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FDA-related information through February 2008 on Fluvoxamine extended-release capsules, dalbavancin, bazedoxifene, HPV vaccine (Cervarix), valrubicin, motexafin gadolinium, COL-003, CDX-110, sugammadex, mecaserim rinfabate, A-001, beclomethasone, clobazam, fludarabine tablets, JZP-8, and AST-120
Natalizumab is a recombinant humanized IgG4-kappa monoclonal antibody. This agent appears to block the molecular interaction of the alpha4-beta7 integrin with mucosal addressin cell adhesion molecule-1, thereby inhibiting the chronic inflammation of Crohn's disease (CD). This agent, which is already approved as monotherapy for the treatment of relapsing forms of multiple sclerosis (MS), was approved on January 14, 2008, for the induction and maintenance of clinical response and remission in adult patients with moderately to severely active CD with evidence of inflammation who have had an inadequate response to or are unable to tolerate conventional CD therapies and inhibitors of tumor necrosis factor-alpha (TNF-alpha).
Efficacy. The efficacy of natalizumab for the treatment of CD was assessed in 3 randomized, double-blind, placebo-controlled clinical trials that enrolled a total of 1,414 adult patients with moderately to severely active CD (defined as Crohn's Disease Activity Index [CDAI] score ≥220 and ≤450). In all 3 studies, concomitant use of TNF-alpha inhibitors was not permitted, but concomitant use of aminosalicylates, corticosteroids, and immunosuppressants (at stable doses) was allowed. The first study evaluated natalizumab's efficacy in inducing a clinical response (defined as a ≥70-point decrease in CDAI score from baseline). In this study, 896 patients were randomized 4:1 to receive 3 monthly intravenous (IV) infusions of either natalizumab 300 mg or placebo. At Week 10, 56% of the natalizumab-treated patients had achieved a clinical response versus 49% of the placebo-treated patients (treatment effect, 7%; 95% CI, –1% to 16%; P=.067). A post-hoc analysis demonstrated that, among patients with elevated C-reactive protein (CRP) levels at baseline, 57% of natalizumab-treated patients achieved a clinical response versus 45% of placebo-treated patients (treatment effect, 12%; 95% CI, 3%–22%; nominal P=.01). The second study assessed natalizumab's efficacy in inducing clinical response (defined as a ≥70-point decrease in CDAI score from baseline) and clinical remission (defined as CDAI score <150) at both Weeks 8 and 12. In this study, only patients with elevated serum CRP were eligible for participation. Patients (N=509) were randomized 1:1 to receive 3 monthly infusions of either natalizumab 300 mg or placebo. At both Weeks 8 and 12, 48% of natalizumab-treated patients had achieved a clinical response versus 32% of placebo-treated patients (treatment difference, 16%; 95% CI, 7%–24%; P<.005); at both Weeks 8 and 12, 26% of natalizumab-treated patients had achieved clinical remission versus 16% of placebo-treated patients (treatment difference, 10%; 95% CI, 3%–18%; P<.005). Study 3 assessed the ability of natalizumab to maintain a clinical response (defined as CDAI score <220 and a ≥70-point decrease in CDAI score from the baseline of the first study) or clinical remission (defined as CDAI score <150) at Months 9 and 15 after initial natalizumab treatment. A total of 331 patients from the first study who had experienced a clinical response to natalizumab at both Weeks 10 and 12 were rerandomized 1:1 to continuing monthly infusions of either natalizumab 300 mg or placebo. At Month 9, 61% of natalizumab-treated patients had maintained a clinical response versus 29% of placebo-treated patients (treatment difference, 32%; 95% CI, 21%–43%; P<.005); at the same time point, 45% of natalizumab-treated patients had maintained clinical remission versus 26% of placebo-treated patients (treatment difference, 19%; 95% CI, 6%–31%; P<.005).
Safety. Cases of progressive multifocal leukoencephalopathy (PML) have been observed in patients treated with natalizumab; because of this risk of PML, natalizumab is available only through a special restricted distribution program. Healthcare professionals should monitor natalizumab-treated patients carefully for possible signs and symptoms of PML, including progressive weakness on 1 side of the body; clumsiness of limbs; vision disturbance; and changes in thinking, memory, and orientation that lead to confusion and personality changes. Hypersensitivity reactions, including serious systemic reactions, have occurred in patients treated with natalizumab. Healthcare professionals should carefully consider whether the benefits of natalizumab treatment outweigh the risks in patients who develop persistent antibodies to natalizumab. Patients treated with natalizumab may be at increased risk for infections; concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may increase this risk. Natalizumab treatment has been associated with clinically significant liver injury. The most common adverse events associated with natalizumab treatment for CD include headache, fatigue, respiratory tract infections, and nausea.