MIAMI BEACH—Four studies presented at the American Academy of Neurology’s (AAN) 57th Annual Meeting discussed the use of natalizumab (Tysabri^®) for the treatment of patients with multiple sclerosis (MS). Prior to those presentations, the FDA issued an advisory (see sidebar) indicating that the drug’s manufacturer, Biogen Idec, was voluntarily suspending marketing of Tysabri due to two serious adverse events associated with its use.

The following reports detail the results of the natalizumab trials as they were presented at the AAN sessions.

THE AFFIRM STUDY

AFFIRM was a double-blind, randomized, placebo-controlled, multicenter study that included 942 patients. Patients were randomized to receive monthly intravenous infusions of natalizumab 300 mg or placebo for up to 116 weeks and were followed for up to 128 weeks. Patients included in the study had relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5.

This study had two primary end points: relapse rate and disability progression, which was defined as a 1-point increase in EDSS score sustained for 12 weeks if the patient’s initial EDSS score was 1 or more. Based on an EDSS score of 0, disability progression was defined as an increase of 1.5 points sustained for 12 weeks. “Eighty-five percent of the study participants had two or more relapses in the three years prior to entering the study,” said Paul O’Connor, MD, MSc, who presented the study results. Dr. O’Connor is Associate Professor and Chief of the Division of Neurology at St. Michael’s Hospital in Toronto.

At two-year follow-up, 17% of patients taking natalizumab had shown progression of disability, compared with 29% of patients taking placebo. “This was a 42% reduction in risk of disability progression, which is highly statistically significant,” Dr. O’Connor said. Additionally, 11% of patients receiving natalizumab and 23% of patients receiving placebo experienced disability progression sustained for six months, which was a 54% reduction in risk of progression, he noted.

The researchers also determined the number of patients who reached an EDSS score of 4 at two years. This occurred in 13% of patients receiving placebo and 5% of those receiving natalizumab, which was a 67% reduction in risk, according to Dr. O’Connor.

Regarding relapse rate, at the end of two years, 28% of natalizumab patients and 56% of placebo patients had experienced a relapse, Dr. O’Connor said. The study found that patients taking natalizumab had a 59% reduction in risk of having one or more relapses. “We also looked at steroid use, and we had a 69% reduction in steroid-treated relapses with natalizumab versus placebo,” he added.

• J. Theodore Phillips Jr, MD, PhD, reported the safety and tolerability results of the AFFIRM study. “The three most commonly reported adverse events in both the placebo and natalizumab groups were headache, fatigue, and arthralgia,” said Dr. Phillips, who is Director of the Multiple Sclerosis Center at Texas Neurology in Dallas and Clinical Associate Professor of Neurology at the University of Texas Southwestern Medical Center.

The most commonly reported infectious adverse events were urinary tract infections and lower respiratory tract infections, and the rate was somewhat higher in the natalizumab group. Additionally, depression and menstrual disorders were 3% more common in the natalizumab-treated group, said Dr. Phillips. Of the serious adverse events reported, 19% occurred in the natalizumab group compared with 24% in the placebo group; the overall rate of serious infectious adverse events reported was 2.6% in placebo-treated patients and 3.2% in natalizumab-treated individuals.

Two deaths and five malignancies occurred in the natalizumab monotherapy group, Dr. Phillips said. Two of the five malignancies arose from lesions existing before natalizumab therapy; one of these proved fatal (metastatic malignant melanoma). The other death occurred as a consequence of accidental alcohol intoxication. Additionally, 24% of natalizumab patients reported an infusion reaction within two hours of the start of the infusion compared with 18% of placebo patients, he noted, and 25 patients experienced 27 hypersensitivity reactions, eight (1.3%) of which were considered severe.

• David Miller, MD, discussed MRI measures of the efficacy of natalizumab. MRI scans were performed at baseline and at one and two years. MRI outcome measures were the number and volume of gadolinium-enhancing lesions, the number of new or emerging T2 lesions, total volume of T2 lesions, the number of new T1 hypointense lesions, and the total volume of T1 hypointense lesions.

