boxed-textTargan SR et al. (2007) Natalizumab for the treatment of active Crohn's disease: results of the ENCORE trial. Gastroenterology 132: 1672–1683

Synopsis

Background

Natalizumab might be an effective induction therapy for patients with moderately to severely active Crohn's disease and active inflammation.

Objective

To establish the efficacy and safety of natalizumab as induction therapy in patients with active Crohn's disease and inflammation.

Design and intervention

From March 2004 to March 2005, the worldwide double-blind, placebo-controlled Efficacy of Natalizumab in Crohn's disease response and Remission (ENCORE) trial enrolled patients aged ≥18 years with a least a 6-month history of moderately to severely active Crohn's disease (Crohn's disease activity index [CDAI] score 220–450) and objective evidence of inflammation (C-reactive protein levels above the upper limit of normal [>2.87 mg/l]). Patients were screened for eligibility and randomly allocated 7–14 days later to receive 3 intravenous infusions on weeks 0 (baseline), 4 and 8 of either natalizumab 300 mg or placebo. At weeks 0, 4, 8 and 12, patients were assessed, CDAI scores calculated, and adverse events recorded. Health-related quality of life was assessed at weeks 0 and 12 using the Inflammatory Bowel Disease Questionnaire (IBDQ) and Short form-36 (SF-36).

Outcome measures

The primary end point was the proportion of patients achieving clinical response—a ≥70-point decrease in baseline CDAI score—at both weeks 8 and 12.

Results

A total of 509 of the 832 patients screened were assigned to treatment with either natalizumab (n = 259) or placebo (n = 250). A greater number of patients receiving natalizumab achieved the primary end point (124 [48%]) than those on placebo (81 [32%]; P <0.001). Likewise, more patients in the natalizumab group achieved remission at week 8 that was sustained at week 12 (68 [26%] vs 40 [16%]; P = 0.002). Response and remission rates were significantly higher as early as week 4 in those receiving natalizumab (P = 0.001 and P <0.009, respectively), and these rates remained significantly higher at weeks 8 and 12 (P = 0.001 for all). Overall, at week 12, 155 (60%) patients receiving natalizumab were responding to therapy and 97 (38%) were in remission, compared with 109 (44%) and 63 (25%), respectively, receiving placebo (P ≤0.001 for all). Week 12 mean improvement in IBDQ scores was greater in patients on natalizumab than in those on placebo (26.7 ± 32.34 points vs 15.2 ± 28.92 points, respectively; P <0.001). Similar numbers of patients in each group experienced adverse effects (222 [85%] in the natalizumab group and 206 [82%] in the placebo group), although more individuals receiving placebo experienced serious adverse effects (24 [10%] vs 13 [5%] in the natalizumab group) and more patients on natalizumab had an infection (90 [35%] vs 75 [30%] in the placebo group)—mostly nasopharyngitis (29 [11%] vs 15 [6%], respectively; P <0.05)—or a hypersensitivity-like reaction (10 [4%] vs 2 [<1%], respectively; P <0.05).

Conclusion

Induction therapy with natalizumab is a safe and effective method of inducing early and sustained response and remission in patients with Crohn's disease and inflammation.

Commentary

The current pathogenic paradigm for Crohn's disease implies a dysregulated adaptive immune response. As a consequence, biological monoclonal antibody therapies for the disease have been targeted at specific immune mediators such as TNFα or α4-integrin. The latter immune mediator has gained attention because it affects the homing of leukocytes, and its antagonism by a humanized antibody, such as natalizumab, might alleviate IBD.

The first study (by Ghosh et al.) that used natalizumab in patients with Crohn's disease was rather disappointing.1 Patients received infusions of natalizumab at one of three different doses on week 0 and week 4, and were evaluated in biweekly intervals up to week 12. Although the soft endpoint of response (a reduction in CDAI of 70) was significant in most treatment arms, the maximal therapeutic gain with respect to remission (CDAI <150) at the primary endpoint of 6 weeks was only 17%.

Nevertheless, a huge natalizumab trial (by Sandborn et al.) was launched recruiting 905 patients.2 As in previous infliximab trials, patients with a response were selected in an induction phase (ENACT-1), and followed up to week 60 in a maintenance study (ENACT-2). All patients received 300 mg natalizumab or placebo on weeks 0, 4 and 8 during the induction phase, and the 428 patients who achieved a response were randomly allocated to receive natalizumab or placebo every month thereafter.

In the induction phase (ENACT-1) the natalizumab and placebo groups had remarkably similar rates of remission (37% versus 30%). Moreover, the difference in response (i.e. the primary end point) failed to reach statistical significance. In the maintenance phase (ENACT-2), sustained remission was achieved in 39% of responders on natalizumab compared with 15% of responders on placebo at week 60. If, however, the initial population and not just the responders (selection bias) are taken into account, corrected data reveals that sustained remission was achieved in 18% of natalizumab patients compared with 7% of placebo patients. This finding is equivalent to a therapeutic gain of ∼11% for natalizumab (i.e. a number needed to treat [NNT] of 9—9 patients have to receive natalizumab in order to obtain one more remission than placebo at week 60).

In the Targan et al. trial (ENCORE), the soft primary end point of response at weeks 8 and 12 was reached, but the percentage of patients attaining sustained remission was only 26% (3 out of 4 failing) for those on natalizumab versus 16% for those on placebo, a marginal therapeutic gain for natalizumab amounting to a mere 10% (NNT 10).

In conclusion, natalizumab induces remission only in a minority of patients. The rates of long-term remission (unbiased by selection) are even more disappointing and safety is an issue: following natalizumab treatment, a JC virus-mediated, and potentially fatal, progressive multifocal leukoencephalopathy has been observed in at least three patients.3 Nevertheless, with the impact factors of the journals publishing these natalizumab studies exceeding therapeutic gains, the 'biologics' hype is enormous in some countries. The therapeutic dilemma might well be caused by use of the wrong paradigm: what if the antibacterial intestinal mucosal barrier defect is the primary disease mechanism for Crohn's disease4,5 and should therefore be the future target for treatment—not secondary proinflammatory molecules?