|Phase 1||Phase 2||Phase 3I|
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 also has 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 U.S. 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 1 trials may test different doses of the drug or increased doses over time.
Phase 2 trials are generally the first trials in patients. Like phase 1 trials, phase 2 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 2 trials usually last longer than phase 1 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 3 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 4 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.
MDA has supported development of gene therapy for a wide range of neuromuscular diseases. Overcoming the obstacles to successful gene therapy in one disease is likely to greatly accelerate efforts in many others, including CMT. MDA has invested nearly $1 million into CMT-specific gene therapy approaches, in addition to significant investment into gene therapy development as a field.
So-called “gene editing” strategies use new tools to target and correct mutations in specific genes. These strategies are currently in the preclinical stage but show promise in other genetic disorders. Success in gene editing in other diseases would lay the groundwork for application in the CMT.
Each of the many CMT-causing genes produces a protein, and each of those proteins is part of a “pathway,” or series of interactions within the cell. A mutated gene leads to a defective protein, and an interruption of those interactions. Understanding the details of the pathway affected by the gene mutation allows researchers to find ways to mitigate the interruptions caused by the mutation. In some cases, a drug might be able to partially substitute for the missing protein. In other cases, a different drug might be able to augment the action of another protein in the pathway, compensating for the loss of the mutant protein. By studying the pathways affected, MDA’s scientists are seeking the best “targets” for intervention in each disease.
One target is the “traffic jam” of accumulating proteins seen in CMT1B, due to mutations in the myelin protein zero (MPZ) gene. In an animal model, the spice and herbal medicine curcumin appears to help break up these molecular traffic jams. Further study of this potential therapy is underway. Another strategy is to speed the regrowth of damaged neurons, a possibility currently being tested by MDA-funded researchers. And a third strategy will test whether the amino acid serine can offer benefit in a rare form of CMT called hereditary sensory and autonomic neuropathy type 1 (HSAN1), based on human and mouse model data indicating that serine can help normalize the levels of two abnormal lipids involved in the disease.
It is likely that, despite the multiple genes involved in the different forms, many of the CMT disorders share similar problems, ultimately leading to loss of functioning nerves. Therapies targeting the health of nerves have been developed in preclinical models and have been tried in clinical trials. One therapy, the antioxidant vitamin C, was shown not to be effective in humans. The biotechnology company Pharnext is moving ahead with testing of PXT-3003, a low-dose formulation combining two approved off-patent drugs and one nutrient, all three already used for other indications. They have joined forces with Ipsen Pharmaceuticals to move the drug into larger clinical trials. Another strategy, currently being tested preclinically, boosts the interaction of myelin and axons by increasing a protein called netrin, in order to protect axons from degeneration. MDA has contributed almost $2.5 million into these types of approaches for CMT.