|Phase I||Phase II||Phase III|
Much of the research MDA supports is what is termed “basic” research: research investigating the fundamental biological processes of nerves, muscles and what goes awry to cause disease. Much of this research is not aimed at one specific disease, but can apply to many neuromuscular diseases. Projects at this stage, for example, may initially seek answers about a muscular dystrophy, but ultimately lead to a therapy for ALS. This is how MDA’s broad coverage of diseases can be so powerful. Basic research that results in the identification of a therapeutic target might also be called “discovery research”.
As the scientific community has developed a better understanding of the biological processes leading toward neuromuscular disease, MDA has also broadened its funding strategy into “translational” research. Translational research covers the work necessary to develop a potential therapeutic from the point when a potential drug has been identified to the stage in which the candidate therapy must be tested in humans (clinical trials). This includes improving the compound, testing to see if it is safe and effective in animal disease models, determining appropriate doses, and other tests required by the Food and Drug Administration (FDA) before a drug can be tested in humans. Once the best, or “lead” compound is identified, this work is also called “preclinical research”.
The most important tests of a potential drug are to determine whether it is safe and effective in humans. This is done through a series of carefully controlled and monitored experiments called “clinical trials”. These are split into three stages, conducted consecutively, and are heavily regulated by the FDA. The FDA analyzes preclinical data to determine if an “Investigational New Drug (IND)” should be approved: this is the go-ahead to initiate clinical trials.
Phase I clinical trials are small safety trials, with the sole purpose of determining whether the therapy is safe in humans. These are usually (but not always) conducted in healthy volunteers, not in patients with the disease. Researchers may collect data to see if there is any suggestion that the drug has an effect, but the trials are designed to look for signals of toxicity and are generally too small (i.e. involve too few test participants) and too short to determine any significant effectiveness of the therapy. Phase I trials may test different doses of the drug, or increased doses over time.
Phase II trials are generally the first trials in patients. Like Phase I trials, Phase II trials usually involve a relatively small number of participants, but often include a placebo arm. That is, some of the participants are given the experimental drug, while the others receive a mock treatment (such as a sugar pill). Often, even the researchers don’t know which participants are receiving the drug. When neither the participants nor the researchers know who has received the therapy and who has received a placebo until the conclusion of the study, it is said to be a “double-blinded” trial. This is important for ensuring that any interpretations of the results are completely unbiased. Researchers will analyze a number of outcomes from these trials, both in terms of safety and evidence that the therapy is effective. Phase II trials usually last longer than Phase I trials, and may be followed by an “extension phase” in which participants may be asked to remain on the drug for longer periods of time.
Phase III trials are typically the final necessary hurdle for FDA approval of an experimental therapy. These are usually large trials, conducted over a lengthy time period, and involve a single dose of the drug and a placebo arm. These trials involve enough people for sufficient time to enable researchers to see a statistically significant difference in outcome between the drug and placebo arms if the drug has an effect. Longer term side effects are closely monitored as well. The FDA reviews the data from the trials, and if it deems the data to demonstrate safety and efficacy, it will approve the drug for use. It may still require post-marketing surveillance (study), phase IV studies, of patients taking the drug to look for long term safety issues, or studies in additional populations (e.g., children) if they were not included in the original studies.
Current drug therapy for MG inhibits the cholinesterase enzyme, prolonging the action of acetylcholine enzyme at the NMJ. The drug pyridostigmine (Mestinon) works this way, and is widely prescribed for MG. An experimental therapy uses “antisense oligonucleotides” (ASO) to bind to and destroy the messenger RNA from the acetylcholinesterase gene, thus reducing the amount of the enzyme available for Ach breakdown. EN101, or Monarsen, is an ASO that targets messenger RNA from one form of the acetylcholinesterase gene. It has shown promise in early clinical trials. The drug, currently under control of Amarin, is no longer in development. MDA has contributed nearly $200,000 to research into this approach.
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a natural immune system growth factor that has been shown to prevent development of a disease in mice resembling MG, called experimental autoimmune myasthenia gravis (EAMG). The treatment increases numbers of T cells and B cells, and the T cells suppressed MG-associated antibodies. MDA-sponsored preclinical work investigating GM-CSF in MG, and a small clinical trial is currently being planned. MDA has sponsored over $500,000 into research into this approach
Bone marrow is the source of new immune cells throughout adult life. An experimental approach to MG therapy is to destroy the marrow cells using powerful immunosuppressants, and then reconstitute the bone marrow population using a patient’s own marrow stem cells collected prior to treatment. Results in animal models have shown some promise, and the treatment is also being explored in other autoimmune diseases. A clinical trial is currently underway to test this in MG. MDA has invested nearly $400,000 into this approach.
Immunosuppression remains the mainstay of immune system therapy in MG, but many patients experience side effects associated with powerful drugs. MDA supported development of intravenous immunoglobulin, which is one of the therapies currently used in MG. However, multiple agents are being tested to see if they offer a more favorable risk/benefit profile. These include methotrexate as an add-on therapy, subcutaneous (as opposed to intravenous) immunoglobulin, and a variety of other immunosuppressants and immunomodulators. MDA has contributed over $4M to therapeutic strategies of this type.
One specific form of novel immunosuppressant involves the complement system, which is a powerful component of the immune system that attacks cell membranes targeted by other immune components. In MG, complement proteins bind to and damage the membrane at the NMJ, thus reducing complement activity may be therapeutic. MDA-supported researchers are currently developing small interfering RNAs (siRNAs) to block complement proteins in a preclinical model of MG. A monoclonal antibody, eculizumab, which inhibits a component of the complement system, showed promising results in a Phase II study. It is on the market to treat two conditions unrelated to MG (paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome).
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