Based on MRI characteristics, approximately 50% of the patients in both groups had gadolinium-enhancing lesions at baseline. The mean number of enhancing lesions was two in the placebo group and 2.2 in the natalizumab group. Ninety-five percent of patients had nine or more T2 lesions, said Dr. Miller, Professor of Clinical Neurology at the Institute of Neurology in London.

At both first- and second-year follow-up, there was a 92% reduction in the number of gadolinium-enhancing lesions in the natalizumab arm compared with placebo. At year 2, 72% of placebo-treated patients had no gadolinium-enhancing lesions, nor did 97% of natalizumab-treated patients. At the opposite end of the spectrum, 16% of the placebo group and 1% of the natalizumab group had two or more enhancing lesions.

Also, there was a mean of 11 new emerging T2 lesions in the placebo group over two years, compared with 1.9 in the natalizumab group—an 83% reduction. Over the two years, 57% of natalizumab-treated patients had no new or emerging T2 lesions, while 68% of placebo patients had three or more new T2 lesions, Dr. Miller said.

When lesion volume was assessed, the investigators found that between baseline and year 1, there was little change in median volume in the placebo group. In the natalizumab group, between baseline and year 1 there was a moderate drop in lesion volume, and at year 2 it remained about the same. When the two-year median percentage change in T2 lesion body was assessed, there was an 8.8% increase in the placebo group and a 9.4% decrease in the natalizumab group, they noted.

Dr. Miller also reported that during two years, there was a mean of 4.6 new T1 hypointense lesions in the placebo arm and 1.1 in the natalizumab arm—a 56% reduction. In the natalizumab group, there was a 74% decrease during the first year and an 83% decrease during the second year. Additionally, 63% of natalizumab-treated patients had no new T1 hypointense lesions during the two-year period. Forty-four percent of patients treated with placebo had three or more new T1 hypointense lesions during two years.

THE SENTINEL STUDY

The objectives of the SENTINEL study were to determine whether natalizumab, when added to interferon-beta-1a (Avonex^®), could provide additional efficacy over interferon-beta-1a alone and to confirm the same in a pharmacokinetic profile of natalizumab plus interferon-beta-1a. SENTINEL was a randomized, double-blind, placebo-controlled, parallel, multicenter study with 1,171 patients. All patients received standard interferon-beta-1a therapy once weekly, and patients were randomized to receive natalizumab 300 mg or placebo by intravenous infusion every four weeks for up to 116 weeks. Trial duration was 120 weeks. Patients were between the ages of 18 and 55 and had a diagnosis of relapsing-remitting MS. Baseline EDSS scores were between 0 and 5. All patients had received interferon-beta-1a therapy for 12 months or more prior to randomization, and they had had at least one relapse while on interferon-beta-1a in the 12 months prior to randomization and an MRI scan demonstrating lesions consistent with MS.

According to Richard Rudick, MD, the interferon-beta-1a–plus-placebo group had an annualized relapse rate of 0.82, while the interferon-beta-1a–plus-natalizumab group had a relapse rate of about 0.38, which was a 53% reduction. Dr. Rudick is Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic Foundation in Ohio. Sixty-seven percent of patients on interferon-beta-1a plus natalizumab were relapse-free, compared with 46% on interferon-beta-1a alone, he said.

Additionally, the annualized rate of relapse requiring steroid treatment was 0.63 in the interferon-beta-1a–plus-placebo arm and 0.25 in the interferon-beta-1a–plus-natalizumab group—a 60% reduction. The annualized rate of MS-related hospitalizations was reduced from 0.09 in the interferon-beta-1a–plus-placebo arm to 0.04 in the interferon-beta-1a–plus-natalizumab arm, a 54% reduction.

