Background: Natalizumab, a humanized monoclonal IgG₄ antibody to α4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied.

Methods: Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score ≥ 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment.

Results: Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (−37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug–drug interactions were noted.

Conclusions: The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone.

(Inflamm Bowel Dis 2007;13:2–11)

REFERENCES

1 Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002; 347: 417–429.
10.1056/NEJMra020831
CAS PubMed Web of Science® Google Scholar
2 Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002; 359: 1541–1549.
10.1016/S0140-6736(02)08512-4
CAS PubMed Web of Science® Google Scholar
3 Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 1997; 337: 1029–1035.
10.1056/NEJM199710093371502
CAS PubMed Web of Science® Google Scholar
4 Sands E, van Deventer JH, Bernstein C, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004; 350: 876–885.
10.1056/NEJMoa030815
CAS PubMed Web of Science® Google Scholar
5 Baert F, Norman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003; 348: 601–608.
10.1056/NEJMoa020888
CAS PubMed Web of Science® Google Scholar
6 Sandborn WJ, Yednock TA. Novel approaches to treating inflammatory bowel disease: targeting alpha-4 integrin. Am J Gastroenterol. 2003; 98: 2372–2382.
10.1111/j.1572-0241.2003.08703.x
CAS PubMed Web of Science® Google Scholar
7 Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease. N Eng J Med. 2003; 348: 24–32.
10.1056/NEJMoa020732
CAS PubMed Web of Science® Google Scholar
8 Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005; 353: 1912–1925.
10.1056/NEJMoa043335
CAS PubMed Web of Science® Google Scholar
9 Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med. 2005; 353: 362–368.
10.1056/NEJMoa051586
CAS PubMed Web of Science® Google Scholar
10 Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005; 353: 369–374.
10.1056/NEJMoa051782
CAS PubMed Web of Science® Google Scholar
11 Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005; 353: 375–381.
10.1056/NEJMoa051847
CAS PubMed Web of Science® Google Scholar
12 Yousry TA, Major E, Ryschkewitsch C, et al. evaluation for progressive multifocal leukoencephalopathy in natalizumab treated patients. N Engl J Med, in press.
PubMed Google Scholar
13 Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976; 70: 439–444.
10.1016/S0016-5085(76)80163-1
CAS PubMed Web of Science® Google Scholar
14 Irvine EJ, Feagan B, Rochon J, et al. Quality of life: A valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Gastroenterology. 1994; 106: 287–296.
10.1016/0016-5085(94)90585-1
CAS PubMed Web of Science® Google Scholar
15 Papadakis KA, Shaye OA, Vasiliauskas EA, et al. Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab. Am J Gastroenterol. 2005; 100: 75–79.
10.1111/j.1572-0241.2005.40647.x
CAS PubMed Web of Science® Google Scholar
16 Sandborn WJ, Hanauer S, Loftus EV, et al. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn's disease. Am J Gastroenterol. 2004; 99: 1984–1989.
10.1111/j.1572-0241.2004.40462.x
CAS PubMed Web of Science® Google Scholar
17 Youdim A, Vasiliauskas EA, Targan SR, et al. A pilot study of adalimumab in infliximab-allergic patients. Inflamm Bowel Dis. 2004; 10: 333–338.
10.1097/00054725-200407000-00002
CAS PubMed Web of Science® Google Scholar
18 Vermeire S, Louis E, Carbonez A, et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn's disease. Am J Gastroenterol. 2002; 97: 2357–2363.
10.1111/j.1572-0241.2002.05991.x
CAS PubMed Web of Science® Google Scholar

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Volume13, Issue1

January 2007

Pages 2-11

Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab

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Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab

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