Kenneth Johnson, MD Chairman of Neurology Arthur Sherwood, PhD, Charles Burgar, MD, Hunter Peckham, PhD, Graham Creasey, MD, Inder Perkash, MD
There is a wealth of expertise within the VA healthcare system in areas critical to Multiple Sclerosis: Immunotherapy, Assisted Movement and Therapies, Bladder and Bowel Management. In addition, compensatory therapies such as Functional Electrical Stimulation are just beginning to explore applications related to Multiple Sclerosis. In this section of the symposium researchers discussed the current state of research in these areas as they relate to the treatment of Multiple Sclerosis.
Since the ability to create new therapies in MS is directly related to the ability to understand the disease, it is important to review the last 30 years of work and discovery in the neuroimmunology of MS. The process begins when an antigen which resembles central nervous system myelin is presented to a naïve T-lymphocyte, a CD-4 cell. The CD-4 cell then begins to recognize the antigen, or a part of the nervous system, as something foreign to the body which should be destroyed. Beta interferon works, in part, because it is able to block antigen-presenting cells from emerging and delivering the antigen. A great deal of work has also gone into evaluating the drug Copaxone, which probably works by displacing the antigen and changing the dynamics between the antigen presenter and its receptor on the T-lymphocyte cell.
CD-4 cells are precursor: they transform and follow one of two pathways. One is a Th-1 cell, a pro-inflammatory cell that is very important for us since inflammation is part of the body's defense mechanism. However, in MS, it can be destructive, and treatment is geared toward reducing the inflammation this type of cell produces. One method is by strengthening and increasing the cells that dampen or inhibit inflammation (another form of T-lymphocyte, the CD-8 cell), reducing the amount of damage produced by MS
Once a cell becomes sensitized to central myelin, to do its damage it has to get to the brain. This requires the presence of certain types of adhesion molecules, which allow lymphocyte and endothelial cell to attach to each other, allowing the lymphocyte to migrate past the blood brain barrier into the central nervous system. Thus another opportunity to intervene is to use pharmaceutical blockade to prevent entry of lymphocytes into the brain.
In fact, knowing about this process—knowing about adhesion molecules, knowing about Th-1 cells, Th-2 cells, and the different types of cytokines produced by these cells—allows us to see many therapeutic opportunities. There are probably 20 different places where, if we knew how to effectively intervene, we would be able to treat MS.
Beta Interferon
While the relatively small number of MS patients classifies it as an orphan disease, pharmaceutical companies are interested because of its chronic nature. Therefore, it has been possible to do the necessary clinical trials. In 1993, beta interferon (Betaseron) was approved by the FDA and became arguably the first MS therapy to favorably alter the course of the disease. Its success emphasizes how critical it is to take a scientific idea and develop it into an available pharmaceutical. We know that these drugs do work. They have made an enormous difference in the course of the disease, and therefore the quality of life for MS patients.
The Betaseron study was a double-blind, placebo-controlled study for 3 years; subsequently it has been open-labeled. For a group of 150 patients, the MS relapse rate went from about 1 ½ attacks per year down to about one every 5 years. In addition, this group's disability rating as defined by the Kurtzke EDSS, the clinical scale we use to look at disability in MS, did not change over a 5 year period, which is a very different course from the natural history of the disease. These results should encourage the research community to keep developing drugs such as other immuno-modulators.
Betaseron was the first beta interferon approved by FDA. Its developer, Berlex, did a secondary progressive trial in Europe, now concluded and published, showing that in the more progressive, more disabling forms of MS, Betaseron does work and the FDA is now considering the extended use of Betaseron for MS patients in this category. A newer interferon, beta 1A, (Avonex) is now in a mono-symptomatic trial to see if it will work in the very earliest stages of the disease. Both require administration by injection.
At present, there is interest in developing oral interferons. Although one might suspect that since interferons are proteins typically when a protein is digested it breaks it down into its component peptides, this is not a logical course of study. However, it turns out that both interferons and Copaxone, may be formulated for successful oral administration.
