|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.
Myotonia, a delay in the relaxation of muscle after contraction, is one of the most clinically prominent signs of MMD. The anti-arrhythmia drug mexiletine has been shown to be safe and effective in reducing myotonia in small trials of MMD. A larger trial is enrolling as of June 2013, with estimated completion date of October 2014.
Muscle degeneration in MMD1 is thought to be largely caused by a reduction in muscle protein production, which in turn is thought to be due to a reduced response of the muscle tissue to certain hormones. Therefore increasing the levels of these hormones is one strategy for mitigating the muscle decline associated with myotonic dystrophy. As such, MDA supported a clinical trial of IPLEX, an experimental drug composed, in part, of a hormone called insulin-like growth factor (IGF1). Early-stage results looked promising for this drug, but the MDA-sponsored trial showed that IPLEX only had a significant effect in a very small proportion of patients. Therefore, this strategy is no longer considered a high priority. However, the trial provided researchers with important knowledge about this disease, which will aid in designing faster and more cost-effective trials in the future. MDA has targeted more than $2.5 million on developing myotonic dystrophy therapies that increase muscle strength, and has supported additional projects in other dystrophies that may also be applicable to DM.
As myotonic dystrophy is caused by the toxic effects of RNA repeat sequences (CUG or CCUG repeats), many therapeutic strategies are based on ways to remove or neutralize the toxic RNA. MDA-sponsored scientists are creating small synthetic segments of RNA (“oligonucleotides”) that bind specifically to the repeat sequences of the toxic RNA molecules. These can be designed to cause the cell to break up the toxic RNA. This strategy is working well in animal models of the disease, and is moving towards human clinical testing. Other strategies involve using enzymes to effectively “cut out” the defective part of the RNA. MDA is funding 4s3 Biosciences, a small biotechnology company that is developing an innovative therapeutic strategy for myotubular myopathy that delivers such enzymes specifically into muscle cells. The company is also planning on applying the technology to myotonic dystrophy. Other approaches for delivering such therapies include gene therapy, which MDA has invested in heavily over the years for many diseases. MDA has invested over $1 million on excision strategies for DM alone.
In addition to cutting out or removing the toxic repeat sequences, scientist believe that they can be made less toxic by being bound to other RNA molecules, thereby sequestering them away from any harm they might cause to the cell. Therefore, many researchers are developing oligonucleotides that bind to the repeats in such a way that they cannot interact with anything else (such as Muscleblind or other repeat-binding proteins). These projects are in preclinical stages, and show some promise. MDA has invested more than $3 million on this strategy.
One of the major proteins affected by the toxic RNA is called muscleblind. This protein is needed so that other cellular proteins can be made correctly, and not enough is available in people with DM because much of it is bound up by the toxic RNA. Studies have shown that if MBNL1 levels can be increased, symptoms such as myotonia (constant muscle contractions) can be improved. Therefore, increasing free MBNL1 is a goal for DM therapies. MDA has funded over $250,000 in projects exploring this approach.
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Along with muscleblind, CUGBP is another protein that is involved in causing DM symptoms. Like muscleblind, CUGBP is needed for cells to make other proteins correctly. Unlike muscleblind, CUGBP is present in excessive levels in those with DM, and therefore therapies aimed at reducing the levels of this protein to normal represent another approach. MDA-supported researchers determined the importance of CUGBP in myotonic dystrophy, and are currently investigating strategies for reducing CUGBP levels and evaluating how effective this strategy may be for treating the disease.
DM is caused by toxic repeating RNAs, which fold into a hairpin-like structure that binds the protein muscleblind. Researchers think that if they can interrupt the ability of the toxic RNA to bind to muscleblind, DM symptoms should be improved. They are seeking compounds that do this as potential therapeutics. One MDA-supported researcher recently reported the identification of a compound (pentamidine) that showed therapeutic potential in an animal model of the disease. Unfortunately, this drug has significant side effects; however, this is a promising lead that could bring about more effective drugs. MDA has invested over $3M in these approaches.