FDA Decision on Antegren Expected Soon
November 11, 2004
On or before November 25, 2004, the U.S. Food and Drug Administration (FDA) is expected to announce its decision about whether or not Antegren® (natalizumab) will be approved as a treatment for multiple sclerosis. Six months ago, the makers of Antegren (Biogen Idec and Elan Corporation), submitted an application to the FDA for early approval of this drug for MS. The application was submitted one year sooner than planned. The decision came after the manufacturers reviewed the one-year data from the two ongoing, two-year phase III trials.
One-Year Data
According to a press release dated November 8, 2004, Biogen Idec and Elan Corporation announced that the one-year data from one of the two phase III trials showed a 66 percent reduction* in the clinical relapse rate for individuals with relapsing-remitting MS (RRMS) taking Antegren, versus those given a placebo. These results were from the trial using Antegren alone. No results were announced regarding the other trial that compares the use of Antegren in combination with Avonex® (interferon beta-1a) versus using Avonex alone. More information on these studies is noted below under Trial Information.
In the Antegren monotherapy trial, participants receiving the active drug were given a 300 mg intravenous (IV) infusion of Antegren once a month. Side effects were experienced by at least five percent of those in the treated group (compared to approximately three percent of the placebo group) and included headache, fatigue, and arthralgia (joint pain). One percent of the placebo group and two percent of the treated group developed serious infection, and one percent of the treated group experienced a serious hypersensitivity-like reaction.
*Please note that this information comes directly from the companies sponsoring the trials. While the results appear positive, the findings have yet to be published in a peer-reviewed journal, which serves to confirm trial results and analysis for professionals and members of the MS community.
Trial Information
Both of the phase III, two-year trials include a combined total of approximately 2100 participants with MS, and are randomized, multi-center, placebo-controlled, and double-blinded. Primary endpoints are based on the Expanded Disability Status Scale (EDSS) and relapse rates. The two trials measure the treatment's potential to slow the progression of disability and reduce the rate of clinical relapses. One trial evaluates Antegren alone, while the other trial evaluates Antegren in combination with Avonex(interferon beta-1a, which is marketed by Biogen Idec).
Results of the earlier, six-month phase II 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). The trial was conducted at 26 centers in the United States, Canada, and the United Kingdom with 213 individuals who had either relapsing-remitting or secondary-progressive MS. Three groups of participants were given a high dose, low dose, or placebo via intravenous infusion once every four weeks for a six-month period.
In this phase II trial, the treated groups experienced 90 percent fewer lesion formations when compared to the placebo group, as well as fewer 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). Relapse rate was significantly lower in the treated group, with 38 percent of the placebo group having relapses, versus 19 percent in the treated groups. No significant changes were seen in disability scores during the relatively short, six-month study period.
How Antegren Works
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.
MSAA's Position
The fact that the FDA is reviewing potential new treatments for MS is very encouraging, notes MSAA Vice President and Chief Medical Officer Jack Burks. He stresses, however, that one needs to reserve judgment until the final data for this new drug is presented. Dr. Burks goes on to say, We have no published data on the efficacy or safety of this drug from the phase III trials. Only one year of data was presented to the FDA from these two-year trials, and while this is exciting, we need to be cautious.
In light of the recent safety findings with Vioxx®, regarding an increased risk of heart-related problems for those taking this drug to treat arthritis, and Prozac®, regarding increased suicide risk in young children taking this drug for depression, safety data with long-term studies need to be carefully scrutinized.
In conclusion, everyone at MSAA is greatly encouraged that research continues at a fast pace for treating MS. But this excitement should not be overstated and recommendations cannot be made until the FDA announces its decision and the final results of the phase III trials are known. By Susan Wells Courtney, MSAA Writer
Multiple Sclerosis Association of America
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