Natalizumab induction and maintenance therapy for Crohn's disease.
BACKGROUND
Natalizumab, a humanized monoclonal antibody against alpha4 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 and NCT00032799.)
Sandborn
William J
WJ
Mayo Clinic, Rochester, Minn 55905, USA. sandborn.william@mayo.edu
Colombel
Jean Frédéric
JF
Enns
Roberts
R
Feagan
Brian G
BG
Hanauer
Stephen B
SB
Lawrance
Ian C
IC
Panaccione
Remo
R
Sanders
Martin
M
Schreiber
Stefan
S
Targan
Stephan
S
van Deventer
Sander
S
Goldblum
Ronald
R
Despain
Darrin
D
Hogge
Gary S
GS
Rutgeerts
Paul
P
D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D003424:Crohn Disease / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D039001:Integrin alpha Chains / Q000037:antagonists & inhibitors*; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced; D008297:Male; D000069442:Natalizumab; D012074:Remission Induction; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015815:Cell Adhesion Molecules; D007166:Immunosuppressive Agents; D039001:Integrin alpha Chains; D000069442:Natalizumab