Positive Results from Antegren® Trial Published
Last year’s Winter 2002 issue of The Motivator included the encouraging results of a six-month study investigating the effects of the monoclonal antibody natalizumab (Antegren) in 213 individuals with relapsing-remitting and secondary-progressive MS. These results were initially presented at the annual meeting of the European Congress on Treatment and Research in Multiple Sclerosis, held in September 2001.
An important step in affirming the results of any trial is to be published in a “peer-reviewed” publication. Antegren has recently been in the news because the results of this study were published in the January 2, 2003 issue of The New England Journal of Medicine (David H. Miller, et al, A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis, vol. 348: 15-23).
As reported in The Motivator, the trial was conducted at 26 centers in the United States, Canada, and the United Kingdom. The 213 participants were divided into three treatment groups: three milligrams of Antegren per kilogram of body weight, six mg per kg, or placebo. Doses were given via intravenous infusion once every four weeks for a six-month period. The study was double-blinded, so neither the participants nor the medical staff conducting the trial knew who was receiving the active drug and who was receiving a placebo.
The primary outcome measure was the number of new gadolinium-enhancing lesions (as seen on magnetic resonance imaging, or MRI) appearing during the six-month treatment period, indicating new disease activity. The treatment period was considered to start one month after starting the drug and continuing until one month after the final dose. Other MRI outcomes were also evaluated. In addition to MRI results, clinical outcomes, i.e., number of relapses, self-reported well-being scores, and changes in disability scores as measured on the EDSS were also noted.
MRI results showed that the placebo group had a mean average of 9.6 new gadolinium-enhancing lesions per participant during the six-month period. Those in the lower-dose treatment group had a mean average of only 0.7, and those in the higher-dose group had a mean average of only 1.1 (the differences in these two latter scores is not significant). This represents about a 90 percent reduction in the formation of lesions when comparing the placebo group to the treated groups. Significant reductions were also seen in the secondary MRI outcomes (such as the number of persistent enhancing lesions, new active lesions, total volume of enhancing lesions, and the percentage of scans showing disease activity).
Looking at clinical outcomes, a significant difference in relapse rate was observed between the placebo and treated groups. Of the 71 individuals in the placebo group, 36 relapses were reported in 27 of the patients (representing 38 percent). In the lower-dose treatment group, 18 relapses were reported in 13 of the 68 participants. In the higher-dose treatment group, 15 relapses were reported in 14 of the 75 participants. The latter two represent 19 percent each – showing that approximately half the number of individuals experienced relapses in the treated groups as compared to those in the placebo group. Self-reported well-being scores were improved in the treated group, but slightly worse in those in the placebo group. No significant changes were seen in disability scores during the relatively short, six-month study period.
Antegren works by interfering with the movement of potentially dangerous immune system cells (activated lymphocytes and monocytes) from the bloodstream across the blood-brain barrier (BBB), into the brain and spinal cord. Passing through the BBB is a necessary step for the cells to attack the myelin and cause damage to the nerves of the central nervous system (CNS). To cross the BBB, immune system cells must first adhere to the wall of the blood vessels. Glycoprotein alpha 4 integrin is expressed on the surface of these damaging cells and plays a critical role in the cells’ ability to adhere to the blood vessel walls and then migrate into the CNS. Antegren is an alpha 4 integrin antagonist, thus interfering with the alpha 4 integrin’s ability to move immune system cells into the CNS.
The drug was originally developed by the Elan Corporation. Biogen Incorporated (makers of Avonex®) has joined the Elan Corporation to test and ultimately seek approval for Antegren. Larger, longer-term studies are presently underway, with the hopes that approval for the drug may be sought in the United States and Europe by the end of 2003. According to The Associated Press, Elan’s president of research and development stated that the drug could be available as early as the end of 2004.
