients has proved to remain inadequate, resulting in a relatively high percentage of patients requiring surgery over time.

• Gut-specific homing is mainly mediated by the expression of MAdCAM-1 on endothelial cells.

• TNF-α increases endothelial MAdCAM-1 expression at inflamed gut tissue in IBD patients.

• PF-00547659 is a fully human mAb against MAdCAM-1, blocking the binding α4β7/MAdCAM-1. Unlike the anti-adhesion molecules that target the α4β7 integrins on circulating leukocytes, PF-00547659 blocking MAdCAM-1 acts directly into the gut with a very selective mechanism of action.

• A phase II study in active UC patients, both naïve and previously treated with anti-TNFs, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12.

• Preliminary results in CD did not show a superiority of PF-00547659 compared to placebo. Further and ongoing trials will evaluate the potential beneficial use of PF-00547659 in CD, assessing disease in different time frames and utilizing novel and more objective tools to detect inflammation

• The unique safety profile of PF-00547659 may pave the way to personalized therapy and allow concomitant use of molecules with different mechanisms of action.

Since MAdCAM-1 has also been detected in joints, eyes, skin, and liver, studies evaluating the effectiveness of PF-00547659 in EIMs of IBD are necessary.

Declaration of interest

No potential conflict of interest was reported by the authors.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.