Also, gadolinium lesions were reduced from 0.8 in the first year of the study to 0.1, an 87% reduction, Dr. Rudick reported.

• Peter Calabresi, MD, presented safety and tolerability results from the SENTINEL study. He is Associate Professor of Neurology at Johns Hopkins University School of Medicine and Director of the Johns Hopkins MS Center in Baltimore.

Dr. Calabresi said that common adverse events from taking natalizumab included nasopharyngitis, depression, insomnia, and influenza. Two patients in the SENTINEL trial died, and both of these patients were in the interferon-beta-1a–plus-placebo group. Infections reported as serious adverse events were not different between the two groups. However, there were 10 hypersensitivity reactions in the interferon-beta-1a–plus-natalizumab group.

THE GLATIRAMER ACETATE AND NATALIZUMAB COMBINATION EVALUATION (GLANCE) STUDY

According to Andrew D. Goodman, MD, the objective of the GLANCE study was to determine whether adding natalizumab to the standard regimen of glatiramer acetate would be safe and well tolerated. GLANCE was a double-blind, randomized, placebo-controlled, parallel-group safety study with 110 subjects. All patients received the standard available dose of glatiramer acetate (20 mg/day). Subjects also received 300 mg of natalizumab or placebo by intravenous infusion every four weeks for up to 24 weeks.

All patients had a definite diagnosis of relapsing-remitting MS, were between the ages of 18 and 55, had a baseline EDSS score between 0 and 5, and were treated with glatiramer acetate for at least 12 months prior to randomization with at least one relapse during this time. The primary safety end point was the rate of development of new active lesions on cranial MRI scans during a six-month period. Safety assessments included the incidence and severity of adverse events, and additional end points included EDSS score and number of relapses, gadolinium-enhancing lesions, T1 lesions, and T2 lesions, Dr. Goodman reported. He is Chief of the Neuroimmunology Unit and Director of the Multiple Sclerosis Clinic in the Department of Neurology at the University of Rochester Medical Center in New York.

The number of new T2 lesions was reduced 62% by using natalizumab, and the number of new gadolinium-enhancing lesions was reduced by 74%. The annualized relapse rate was reduced by 40%, although this was not statistically significant, Dr. Goodman noted. There were no hypersensitivity reactions during the time of infusions. Regarding immunogenicity, the incidence of persistent positive antibodies in this study in the combination group was 13%.

“Natalizumab in combination with glatiramer acetate was safe and well tolerated over the six months of observation. There was a statistically significant positive effect seen on MRI as well as a positive effect—although not significant—that was seen on clinical end points,” Dr. Goodman said.

IMMUNE CELL ADHESION AND MIGRATION INVESTIGATED

Amit Bar-Or, MD, PhD, and colleagues from McGill University in Montreal conducted a study to establish biological proof of concept that in vivo anti–VLA-4 treatment of patients with MS results in decreased functional VLA-4 expression and migratory capacity of immune cells. They also sought to develop a simple in vitro assay that could be applied to monitor therapeutic response.

This study was an open-label phase of an ongoing clinical trial of natalizumab in relapsing-remitting MS. Patients provided venous blood immediately prior to and one hour after monthly 300-mg intravenous natalizumab infusions. Levels of VLA-4 surface expression on circulating immune cell subsets were assessed by flow cytometry, and the migratory capacity of immune cells was evaluated in a standard two-compartment Boyden chamber, known to capture VLA-4–mediated migration of human immune cells.

“We observed that expression of VLA-4 on circulating immune cells was significantly reduced after in vivo natalizumab infusions. The effect was observed on all immune cell subsets but was greatest on T cells compared to B cells or monocytes,” Dr. Bar-Or said.

In the functional assay, migration of postinfusion immune cells was significantly decreased compared to the migration of corresponding preinfusion cells. The decrease in observed VLA-4 surface expression correlated well with the decrease in migratory function of the corresponding immune cells following infusions.

NR

—Michelle Stephenson

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