Natalizumab Receives Accelerated FDA Approval For MS

Special update

Synopsis: Natilizumab will become an important option for newly diagnosed MS patients starting treatment, or for patients currently on interferon beta-1a or glatiramer acetate with refractory breakthrough disease.

Biogen Idec and Elan Corporation received FDA approval for natalizumab in the treatment of relapsing-remitting MS on November 23, 2004. One-year data from the Phase III TYSABRI® (natalizumab) AFFIRM trial met the primary end point of clinical relapse rate reduction. In this international study of 942 patients with relapsing-remitting multiple sclerosis (RRMS), natalizumab significantly reduced the rate of relapses by 66%, compared to placebo. All secondary end points for brain MRI were also met.

Natalizumab is a humanized monoclonal antibody against the alpha-4 integrin selective adhesion molecule (SAM), which blocks the attachment to the corresponding VCAM receptor on the vascular endothelium of the blood-brain barrier. This limits the trafficking of activated T-cells into the nervous system.

The AFFIRM trial is a 2-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients evaluating the effect of natalizumab monotherapy on the progression of disability in MS and the rate of clinical relapses. An annualized relapse rate of 0.25 was seen with the natalizumab-treated patients vs 0.74 with placebo-treated patients. The proportion of patients who remained relapse free was 76% in treated patients, compared to 53% in the placebo group (P < 0.001). Secondary end points at 1 year included the number of new or newly enlarging T2-hyperintense lesions, the number of gadolinium-enhancing lesions, and the proportion of patients who were relapse free. On 1-year data, 96% of natalizumab-treated patients had no gadolinium-enhancing lesions, compared to 68% of placebo-treated patients (P < 0.001). To enroll, patients had to be diagnosed with a relapsing form of MS and had to have experienced at least 1 relapse in the previous year. Patients were randomized to receive a 300 mg IV infusion of natalizumab (n = 627) or placebo (n = 315) once a month.

Adverse events occurring in at least 5% of natalizumab-treated patients that were 2% more common than in placebo-treated patients included headache, fatigue, and arthralgia. The overall incidence of infection was similar between the groups. Serious infections occurred in 1% of placebo-treated patients and 2% of natalizumab-treated patients. Serious hypersensitivity-like reactions occurred in approximately 1% of natalizumab-treated patients. Unfortunately, a small percentage of patients who developed binding antibodies to natalizumab seemed to lose the effectiveness of drug.

A second Phase III trial now in progress, SENTINEL, is a 2-year controlled study of approximately 1200 patients with relapsing-remitting MS, evaluating the effect of the combination of natalizumab and interferon beta-1a, 30 m IM/week (AVONEX®), compared with interferon beta-1a alone on the progression of disability and the rate of clinical relapses. At 1 year, the natalizumab plus interferon beta-1a treated group experienced a 54% reduction in the rate of clinical relapses, compared to the effect of interferon beta-1a alone. In addition, 96% of natalizumab plus interferon beta-1a treated patients had no gadolinium-enhancing lesions on MRI, compared to 76% in the interferon beta-1a plus placebo group. Sixty-seven percent of the natalizumab plus interferon beta-1a treated group remained relapse-free, compared to 46% in the interferon beta-1a plus placebo treated group.

This therapeutic strategy of selective adhesion molecule blockade may represent a significant advance in our treatment of multiple sclerosis. Natilizumab will become an important option for newly diagnosed patients starting treatment, or for patients currently on interferon beta-1a or glatiramer acetate with refractory breakthrough disease. We eagerly await the full 2-year data sets in the above clinical trials to see if benefits are sustained, and if there is any impact of natalizumab ultimately on progression of disability in multiple sclerosis. — Brian R. Apatoff

Dr. Apatoff, Associate Professor of Neurology, New York Presbyterian Hospital- Cornell Campus, is Assistant Editor of Neurology Alert.