|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.
If a functional copy of the mutated gene can be inserted into at least a proportion of the patient’s cells and it expresses the correct version of the protein, the patient’s condition will improve. This is the aim of gene therapy approaches to LGMD. MDA is supporting Dr. Jerry Mendell to investigate this approach in the form of LGMD caused by mutations in the alpha-sarcoglycan gene (LGMD2D), and early results are very promising. Dr. Mendell has successfully demonstrated that a single injection of the therapy resulted in the patient’s cells producing the missing protein. MDA is now supporting working leading to a trial where we hope to see protein produced throughout an entire limb. If successful, this general approach can be used in any patient where the disease –causing mutation is known. MDA supported researchers have developed similar technologies for many forms of LGMD.
An alternative gene therapy approach would be to replace not the defective gene, but a different gene that would cause the patient’s cells to get bigger and stronger. MDA is also supporting researchers starting trials in these therapies, which would be applicable to multiple muscular dystrophies. One such protein, called SERCA1, helps reduce calcium levels inside muscle fibers by pumping calcium into sequestered storage areas in the fibers. A team of U.S. researchers has found that increasing SERCA1 protein levels results in dramatic amelioration of symptoms in mice with a disease resembling either Duchenne muscular dystrophy or the type 2F form of LGMD. Overall, MDA has spent over $12 million on gene therapy specifically for LGMD, and close to $40M in total over all the MDs.
As with most muscular dystrophies, LGMD patients would be expected to benefit from a drug that increases muscle strength. Early studies in animal models of LGMD have shown that blocking myostatin can improve strength. 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. In total, MDA has spent over $1M on muscle building compounds for LGMD, and another $6M for similar strategies in other MD’s, with direct relevance to LGMDs.
If the mutated gene can be repaired in at least some proportion of cells, they will produce the missing protein and the patient’s condition will improve. Nonsense suppression compounds read through a type of mutation that leads to a truncated (non-functioning protein). Dr. Jerry Mendell has tested one such compound in a LGMD model with some success, and several groups are developing such compounds. The most advanced tests of such compounds were done by PTC Therapeutics, which tested PTC-124 or ataluren in a large Phase II trial for Duchenne muscular dystrophy (DMD). Unfortunately, the trial failed to meet its primary endpoint, although there are indications of effect at some doses. PTC is currently recruiting participants for a Phase III trial of ataluren in DMD. MDA is also supporting development of other read-through compounds; the most advanced compounds of this type are still preclinical for LGMDs. Although MDA has only funded one grant looking at these compounds in LGMD, it has invested heavily in the development of such compounds for DMD. Once such a compound is effective in one disease, it would be expected to show effect in many others.
One serious consequence of LGMDs (and several other muscular dystrophies) is cardiomyopathy. Phrixus Pharmaceuticals is developing a compound called Poloxamer-188 which is designed to seal leaks in the membranes of the dystrophic heart, reducing the risk of heart failure. This has shown promising results in pre-clinical experiments. Phrixus is in discussions with the US Food and Drug Administration about conducting a trial in DMD. This therapy would likely be used in combination with other therapies to treat associated cardiac problems. MDA has funded over $1.6 million on projects aimed at developing novel heart therapies for LGMD specifically, and much more on treatments that might relate to multiple dystrophies.
Some of the degeneration caused by some forms of LGMD may be alleviated by reducing inflammation, a reaction to muscle disease mounted by the body’s immune system, which may indirectly reduce fibrosis. Two studies have found corticosteroids (which may work through anti-inflammatory pathways) to be effective in certain forms of LGMD, while other forms appear resistant to steroid treatments. Unfortunately, corticosteroids carry significant side effects. Companies such as Reveragen Biopharma and Catabasis Pharmaceuticals are working to develop effective inhibitors of the anti-inflammatory pathways that will have fewer side effects than corticosteroids. The most advanced of these “next generation” compounds are in preclinical testing, and MDA is funding academic researchers to study Reveragen’s compound in an animal model of one of the LGMDs. MDA has spent over $1.3 million on looking at such compounds in LGMDs, in addition to spending on such compounds for other dystrophies.
Since many of the proteins defective in LGMD patients are membrane proteins, it is thought that much of the muscle damage is due to the membranes becoming leaky. A compound called MG53, which causes the membranes in the muscles to seal, is being developed by TRIM-edicine, with Duchenne muscular dystrophy as one of their first indications of interest. The company has published promising preclinical data in a DMD mouse model, suggesting that its compound would also be effective in LGMDs. MDA researchers are now exploring this possibility. This type of therapy would not be dependent on which mutation a particular patient had, so this is a very attractive therapeutic option. Other potential therapies that are at an earlier stage include changing levels of proteins such as dysferlin and LARGE that might help stabilize the membranes. In total, MDA has spent over $1.5million on this strategy for LGMD.
Stem cells that express the missing gene normally may be able to be introduced to the muscle, producing the missing protein. This would be expected to alleviate symptoms, if enough cells could be introduced. A number of early-stage researchers are looking at the possibility of using stem cells in animals with LGMDs. This is very early-stage research that looks promising. MDA has spent over $2.7 million on these strategies.
Many researchers think that one of the problems encountered in muscular dystrophies is that the muscle reaches the end of its capacity to repair itself. Early on in the disease progression, the weakened muscle fibers tear frequently. As time goes on, the body’s repair mechanisms are insufficient to fix the tears, and the muscle gets weaker. Therefore some MDA-supported researchers are investigating the possibility that increased muscle repair would slow down progression of muscular dystrophies. MDA has spent over $1.9 million on these technologies for LGMDs.
Researchers think that some types of LGMD (and some congenital muscular dystrophies) may be caused by the triggering of a cellular pathway that kills off the muscle cells. 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 $2.6 million on these technologies.
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 LGMD.
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