|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.
Researchers think that some types of CMD may be caused by the triggering of a cellular pathway that kills off the muscle cells, which may occur when a cell loses contact with the extracellular matrix. This pathway normally exists in cells to remove toxic and dying cells, but may kill off too many muscle cells in some patients. Potential therapeutics that prevent the triggering of these pathways may therefore protect the muscle cells from dying, and thus increase muscle strength. Encouraging results have been seen in some cell and animal models of the disease. MDA has spent over $1.8M on these technologies for CMDs. The most advanced compound in this class is Omigapil, in development by Santhera Pharmaceuticals. Santhera is currently preparing a phase I study in pediatric CMD patients, which will investigate whether the drug is safe and tolerable, and how it is distributed through the body. This study is not yet recruiting as of August 2013. Other researchers are investigating the involvement of a cell molecule called BAX, which promotes cell death, and will seek to develop drugs to target BAX in CMDs.
Gene therapy, or gene transfer, refers to the delivery of genes as therapeutic agents. Since genes carry the instructions for protein synthesis, they can lead to production of proteins that are directly or indirectly therapeutic in neuromuscular diseases. Because transferred genes potentially can continue to produce protein for some time, gene therapy may offer a more permanent fix than other therapies. But gene therapy faces many technical challenges, as well as a high bar set by regulatory agencies like the U.S. Food and Drug Administration (FDA). Gene therapy approaches are specific to the type of CMD that a patient has, as typically they aim to replace the defective gene. In the CMDs, MDA-supported researchers have looked at gene therapies using agrin and dysferlins.
Currently, MDA scientists are pursuing gene therapy with Galgt2, a glycosylating enzyme that increases expression of other muscle proteins that ultimately reduce damage to the muscle. For well over two decades, MDA has been a leader in supporting the development of gene therapies for neuromuscular diseases, with DMD being in the forefront of such research. MDA has devoted over $1.3 million to gene therapy development for CMDs, and over $ 28 million to gene therapy for muscular dystrophies in general.
In addition to therapies targeting the root cause of the disease, a number of therapies in development act indirectly to alleviate symptoms, such as loss of strength. Many of these therapies may be applicable to multiple muscular dystrophies and possibly to other neuromuscular disorders. For example inhibitors of myostatin have received much attention from the neuromuscular disease research community ever since it was found several years ago that people and animals with a genetic deficiency of myostatin appear to have large muscles and good strength without apparent ill effects. The biotechnology company Acceleron Pharma developed a drug based on inhibiting myostatin and began testing it, with MDA support, in boys with DMD. Unfortunately, unexpected safety issues arose during that trial, causing Acceleron to terminate it in 2011; the development program has now been halted permanently. Other strategies to inhibit myostatin, such as injecting genes for the myostatin-blocking follistatin, also are under consideration, as are strategies to accelerate muscle growth with insulin-like growth factor 1 (IGF-1), which is inhibited by myostatin. MDA has devoted over $6 million on muscle strengthening approaches, $850,000 specifically for CMDs.
If healthy cells can be introduced into the muscle, it is hoped that they will substitute for the patients’ own cells to improve muscle function and health. A number of researchers are investigating the possibility of using stem cells in the CMDs. There were high expectations for such strategies, particularly myoblast transfer, in the 1990s, and considerable effort was devoted to such therapies. Despite major technological hurdles, research on this therapeutic approach continues to advance. The most advanced stem cell project to date is being conducted by Giulio Cossu, of the San Raffeale Scientific Institute in Milan, Italy, who is using a special kind of stem cell, termed a “mesoangioblast,” that can be isolated from muscle biopsies of living donors in DMD, but the same concept would work for other muscular dystrophies. MDA has funded almost $2 million toward such strategies specifically for the CMDs.
It is likely that one contributor to muscle weakness is an increase in protein breakdown in injured muscles. Therefore, it may be therapeutic to slow down the breakdown process. Cells use a protein recycling process called autophagy (aw-TOFF-uh-gee) to degrade proteins. MDA researchers are currently investigating autophagy inhibitors in models of CMDs to determine if they are therapeutic. Similarly, scientists are investigating several ways to increase muscle regeneration, which will also reduce muscle loss. In total, MDA has invested over $1.6M into this approach for the CMDs.
As muscles degenerate in a person with some CMDs, the muscle fibers are replaced by fat and connective tissue in a process called “fibrosis.” Many researchers believe that muscles might be protected by medications, termed “anti-fibrotics,” that reduce this fibrotic process. Reducing fibrosis may also help increase the efficacy of other potential therapies. These drugs are still in the preclinical phases of development, with the most advanced drug being halofuginone, in development by Halo Therapeutics for DMD. MDA has invested more than $1 million into investigating the potential of such therapies for CMDs.
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 CMDs.
Many CMDs are caused by defects in proteins that surround the muscle surface, effectively holding the muscle cells together. While gene therapy proposes to introduce a gene to make the correct protein, protein replacement therapy provides the protein itself. These therapies are still in early development, but are very promising for several CMDs. Laminin 111, in development by Prothelia for merosin deficient CMD, is the most advanced candidate of this type. MDA has invested over $1 million into investigating the potential of such therapies for CMDs in addition to a lot more on understanding how the cells work and what is going wrong in individual CMDs.
Inflammation is an immune system response seen in tissue that has been damaged. In the short term, inflammation can help clear debris and set the stage for repair, but prolonged inflammation is harmful. Drugs that reduce inflammation being investigated in models of CMDs include cyclosporine, losartan, and doxycycline. MDA has committed over $600,000 to this approach specifically for CMDs, but also has much more invested in anti-inflammatory drugs for other MDs, which also have potential for CMD patients.
Many researchers believe the best way to reduce the damage caused by CMDs may be to combine different therapeutic strategies. MDA is supporting a study combining anti-inflammatory and anti-fibrosis therapies, to determine if they offer superior results to either treatment alone. In total, MDA has committed over $350,000 to combination therapies.
As the CMDs are caused by many different genes, there are a number of potential therapies that may be specific to one, or a subset, of CMDS. These include carbohydrate/sugar replacement therapies, designed to help the extracellular matrix retain its stickiness – and therefore hold together better during muscle contractions. MDA has invested nearly $700,000 in these types of strategies. MDA has funded an additional $800,000 in grant supporting development of other such strategies.