Natalizumab May Be Effective for Multiple Sclerosis CME

News Author: Laurie Barclay, MD
CME Author: Hien T. Nghiem, MD

Disclosures

March 2, 2006 — Natalizumab is effective for the treatment of multiple sclerosis, according to the results of a randomized study reported in the March 2 issue of The New England Journal of Medicine. A second randomized study suggests that adding natalizumab to beta-interferon is more effective than beta-interferon alone, and a third study found that the risk for progressive multifocal leukoencephalopathy (PML) is about 1/1000 at 17.9 months of follow-up.

"Natalizumab is the first α4 integrin antagonist in a new class of selective adhesion-molecule inhibitors," write Chris H. Polman, MD, from the Vrije Universiteit Medical Center in Amsterdam, the Netherlands, and colleagues from the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) Investigators. "On the basis of the favorable results of a phase 2 trial of natalizumab in patients with relapsing multiple sclerosis, a two-year phase 3 clinical trial, the AFFIRM study, was initiated to confirm the efficacy of natalizumab in relapsing multiple sclerosis and to evaluate the safety of long-term treatment."

Of 942 patients, 627 (66.6%) were randomized to receive 300 mg of natalizumab and 315 to receive placebo by intravenous (IV) infusion every 4 weeks for more than 2 years. The main outcomes were the rate of clinical relapse at 1 year and the rate of sustained progression of disability, measured with the Expanded Disability Status Scale, at 2 years.

For 2 years of treatment, natalizumab was associated with a 42% reduction in the risk for sustained progression of disability (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.43 - 0.77; P < .001). Kaplan-Meier analysis revealed that the cumulative probability of progression was 17% with natalizumab and 29% with placebo.

Natalizumab was associated with a 68% reduction in the rate of clinical relapse at 1 year (P < .001) and with an 83% reduction in the accumulation of new or enlarging hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) for 2 years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P < .001). At both 1 and 2 years, there were 92% fewer lesions on gadolinium-enhanced MRI in the natalizumab group than in the placebo group (P < .001).

Adverse events that were more frequent in the natalizumab group than in the placebo group were fatigue (27% vs 21%; P = .048) and allergic reaction (9% vs 4%; P = .012). Of the patients receiving natalizumab, 25 (4%) had hypersensitivity reactions of any kind, and 8 patients (1%) had serious hypersensitivity reactions.

"Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis," the authors write. "Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis."

Biogen Idec and Elan Pharmaceuticals supported this study and analyzed the data. Biogen Idec employs 3 of the authors. Some of the other authors have disclosed relevant financial relationships with Biogen Idec, Schering, Teva, Serono, Novartis, GlaxoSmithKline, Antisense Therapeutics, Wyeth, Pfizer, Amgen, Bristol-Myers Squibb, Sanofi-Aventis, BioMS, UCB Pharma, Berlex, and/or Genentech.

The second randomized trial, by Richard A. Rudick, MD, from Cleveland Clinic Foundation, and colleagues from the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) Investigators, evaluated natalizumab plus interferon beta-1a for relapsing multiple sclerosis. This 2-year, phase 3 clinical trial was designed to determine whether natalizumab added to interferon beta-1a was more effective than interferon beta-1a alone and to confirm the safety of this combination treatment in patients who had experienced at least one relapse during the previous 12-months despite interferon beta-1a therapy.

Of 1171 patients who were randomized, 589 received continued interferon beta-1a in combination with 300 mg of natalizumab, and 582 patients received continued interferon beta-1a with placebo IV every 4 weeks for up to 116 weeks. The main outcome measures were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years.

Combination therapy was associated with a 24% reduction in the relative risk of sustained disability progression (HR, 0.76; 95% CI, 0.61 - 0.96; P = .02). Kaplan-Meier estimates of the cumulative probability of progression at 2 years were 23% with combination therapy and 29% with interferon beta-1a alone. For a 2-year period, combination treatment was associated with a lower annualized rate of relapse than was interferon beta-1a alone (0.34 vs 0.75; P < .001) and with fewer new or enlarging lesions on T2-weighted MRI (0.9 vs 5.4; P < .001).

Adverse events reported with combination treatment were anxiety, pharyngitis, sinus congestion, and peripheral edema, as well as 2 cases of PML, one of which was fatal.

"Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis," the authors write. "Additional research is needed to elucidate the benefits and risks of this combination treatment."

Study limitations include insufficient power to assess the treatment effect on disability sustained for 24 weeks, and inability to determine long-term safety of combination therapy or whether combination therapy with natalizumab and interferon beta-1a is more efficacious than natalizumab alone.

Biogen Idec and Elan Pharmaceuticals supported this study and employs 3 of its authors. Several other authors have disclosed relevant financial relationships with Biogen Idec, Teva, Schering, Novartis, Genentech, Sanofi-Aventis, Serono, Acorda, Merck, Berlex, Schering-Plough, Pfizer, Amgen, Avanir, and/or Antisense Therapeutics.

The third study by Tarek A. Yousry, DrMedHabil, from Queen Square, London, and colleagues, evaluated whether other patients treated with natalizumab developed PML. Of 3417 patients who had recently received natalizumab while enrolled in clinical trials, 3116 (91%) who were exposed to a mean of 17.9 monthly doses were evaluated for PML.

Of 44 patients referred to an expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus, none had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but the lack of data on cerebrospinal fluid testing and follow-up MRI prevented ruling out PML in the remaining patient. The only confirmed cases of PML were the 3 that previously had been reported (1.0 per 1000 treated patients; 95% CI, 0.2 - 2.8 per 1000).

"A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months," the authors write. "The risk associated with longer treatment is not known."

