|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.
Excess iron in cells is thought to be toxic because it causes oxidative stress. In the absence of frataxin, proteins that are important for mitochondria do not function properly, which also results in oxidative stress. Therefore many researchers are attempting to develop antioxidants as potential therapies. These compounds are very powerful antioxidants, often specifically targeted to mitochondria. Many are also designed to specifically substitute for the mitochondrial proteins that aren’t properly formed when mitochondrial iron levels are not balanced. Several such compounds are in development. Idebenone, under development by Santhera, has been the most extensively tested, and appeared to improve FA symptoms in some early stage trials. However, two Phase III trials have failed to show significant improvement with this compound. Other antioxidants are in earlier stages of development, including compounds from Penwest, Edison, ViroPharma, INSERM and Ipsen. Many of these drug candidates are already being tested in patients, or will soon enter clinical trials. Natural products being tested include resveratrol and an extract from Ginkgo tree leaves. This is an exciting avenue of research. MDA has invested almost $500,000 on antioxidant approaches for FA therapy.
Frataxin protein is involved in importing iron into mitochondria. Iron plays critical roles in the function of mitochondria, but is toxic at excessive levels. Therefore many researchers propose that regulating iron levels in the cell may improve symptoms for patients. Dr. Des Richardson, at the University of Sydney, has pioneered much of this work. A company called ApoPharma is developing Deferiprone, a compound designed to remove excess iron from cells. This compound is currently being tested in Phase II trials.
FA is caused by mutations in the frataxin gene. FA patients do not produce enough frataxin protein, or their frataxin protein does not function properly. Therefore, increasing levels of frataxin protein is a reasonable strategy for mitigating the disease. Several research groups around the world are screening collections of compounds (including drugs that are FDA-approved for other conditions) to identify those that can bring about increased frataxin levels in cells. Several groups have “lead compounds” that are moving into further drug development.
One of these lead compounds, under development by Boston-based Repligen Corporation, is a histone deacetylase inhibitor (HDACi). MDA has awarded two consecutive grants totaling more than $1.7M to Repligen to help finance the development of this compound as a therapy. The company has completed a small clinical trial in Italy, and is seeking partners to move the compound into later stage trials in the U.S. In total, MDA has invested almost $3 million on strategies to boost frataxin levels.
Another frataxin-inducing compound, at least in vitro, is the hormone erythropoietin (EPO). EPO itself and chemically modified versions of the hormone are being studied for their safety and efficacy in early clinical trials. A trial published in 2012 indicated no effect from EPO treatment.
Another potential approach for boosting frataxin levels in cells is to replace the defective gene through gene therapy. Gene therapy technology is still in its infancy. Michael Koob, at the University of Minnesota, is attempting to develop gene therapy specifically for mitochondrial diseases such as FA. Dr. Koob’s experiments are in the preclinical stage.
Another gene-related strategy is to fix the defective gene by removing the extra GAA units. Such “gene editing” approaches are also quite preliminary, but are being developed for FA. MDA has invested nearly $500,000 into gene therapy approaches specific to Friedreich’s Ataxia, in addition to considerable investment into gene therapy technologies in general.
Replacing frataxin by a protein infusion may be another potential therapeutic option for FA. However, the supplemental frataxin not only must enter cells, but it needs to further travel into the mitochondria within cells, presenting considerable technological hurdles. Academic researchers are developing strategies to overcome these obstacles, for instance, by attaching the frataxin protein to an adapter molecule, called “TAT” that will usher the protein to the appropriate part of the cell. This approach is still in early preclinical stages of development.
One of the significant consequences of loss of frataxin is that the mitochondria (organelles within each cell responsible for generating energy) cease to function normally. This is thought to contribute significantly to the symptoms of FA. As such, drugs that improve the function of mitochondria even when frataxin levels are low would be expected to improve FA symptoms. MDA has contributed almost $300,000 to investigating this approach.