"Natalizumab Induces Sustained Response and Remission in Patients With Active Crohn's Disease: Presented at UEGW"
By Chris Berrie
BERLIN, GERMANY -- October 27, 2006 -- Natalizumab is well tolerated and provides significant benefits in the induction of sustained response and remission in patients with moderate to severe active Crohn's disease (CD), according to a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 study.
The study was presented here on October 23[rd at the United European Gastroenterology Week (UEGW) 2006 on behalf of the Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE) investigators.
Natalizumab is a recombinant humanised IgG4 monoclonal antibody against the adhesion molecule alpha4 integrin. In previous studies, this agent has shown promise for treatment of patients with Crohn's disease, said co-investigator Martina E. Spehlmann, MD, assistant physician in gastroenterology, internal medicine, Asklepios Westklinikum, Hamburg, Germany.
"At present there is the first level of treatment with the standard biologicals for anti-tumour necrosis factor [TNF] treatment, although some 30% [of patients] do not respond to these, so natalizumab would be the most effective treatment for patients who do not respond to standard anti-TNF treatment anymore."
Dr. Spehlmann and colleagues conducted their study to determine the ability of natalizumab to induce sustained response and remission in patients with moderate to severe CD and active inflammation, as seen by their elevated C-reactive protein (CRP) levels.
The main inclusion criteria were 18 years of age or more, at least 6 months since CD diagnosis, CD Activity Index (CDAI) scores between 220 and 450, CRP levels >2.87 mg/L upper limit of normal, and no previous natalizumab treatment.
Study subjects were permitted to take stable doses of 5-aminosalicylates, corticosteroids, budesonide, immunosuppressants and antibiotics. Patients had to be off anti-TNF treatment for 12 weeks prior to study entry.
The primary study endpoint was a clinical response, as defined by a reduction of 70 points or more in CDAI score over baseline at week 0 (CR-70).
Of 832 patients screened, eligible patients were 250 who were randomised to placebo (male, 41%) and 259 to natalizumab 300 mg (male, 41%). Natalizumab was infused at weeks 0, 4 and 8 of the 12-week treatment phase.
Demographic and baseline characteristics, including disease location, concomitant CD medications, and prior use of anti-TNF agents, were not significantly different between the 2 treatment groups. Mean CRP levels at baseline were 23.4 mg/L in the placebo group and 23.0 mg/L in the natalizumab group.
The natalizumab group achieved response by week 8 that was sustained to week 12 in significantly more patients than the placebo group (32% vs 48%, respectively; P < .001). For the natalizumab-treated patients, CR-70 was significantly greater than for placebo patients by week 4 (37% vs 51%; P = .001).
Remission from week 8 to week 12 was seen in significantly more patients in the natalizumab group (16% vs 26%; P = .002). As with the early response, significantly superior remission rates were evident with natalizumab at week 4 (16% vs 24%; P = .009).
The researchers also noted similar significantly superior effects with natalizumab over placebo for clinical response and remission rates in a subgroup analysis for patients with CDAI 330 or greater at trial entry. The overall (8 weeks plus 12 weeks) responses and remissions were seen as 27% versus 51%, respectively (P = .002); 3% versus 14%, respectively (P = .025).
A final subgroup analysis showed significant benefits over placebo for clinical response and remission in patients with a history of anti-TNF failure, respectively: 15% versus 38% (P = .001); 5% versus 17% (P = .012).
Overall incidence and severity of treatment-emergent adverse events (AEs) were comparable in the 2 treatment groups. However, infections occurred slightly more often over placebo with the natalizumab group (30% vs 35%), and were primarily due to the more frequent occurrence of nasopharyngitis in the natalizumab group (6% vs 11%).
Of note, acute infusions reactions (reported within 120 minutes of start of infusion) occurred in 7% of placebo patients and 9% of natalizumab patients. However, hypersensitivity-like reactions occurred in <1% on placebo, but in 4% with natalizumab.
Although 9.5% of patients tested positive for anti-natalizumab antibodies, these did not appear to impact the overall incidence of AEs. However, these patients did suffer from a higher frequency of acute infusion reactions.
Dr. Spehlmann said, "Natalizumab is a very effective treatment, with the responses showing significance over placebo from week 4 to week 12, and it is also very important that the number of side effects were not higher in the natalizumab group compared to placebo."
Thus, he said, this ENCORE study met all of the prespecified endpoints and showed that natalizumab was well tolerated, with safety results consistent with those previously reported in trials of the drug.
Crohn's disease is a chronic progressive inflammatory disease that involves persistent recruitment of circulating leukocytes into gut tissue that is accompanied by dysregulated activation of immune cell function. Inhibition of this alpha4-integrin-mediated leukocyte recruitment and migration may thus ameliorate the chronic inflammation characteristics of Crohn's disease.
This study was sponsored by Elan Pharmaceuticals Inc. and Biogen Idec Inc.
[Presentation title: Natalizumab Induces Sustained Response and Remission in Patients With Active Crohn's Disease: ENCORE Trial Results. Abstract Mon-G-110]
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