Research News
Antegren Submitted One Year Early for FDA Approval
The makers of Antegren® (Biogen Idec and Elan Corporation) announced they are going to be submitting an application for approval of Antegren (natalizumab) as a treatment for multiple sclerosis to the U.S. Food and Drug Administration (FDA) one year earlier than planned. They expect to submit the filing mid-year 2004. The decision came after reviewing the one-year data from the two ongoing two-year phase III trials. The companies did not disclose the one-year data to protect the integrity of the trial.
About the Trial
Approximately 900 patients are participating in the AFFIRM (natalizumab safety and efficacy in relapsing-remitting MS) trial, a two-year randomized multi-center, placebo-controlled, double-blinded study. The focus of this trial is to evaluate Antegren's ability to slow the progression of disability in MS and reduce the rate of clinical relapses.
The second trial, SENTINEL (safety and efficacy of natalizumab in combination with Avonex® [interferon beta-1a]), includes approximately 1200 patients with relapsing-remitting MS and is a two-year, randomized, multi-center, placebo-controlled, double-blinded study. The study is evaluating the effect of the combination of Antegren and Avonex compared to the treatment with Avonex alone in slowing the progression of disability and reducing the rate of clinical relapses.
The protocol of both studies includes a one-year analysis of the data. The primary endpoints for both phase III two-year trials in MS are based on the Expanded Disability Status Scale (EDSS) and relapse rates.
Background on Antegren Trials
The Motivator has chronicled the development of Antegren from its clinical phase. The 2002 winter issue of The Motivator article focused on the clinical trial and previewed both the AFFRIM and SENTINEL trials. The 2003 winter issue of The Motivator reported on the progress of the two trials and the important process of affirming the results in a "peer-reviewed" publication. The results of the 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). Anyone wishing to see copies of these two MSAA articles may request them by calling MSAA's Helpline at (800) 532-7667.
More on Antegren
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 the 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 blood vessels. Glycoprotein alpha 4 integrin appears on the surface of these damaging cells, enabling them 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 integrins ability to move immune system cells into the CNS.
Antegren was originally developed by the Elan Corporation, and has since joined with Biogen Idec Incorporated (makers of Avonex) to test and ultimately seek approval for Antegren.
Oral Cladribine Efficacy Trials Slated to Begin This Year
Recently, Serono (makers of Rebif) and Ivax Corporation announced their test results from two clinical trials with a new oral formulation of cladribine. The study results showed that the formulation of oral cladribine has met the targets for an orally administered product, with blood levels of cladribine reaching the desired levels. Cladribine inhibits immune reactions by disrupting the production of certain white blood cells, particularly lymphocytes, which are involved in the disease process of multiple sclerosis. Investigators are planning further efficacy studies of oral cladribine in MS patients for late 2004.
Previous phase II and phase III clinical trials of injectable cladribine demonstrated some effects in people with MS. In these trials there was a reduction in new lesion development in the brain as seen on MRI scans, although total lesion volume did not appear to be affected. Individuals with relapsing-remitting MS also experienced clinical benefits (with an exacerbation rate approximately half of the rate experienced by individuals taking placebo). Disability in terms of EDSS was not affected. The results of these studies, however, were considered to be mixed and could not be replicated in a recent phase III study (which may be due to participants having more advanced MS than in previous studies).
Researchers determined that further studies were needed, employing participants who have MS in earlier stages. But in these upcoming trials, investigators will be able to use an oral formulation rather than giving the drug through injections. Medications in drug trials are frequently administered via injection, as this method can deliver higher amounts into the blood system as opposed to drugs taken orally. As mentioned earlier, however, the oral formulation of cladribine was able to reach the desired level in the blood. For this reason, investigators are now able to conduct trials with the oral version, which is both painless and more convenient for the participants.
More Patents and Trials Continue with MBP8298
BioMS Medical, based in Edmonton, Alberta, has recently received 17 additional patents for MBP8298 in conjunction with the University of Alberta. In total, 50 patents have been granted to the University of Alberta for MBP8298 in 29 countries worldwide, including three patents issued in the United States. MBP8298 stands for Myelin Basic Protein Peptide and is comprised of 17 amino acids. The drug, which has been in research for 26 years, is going to phase III of clinical trials, with successful results in the pre-clinical, phase I and phase II human clinical trials in Canada.
Background on MBP8298
MBP8298 works by reducing the disease-associated production of a group of anti-MBP antibodies that are reactive with the central nervous system. The four-year phase II trial enrolled 32 patients with either primary or secondary-progressive MS. The study had two phases, a two-year randomized double-blinded, placebo-controlled phase, followed by a two-year open label phase. During the double-blinded phase patients were given 500mg of the MBP8298 peptide intravenously every six months. Data from the trial was analyzed both in terms of overall results, and in terms of patients who carried either HLA-DR2 or HLA-DR4 immune response genes ("DR2/4"). These genes are associated with helper T-cells involved in the production of anti-MBP antibodies targeted by the MBP8298 peptide.
In the normal population, the DR2/4 gene is relatively low. In the MS population, however, individuals with either the DR2 or DR4 genes account for approximately 75 percent of the estimated two million MS patients worldwide. Of the 32 participants enrolled in the double-blinded phase of the trial, there was a representative sample of 20 patients that carried either the DR2 or DR4 genes, which were evenly divided between patients dosed with MBP8298 and placebo.