Other Immunotherapies
Altered peptide ligands is a new approach which offers a complex immunologic idea, probably similar to that of copaxone, but this trial is just getting under way.
Unfortunately several promising experimental paths have failed. Studies involving T-cell receptor peptide vaccines have not shown positive results. Outcomes for therapies using monoclonal antibodies to adhesion molecules did not differ from placebo therapies. A pilot study involving IL-10, one of the anti-inflammatory cytokines, was negative. Interest in tumor necrosis factor (TNF) inhibitors sparked interest in Canada. However, soluble TNF receptor inhibitors were tested and shown not to work.; in fact, subjects who received the TNF receptor had more MS activity than the placebo group. Anti-TNF antibodies have not yet been tested.
Two studies have involved T-cell adhesion-related molecules. Tests of one show therapies not to work, and the other is still in testing. An interesting area of study may be matrix metaprotinase inhibitors, treatments which block the enzymes that allow the lymphocyte to go through the blood-brain barrier into the brain, but very little clinical research in humans has been done to date.
To interfere with trimolecular complex, formed when the antigen-presenting cell presents the antigen to the CD4 lymphocyte, there is the possibility of vaccination with T-cell receptors or receptor peptides. Early
studies of this approach have not worked. Treatment with antibodies to the T-cell receptors is a controversial, but interesting idea; there are some early studies in the phase II stage in Europe.
Gene therapy is presently a "buzzword" in clinical research. Perhaps means for developing a vehicle—a virus or some kind of a cell—to bring what we want into the central nervous system, to allow the therapeutic modality to work.
Finally, combination therapies are being considered. Many different combinations are possible. A very rigorous trial that takes patients who have been on Avenex, one of the interferons, for about 6 months, and then adds Copaxone is just being started. Multiple MRIs are to be used to see whether the disease is ameliorated by this combination.
This is not by any means a complete list. The field is extremely active and there are many worthy ideas. None of the currently available treatments are able to control the disease completely, so new therapies and better ways to administer them must be pursued.
Requirements for Clinical Trials
Progress, has paradoxically made it more difficult to carry out the necessary comparison trials. Back in the early 1990s, when we were developing these drugs, there was nothing else. It was quite easy to recruit people, and it was easy to do a comparison between placebo and real drug. Now we are concerned with whether we can improve upon one of the approved drugs. This is much more complex and probably much more costly.
It is also important to consider the very specific phases that are involved in developing any type of pharmacological agent. Pre-clinical studies, that is, studies in animals, are conducted first to see whether it is safe enough to expose humans to a molecule of some kind.
Then the molecule faces four phases of human studies well defined by FDA. Phase One studies are usually of either human volunteers or of patients who have a specific disease like MS. These involve 10 to 20 subjects and are only done to determine whether there is a real safety issue. They are not intended to produce any significant results.
The Phase Two Trial commonly involves between 25 and 100 patients with the disease. These trials are usually based on MRI changes and are commonly dose-finding studies. They often take 12 to 18 months to give enough confidence to proceed to a Phase Three trial.
The Phase Three Trial is called the pivotal trial. It often consists of 250 to 900 patients in MS trials and is double-blind, placebo-controlled, and leads to FDA approval. These studies rarely are less than 2, and sometimes over 3 to 4 four years in length. Positive results from these trials are necessary before a drug can be licensed.
Phase Four Trials are post-marketing studies, necessary to see whether, in fact, some number of patients have toxicity not recognized in the earlier trials. For instance, when Betaseron was licensed, there actually were only 250 MS patients who had been exposed to it at the time the FDA decided to license the drug. Of 375 patients, 125 got placebo and 250 got the real drug. Post licensing, approximately 30,000 people have received Betaseron. Within this, there may be small sub populations of patients who have serious side effects not noted in the sampling necessary for Phase Three Trials.
Not surprisingly, this process takes anywhere from 4 to 6 years and can cost a drug company anywhere from $10 to $60 million. That is why not every drug can be tested. This is also why it is important for entities like the Alzheimer's disease group to be around so drugs not protected by patents and not likely to be developed by drug companies can be tested.
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