Integrin antagonists as potential therapeutic options for the treatment of Crohn’s disease

ABSTRACT

Introduction: Anti-integrin therapy for the treatment of patients with Crohn’s disease is rapidly evolving. Two agents, natalizumab and vedolizumab, are approved by the United States Food and Drug Administration for the treatment of Crohn’s disease, with vedolizumab the primary anti-integrin used due to a more favorable safety profile. Several other anti-integrins are in various stages of development.

Areas Covered: This review discusses the current state of anti-integrin therapy as well as suggestions for positioning of these agents in clinical practice. Emerging anti-integrin therapies, their underlying mechanisms of action, and available safety and clinical data are also reviewed.

Expert Opinion: Anti-integrins are effective for the treatment of Crohn’s disease, even in patients refractory to other therapies. Their use should be considered in patients with Crohn’s disease who do not respond to, develop non-response to, or have contraindications to anti-TNF therapy. Anti-integrin therapies can be offered as a first biologic therapy, in particular for older patients, patients with concurrent multiple sclerosis (natalizumab only), and in patients with contraindications to anti-TNF therapy. In patients with more severe symptoms, providers should consider co-induction with corticosteroids if possible to hasten remission.

KEYWORDS:

• Crohn’s disease
• ulcerative colitis
• inflammatory bowel disease
• leukocyte trafficking
• natalizumab
• vedolizumab
• etrolizumab
• AJM300
• AMG 181
• PF-00547659
• alicaforsen

Declaration of interest

This work was supported by AHRQ grant R01 HS-018975 to RK Cross and NIH grant P30 DK0-090868 to LP McLean. In addition, RK Cross has received an educational grant and income from consulting for Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Article highlights

• CD is a chronic inflammatory disorder of the GI tract. Medical management of CD is generally favored, except for severe cases that may require surgical resection.

• Traditional biologic agents target the pro-inflammatory cytokine TNF-α. Anti-integrins block efflux of immune cells from the vascular compartment into GI mucosal tissues.

• In the United States, two anti-integrin agents, natalizumab and vedolizumab, are approved for the treatment of CD. Several additional anti-integrin molecules are in various stages of development.

• Natalizumab is linked to the development of PML, an often fatal neurologic disease.

• Vedolizumab gained regulatory approval in 2014 and is not linked to PML.

• Anti-integrin molecules may be used to induce and maintain remission in patients with CD.

• Anti-integrins can be used for maintenance therapy in patients who undergo induction therapy with corticosteroids. They may also be used in patients who do not respond to, who lose response to, or in those with contraindications to anti-TNF therapy.

• Additional data demonstrating efficacy of novel anti-integrin agents for the treatment of CD will be required prior to their introduction to the market.

• Continued development and eventual regulatory approval of additional anti-integrins for the treatment of UC is expected.

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