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Natalizumab
Natalizumab is a recombinant humanised monoclonal IgG4 antibody against the
integrin subunit α4 that blocks both α 4 β7 and α 4 β1. The α 4 β7/MAdCAM-1 interac-
tion is gut-specific, whereas the α 4 β1–VCAM-1 interaction interferes with lympho-
cyte migration to the central nervous system [ 9 ]. Natalizumab was the first
monoclonal antibody to be approved for the treatment of relapsing–remitting mul-
tiple sclerosis demonstrating considerable and sustained efficacy [ 14 ]. Mechanistic
support for its use as induction therapy in active IBD came from the finding that
VCAM-1 and MAdCAM-1 are increased in gut inflammation and that natalizumab
interferes with this interaction [ 15 , 16 ].
Natalizumab was first assessed in 30 patients with mild to moderate active CD in
a randomised double-blind placebo-controlled trial. A single infusion of natali-
zumab 3 mg/kg showed superior efficacy in inducing remission at week 2 and was
well tolerated [ 17 ]. The effect was short-lived with majority of patients requiring
rescue therapy at a median of 22 days post-infusion.
In a subsequent double-blind, placebo-controlled trial, natalizumab was admin-
istered to 248 patients with moderate to severe CD [ 18 ]. Patients were randomly
assigned to receive one of four treatments: two infusions of placebo, one infusion of
3 mg/kg natalizumab followed by placebo, two infusions of natalizumab 3 mg/kg or
two infusions of natalizumab 6 mg/kg. The group receiving two infusions of 3 mg/
kg achieved the highest remission at 44% and a high response rate at 71% at week
6 with reduction in CRP and improvement in quality of life [ 18 ]. The efficacy of
natalizumab to induce remission was evaluated further in the ENACT-1 and
ENACT-2 (Efficacy of natalizumab as Active Crohn’s Therapy) and ENCORE
(Efficacy of natalizumab in Crohn’s Disease Response and Remission) trials [ 19 ,
20 ]. In the first trial (ENACT-1), 905 patients were randomly assigned to receive
natalizumab or placebo at weeks 0, 4 and 8. Rates of response (56% and 49%,
respectively; p = 0.05) and remission (37% and 30%, respectively; p = 0.12) for
drug and placebo were similar at 10 weeks. In the second trial (ENACT-2), 339
patients who had responded to natalizumab were randomly assigned to receive
300 mg natalizumab or placebo every 4 weeks through week 56. Although there was
no difference between natalizumab and placebo in the first trial (ENACT-1), con-
tinuing natalizumab in patients who had a clinical response resulted in higher rates
of sustained response (61% vs. 28%, p < 0.001) and remission (44% vs. 26%
p < 0.003) than placebo at week 36 [ 19 ].
The ENCORE study evaluated the efficacy of natalizumab therapy in patients
with moderate to severely active CD and elevated CRP concentrations in a ran-
domised, placebo-controlled trial [ 20 ]. Of 509 patients enrolled, 48% demonstrated
a sustained response at week 8 through week 12 as compared to 32% of patients
treated with placebo (p < 0.001) while sustained remission was noted in 26% given
natalizumab and 16% who received placebo [ 20 ].
A recent meta-analysis showed that natalizumab was superior to placebo for the
induction of remission in CD (RR, 0.86; 95% CI, 0.80–0.93), being equally
J.K. Limdi and F.A. Farraye