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Natalizumab is a “humanized” monoclonal antibody created by grafting a murine monoclonal antibody to human IgG4 immunoglobulins. It is currently in Phase III trials to determine effectiveness in MS through slowing the progression of disability and decreasing incidence of clinical relapses. In addition to monotherapy, natalizumab has been combined with interferon ß-1a (Avonex) to slow down the progression of disability. Natalizumab was evaluated fairly extensively in Crohn's disease showing effectiveness in two intravenous infusions four weeks apart of 3 mg/kg of body weight. There are some preliminary studies that suggest that there may be some role for natalizumab in treating ulcerative colitis as well. A 100 mL infusion (diluted in normal saline) generally requires 25 to 75 minutes to administer. Pharmacokinetic studies suggest that peak plasma levels are achieved by 45 minutes post infusion (range 0.7-2.0 hours) and that clearance is approximately 0.4 mL/hour/kg of body weight. The half-life for elimination ranges between 90 to 170 hours. Side effects may include fatigue and infections. Very rare anaphylaxis has been reported. The body is capable of developing antibodies during therapy, though the clinical significance of this phenomenon remains unclear. Frequencies of administration were recommended based on recent studies vary according to the disease state. Crohn’s disease may require a total of two treatments given four weeks apart at a dose of 3 mg/kg body weight for patients with moderate to severe. In ulcerative colitis a single infusion at the 3 mg/kg body weight dose was suggested to be beneficial, although optimal doses have not yet been established. For MS the most recently reported study (reviewed here as Study #2 in this Journal Club) used treatment doses of 3 mg/kg and 6 mg/kg body weight every 28 days for a total of six months of treatment followed by six months of follow-up observation. Previous studies explored doses in healthy controls that can saturate the a4 integrin receptor to potentially prevent the migration of leukocytes across the blood-brain barrier. Questions remain about the potential adverse effects and loss of treatment efficacy and due to the development of antibodies to the drug. Contraindications currently listed (due to a lack of safety data) include renal and hepatic insufficiency, pregnancy, and lactation. Elan Pharmaceuticals notes that they expect to file a NDA with the Food and Drug Administration for the Crohn’s disease indication during the fourth quarter of 2003. A detailed discussion and visual explanation on the use of natalizumab in autoimmune diseases (with a particular emphasis on Crohn’s disease) can be found in the January 2, 2003 issue of the New England Journal of Medicine.⁹

Integrin is a type of adhesion molecule that allows the migration of leukocytes from vascular spaces into the central nervous system. Previous studies showed a beneficial effect of anti-a4 integrin to prevent the clinical symptoms and objective MRI detection of acute experimental allergic encephalomyelitis. This led researchers to propose that the use of the anti-adhesion therapy natalizumab (Antegren) could be used to treat MS attacks during acute stages and possibly prevent or reduce the incidence of subsequent attacks. A preliminary study¹⁰ of 70 patients randomized to receive either natalizumab (n=37) or placebo (n=33) in two infusions at 4-week intervals followed by observation for 24 weeks after the first infusion was previously conducted. That study was the first to use monoclonal antibodies as a treatment option in MS. Researchers examined the effect of natalizumab (Antegren) on new and persistent brain-lesion activity associated with MS. Even though it was a relatively small study, it did suggest that after two infusions with natalizumab, patients experienced fewer new lesions and a decrease in exacerbations than seen in the placebo group. Further study was recommended with a larger number of patients to determine the effect of natalizumab on MS patients, the optimal dosing and frequency of treatment required for a sustained effect, and the potential for loss of efficacy over time with chronic administration.

The design of the follow-up study (reported here) was randomized, placebo-controlled, and double-blinded for the intravenous infusion of natalizumab in patients with clinically definite RRMS or SPMS. 213 patients were enrolled and randomized to receive six monthly treatments with 3 mg/kg body weight (n=68), 6 mg/kg body weight (n=74), or placebo (n=71). The study extends to an additional six months after the last treatment to further determine any adverse effects. The primary endpoint was detectable brain lesion activity through magnetic resonance imaging (MRI), which was conducted at study enrollment (one month before baseline treatment), immediately before baseline and immediately before each of the monthly treatments (months 0-5), at one month following the last treatment (month 6), and quarterly thereafter (months 9 and 12). Additional outcomes included lesions previously identified that continued to appear on tests beyond baseline (“persistent enhancing”), volume of enhancing lesions, and those that were first identified after baseline treatment (“new enhancing”). Additional outcomes included clinical evidence of relapse, EDSS score changes, and patient-reported well-being.

Baseline values were not significantly different between the three groups. Treatment was discontinued early in five placebo, five 3 mg/kg, and eight 6 mg/kg participants. Three in the placebo group, four in the 3 mg/kg group, and one in the 6 mg/kg group continued their participation in the study after discontinuing therapy. For data analysis on the primary MRI endpoint, 6.3% of the values were missing and were therefore imputed (which are calculated average values to fill in holes in the data set). During the study serum levels of the drug were proportional to the dose with the 3 mg/kg group achieving an 80% saturation and the 6 mg/kg group achieving 90% saturation of α-integrin receptors in the peripheral leukocytes. In addition, a prolonged saturation was seen in the 6 mg/kg group.

The number of new enhancing lesions was 9.6 for the placebo group, 0.7 for the 3 mg/kg group (p<0.001), and 1.1 in the 6 mg/kg group (p<0.001) during the treatment phase. While there was a significant difference between treatment and placebo groups, there were no significant differences between the treatment arms. The researchers performed data analysis including and excluding imputed data points with similar results. In addition, there was a significant difference in the number of persistent and new active lesions as well as a reduced volume of enhancing lesions in the treatment arms compared to the placebo arm. The post-treatment period MRI data showed that lesion activity was not significantly different between the three groups.

A strong trend toward a reduced number of reported relapses was seen in the treatment arms (p=0.02). Objectively documented relapses showed varied results compared to the placebo group (p=0.004 in the 3 mg/kg group and p=0.11 in the 6 mg/kg group). Post-treatment evaluation showed that the number of relapses reported or confirmed became similar between the three groups.

A trend toward improvement in well-being was reported in both the 3 mg/kg (p=0.04) and 6 mg/kg (p=0.03) groups compared to a trend toward a decline in well being for the placebo group. There were no notable changes in EDSS scores for any of the groups.

As in previous studies leukocyte counts increased in the treatment arms staying within acceptable limits and returning to baseline by the fourth month after the last treatment. NAb were present in 11% of the treatment groups, mostly during the treatment phase.

Adverse events were seen in all groups with 11 serious events reported in seven placebo group patients, five in five patients in the 3 mg/kg group and four in three of the 6 mg/kg group. Four of the severe events were considered related to the drug, one of which was an anaphylaxis event that was successfully treated with antihistamines and corticosteroids.

The authors reported significant differences in the primary and secondary outcomes of patients treated with natalizumab in both the 3 mg/kg and 6 mg/kg treatment arms compared with placebo during treatment phases. The effect to reduce new active lesions was estimated at 90% in both treatment arms. Authors compared these results favorably with those reported for IFNβ (50-80%) and glatiramer acetate (30%).

The authors suggested caution in interpretation and comparison of patient-reported well-being though they considered the treatments well tolerated and safe (comparable to placebo). The study, though expanded from the preliminary work done by this group, is still relatively small and of short duration for the outcomes evaluated. Thus the authors recommend longer-term studies to provide the results needed to support the use of intravenous natalizumab as an effective treatment in MS and to compare the effects on disability progression with other currently available treatments.