September 29, 2000
Two clinical trials of a targeted peptide therapy in patients with relapsing-remitting multiple sclerosis (MS) have been halted due to adverse effects in some study participants. Despite these adverse effects, the findings confirm that the targeted peptide plays a role in the disease and provide valuable information that may help refine this type of therapy for MS as well as other autoimmune diseases. Results of the two studies will be published in the October 1, 2000, issue of Nature Medicine.1,2
Investigators at the National Institutes of Health, Stanford University, and 13 other research centers tested a type of targeted immunotherapy designed to alter immune reactions to a specific protein, thereby treating the disease without compromising other immune functions. In this case, the therapy was an altered version of one segment of a protein called myelin basic protein (MBP). Therapies using altered peptides of this type are referred to as altered peptide ligand or APL therapies. MBP is a component of myelin, a fatty substance that surrounds and insulates nerve fibers. It is released during flare-ups of relapsing-remitting MS, and it is believed to be one of the proteins which is attacked by the immune system, causing symptoms of the disease.
Relapsing-remitting MS is marked by periodic increases in brain inflammation and disease symptoms, interspersed with periods of full or partial recovery. Previous research suggested that introducing an altered form of MBP into MS patients might cause the body to react to the normal MBP in a protective way instead of a harmful way, thereby stopping flare-ups of the disease.
In the first study, researchers led by Roland Martin, M.D., of the National Institute of Neurological Disorders and Stroke (NINDS) Cellular Immunology Section tested the therapy in 24 patients with active relapsing-remitting MS. The study was partially sponsored by Neurocrine Biosciences, Inc., which owns the rights to this therapy, under a Cooperative Research and Development Agreement (CRADA). After studying the patients' normal disease patterns for 6 months, the researchers administered 50 mg of APL weekly for up to 9 months while using clinical tests, immunology work-ups, and MRI scans to carefully monitor the effects of the therapy in patients. Two out of eight treated patients showed an increase in inflammatory brain lesions that was linked to the APL therapy by sophisticated studies of their immune cells. One patient developed a general hypersensitivity reaction and three others discontinued dosing due to side effects that could not be directly linked to the therapy. Hypersensitivity is a condition in which the body over-reacts to a protein or other stimulus. After the first seven patients showed adverse effects, the dose was reduced to 5 mg for the eighth patient. When this patient also showed an increase in MS lesions that appeared to be related to the therapy, the trial was halted prematurely.
In the second study, Ludwig Kappos, M.D., of the University of Basel, Switzerland, Lawrence Steinman, M.D., of Stanford University Medical School, and collaborators at 14 research centers in the United States, Europe, and Canada conducted a randomized, double-blind clinical trial designed to test the therapy in 144 patients. The study was sponsored by Neurocrine Biosciences, Inc., and by Novartis. After a 1-month monitoring period, patients in this trial received either a placebo or a 5-, 20-, or 50-mg dose of the therapy weekly for 4 months. Patients were then offered the therapy at a dose of 5 mg weekly. In this study, the researchers found no significant difference in the frequency or number of relapses in patients receiving the therapy vs. the placebo, although the volume of new inflammatory brain lesions was reduced in some patients who received the 5-mg dose of the therapy. However, 9 percent of the patients enrolled in the study developed systemic hypersensitivity to the therapy. These reactions caused the trial to be stopped after only 53 patients had completed the double-blind phase. The scientists point out that neither of the studies tested the therapy in enough patients to show whether it can actually relieve patients' symptoms.
While the adverse effects in these studies were disappointing, the increase in brain lesions in some patients proves that MPB can induce an immune response in MS and is therefore a good target for MS immunotherapy, the researchers say. "There is no longer any doubt in my mind that MBP is one target autoantigen (a protein that triggers an immune response) in MS," says Dr. Martin.
These studies provide valuable information about how to design, refine, and test targeted immunotherapies. Results from both studies suggest that lower doses of this therapy are better than higher doses. The adverse reactions found in these studies were not predicted by previous studies in animals or humans, which highlights the importance of proceeding carefully with clinical research even when an experimental therapy looks promising, says Dr. Martin. The NIH researchers also feel their study demonstrates the importance of immunological tests to determine how targeted immunotherapies work in patients.
While these studies provide valuable information about APL therapies, researchers need to determine why some individuals responded differently than others to this therapy and what dose, frequency, and mode of administration provide the best results. More carefully controlled clinical trials of this or similar therapies should eventually reveal the answers to these questions.
The NINDS, part of the National Institutes of Health in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system. The NINDS is now celebrating its 50th anniversary.
This release will be posted on EurekAlert! at http://www.eurekalert.org and on the NINDS website at http://ninds.nih.gov/news_and_events/index.htm. 1 Bielekova B., Goodwin B., et al. "Encephalitogenic potential of myelin basic protein peptide (83-99) in multiple sclerosis - results of a phase II clinical trial with an altered peptide ligand." Nature Medicine, October 2000, Vol. 6, No. 10, pp. 1167-1175. 2 Kappos L., Comi G., et al. "Induction of a non-encephalitogenic Th2 autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo controlled, randomized phase II trial. " Nature Medicine, October 2000, Vol. 6, No. 10, pp. 1176-1182.
The National Institute of Neurological Disorders and Stroke is a component of the National Institutes of Health, U.S. Department of Health and Human Services