Study limitations include underlying neurologic dysfunction in patients who had multiple sclerosis, including lesions on MRI; the occurrence of incidental lesions on MRI in those who had rheumatoid arthritis or Crohn disease; the possibility that PML might have different clinical behavior in the setting of natalizumab; inability to rule out nonprogressive disease; the possibility that PML might develop in a clinically silent area of the brain; collection of data only after the discontinuation of natalizumab; inability to determine the duration of exposure to natalizumab required to put patients at risk for PML; and exclusion of commercially treated patients and those treated in trials that were not included in this evaluation.

The National Institutes of Health supported this study, along with Biogen Idec and Elan Pharmaceuticals. Some of the authors have disclosed relevant financial relationships with Biogen Idec, Novartis, Sanofi, Boehringer Ingelheim, Pfizer, Genzyme, Bristol-Myers Squibb, Savient Pharmaceuticals, NeurogesX, Schering-Plough, Roche, and/or Bavarian Nordic.

In an accompanying editorial, Allan H. Ropper, MD, from Caritas St. Elizabeth's Medical Center in Boston, Mass, notes that these 3 studies extend the efficacy of natalizumab to the 2-year mark and offer reassurance that the risk for PML is small with relatively brief use.

"It seems that less than two years of treatment with natalizumab alone is relatively safe, but the possibility remains that PML will develop in 1 in 1000 patients," Dr. Ropper writes. "At the moment, it is doubtful that neurologists will chance using natalizumab in conjunction with other immunosuppressive agents, with the possible exception of corticosteroids when they are required for acute relapses."

Dr. Ropper has disclosed having been the principal investigator for a multicenter trial of interferon for the treatment of peripheral neuropathy that was supported by Biogen.

N Engl J Med. 2006;354:899-933, 965-967

Clinical Context
Relapsing multiple sclerosis occurs as an intermittent development of inflammatory lesions in the brain and spinal cord, resulting in plaques of demyelination and axonal loss. The adhesion molecule alpha4 beta 1 integrin is a key initiator of the inflammatory cascade involved in the pathogenesis of multiple sclerosis. Currently, interferon-beta is used to interrupt the course of relapsing multiple sclerosis. However, despite interferon-beta therapy, many patients have relapses.

Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion molecule inhibitors. It binds to alpha4 integrin on the surface of leukocytes, inhibiting their migration into the brain and thereby reducing inflammation. The results of 2 studies, the AFFIRM and the SENTINEL, a 2-year phase 3 trial of natalizumab monotherapy and a 2-year phase 3 trial of natalizumab plus interferon beta-1a, respectively, indicate the effectiveness of using natalizumab in patients with relapsing multiple sclerosis.

Study Highlights
In the AFFIRM study, 627 were assigned randomly to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by IV infusion every 4 weeks for more than 2 years.
Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and were accompanied by new neurologic signs found by the neurologist. Relapses were treated with IV methylprednisolone.
The primary end points were the rate of clinical relapse at 1 year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at 2 years.
Findings revealed that natalizumab reduced the rate of clinical relapse at 1 year by 68% from 0.75 to 0.24 (P < .001).
It reduced the risk for sustained progression of disability by 42% for 2 years (HR, 0.58; 95% CI, 0.43 - 0.77; P < .001). The cumulative probability of progression was 17% in the natalizumab group and 29% in the placebo group.
Detected by T2-weighted MRI, the natalizumab-treated group demonstrated an 83% reduction in the accumulation of new or enlarging hyperintense lesions for 2 years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P < .001).
92% fewer lesions existed in the natalizumab vs the placebo group at both 1 and 2 years (P < .001).
The proportion of relapse-free patients was significantly higher in the natalizumab vs the placebo group at 1 year (77% vs 56; P < .001) and at 2 years (67% vs 41%; P < .001).
The adverse events that were significantly more frequent in the natalizumab vs placebo group were fatigue (27% vs 21%; P = .048) and allergic reaction (9% vs 4%; P = .012).
In the SENTINEL trial, 1171 patients who had at least 1 relapse during the 12-month period before randomization, despite interferon beta-1a therapy, were randomly assigned to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) IV every 4 weeks for up to 116 weeks.
Baseline characteristics were similar in both groups, with the exception of the duration of the disease (median, 7 years in the combination-therapy group and 8 years in the group assigned to interferon beta-1a alone; P = .02)
The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years.
The 1-year rate of relapse was 0.38 in combination therapy and 0.82 in interferon beta-1a alone (P < .001), showing that combination therapy reduced the rate of clinical relapse at 1 year by 54% (P < .001). This was maintained at 2 years.
Also, combination therapy resulted in a 24% reduction in the relative risk of sustained disability progression (HR, 0.76; 95% CI, 0.61 - 0.96; P = .02). Kaplan-Meier estimates of the cumulative probability of progression at 2 years were 23% with combination therapy and 29% with interferon beta-1a alone.
Combination therapy was associated with fewer new or enlarging lesions on T2-weighted MRI (0.9 vs 5.4; P < .001) and gadolinium imaging (0.9 vs 0.1; P < .001), and a greater proportion of relapse-free patients at 2 years (54% vs 32%; P < .001).
Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema.
3 PML cases were diagnosed in clinical trials with natalizumab-treated patients. Further analysis showed that the risk for PML was roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. Further studies are needed to assess the risk associated with longer treatment therapy.

Pearls for Practice
Natalizumab is an alpha4 integrin antagonist that binds to alpha4 integrin on the surface of leukocytes, inhibiting their migration into the brain and thereby reducing inflammation in relapsing multiple sclerosis.
Natalizumab, not only alone but also in combination with interferon beta-1a, reduced the risk for the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis.

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