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.
Gene replacement has been a focus of MDA-supported research, first in a mouse model of MTM, and now in a dog model of the disease, delivering the MTM1 gene via a viral carrier (adeno-associated virus). Success in the dog model may set the stage for trials in humans. MDA has funded Dr. Casey Childers to study this type of therapy in collaboration with Genethon, and results are encouraging. Audentes Therapeutics is now bringing this therapy forwards. MDA has invested over $600,000 in this approach.
MDA is funding Valerion Therapeutics in the development of a therapy for MTM in which the myotubularin protein, rather than the gene, is delivered directly to muscle cells. A major challenge in delivering protein is to get the protein across the muscle cell membrane. The strategy being pursued, first in mice, is to couple the protein to a fragment of an antibody (an immune system protein) to promote its trans-membrane passage. Muscle cell membranes contain a receptor that specifically receives the antibody fragment. The combination of the protein and antibody is known as 3E10Fv-MTM1. Initial studies in MTM mice indicate that treatment has the potential to improve strength. MDA has invested nearly $1.5 million into development of these types of therapies.