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Original Article
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Volume 353:1912-1925 November 3, 2005 Number 18
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Natalizumab Induction and Maintenance Therapy for Crohn's Disease
William J. Sandborn, M.D., Jean Frédéric Colombel, M.D., Roberts Enns, M.D., Brian G. Feagan, M.D., Stephen B. Hanauer, M.D., Ian C. Lawrance, M.D., Ph.D., Remo Panaccione, M.D., Martin Sanders, M.D., Stefan Schreiber, M.D., Stephan Targan, M.D., Sander van Deventer, M.D., Ph.D., Ronald Goldblum, M.D., Darrin Despain, M.S., Gary S. Hogge, D.V.M., Ph.D., Paul Rutgeerts, M.D., Ph.D., for the International Efficacy of Natalizumab as Active Crohn's Therapy (ENACT-1) and the Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Groups

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ABSTRACT

Background Natalizumab, a humanized monoclonal antibody against {alpha}4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.

Methods We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).

Results In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P<0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.

Conclusions Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy. (ClinicalTrials.gov numbers, NCT00032786 [ClinicalTrials.gov] and NCT00032799 [ClinicalTrials.gov] .)


Source Information

Drs. Sandborn and Rutgeerts contributed equally to the article.

From the Mayo Clinic, Rochester, Minn. (W.J.S.); Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, Lille, France (J.F.C.); St. Paul's Hospital, University of British Columbia, Vancouver, Canada (R.E.); Robarts Research Institute, University of Western Ontario, London, Canada (B.G.F.); the University of Chicago, Chicago (S.B.H.); the School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Australia (I.C.L.); the University of Calgary, Calgary, Alta., Canada (R.P.); ProPharma International Ventures, Hillsborough, Calif. (M.S.); University Hospital Schleswig-Holstein, Christian Albrechts University, Kiel, Germany (S.S.); Cedars–Sinai Medical Center, Los Angeles (S.T.); Academic Medical Center, Amsterdam (S.D.); Elan Pharmaceuticals, San Diego, Calif. (R.G., D.D., G.S.H.); and Universitaire Ziekenhuizen Leuven, Leuven, Belgium (P.R.).

Address reprint requests for the ENACT-1 trial to Dr. Rutgeerts at Universitaire Ziekenhuizen Leuven, Inwendige Geneeskunde, UZ Gasthuisberg, Herestraat 49-B-3000, Leuven, Belgium, or at paul.rutgeerts{at}uz.kuleuven.ac.be.

Address reprint requests for the ENACT-2 trial to Dr. Sandborn at the Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or at sandborn.william{at}mayo.edu.

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