|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.
Several companies are developing compounds that show potential to protect neurons against the degeneration seen in SMA or ALS. Trophos has developed a cholesterol-oxime compound called olesoxime that preserves mitochondrial integrity in stressed cells, a potentially significant protective function in SMA motor neurons. In February of 2013, interim safety results in a pivotal trial indicated the compound was safe for continuation of the study; efficacy results are expected in late 2013.
Other compounds are in preclinical development based on results in cell or animal models. MDA has invested over $1.4M in developing neuroprotective compounds for SMA specifically, and has funded additional projects for developing similar compounds for ALS.
In addition to SMN1, humans have a duplicate gene called SMN2. This is functionally similar to SMN1, but is not expressed to a high enough level to compensate for the loss of SMN1 in most patients. Patients who express more SMN2 develop less severe symptoms, and at a later age, than patients who express less. Therefore several companies are developing compounds that increase SMN2 expression. Most of these compounds have been identified though small molecule screens. These include celecoxib and riluzole, and are still being explored preclinically. It is not yet known if any of these compounds increase SMN in people.
Most SMN2-targeting compounds are in the preclinical phase, but one, which has been supported by MDA is called RG3039 and has completed Phase I safety testing. The compound, originally developed by Families of SMA and licensed to Repligen, has now been licensed to Pfizer, which has stated its interest in proceeding with development. RG3039 is a quinazoline compound that inhibits scavenger decapping enzyme (DcpS), delaying the degradation of SMN2 messenger RNA and thus increasing protein production. The compound also increases the activity of the SMN2 gene promoter, the section that induces gene transcription (the first step in making the protein). MDA supported the clinical program for this compound at Repligen.
Other companies are testing compounds called “histone deacetylase (HDAC) inhibitors” that selectively cause upregulation of groups of genes. Several HDAC inhibitors that have been approved by the FDA for other diseases have been tested in Phase II trials in SMA.
One strategy for increasing SMN production is to force the protein-making machinery to “read through” the mutation that normally stops production of SMN. This approach has been taken by PTC Therapeutics, which in 2011 licensed its SMA program to Roche. Overall, MDA has contributed nearly $3M to general strategies to increase SMN2, in addition to nearly $2.5M to exon 7 inclusion, which is one specific approach which has been successful to date.
One specific strategy for increasing the level of SMN2 protein is through forcing the cell to process SMN2 into the same form as SMN1, prolonging the life of the messenger RNA (a temporary working copy of the gene, which serves as the template for manufacturing the SMN protein) in the cell (SMN2 messenger RNA is typically broken down rapidly, resulting in less protein production). This might be achieved through treatment with antisense oligonucleotides (ASOs), an approach under development by Isis, or through small molecule treatments, a strategy being pursued by Summit Plc.
As of August 2013, Isis is testing safety, tolerability, and pharmacokinetics of an ASO compound (ISIS-SMNRx) in patients with infantile-onset SMA, the most severe form. MDA provided support for the early development of this approach in SMA. Early results from preliminary trials of this compound suggest that the approach is safe, and there are even hints of effect, although more trials are needed before this can be confirmed. A Phase II trial has been initiated. Overall, MDA has contributed almost $2.5M to this type of approach.
Gene therapy, in which a replacement copy of the SMN1 gene is inserted into cells, offers a possible route for therapy. Recent studies in academic laboratories and at Genzyme have offered promising results that demonstrate proof-of-principle for gene therapies for SMA in mouse models of the disease. Oxford Biomedica is also pursuing the possibility of providing neuroprotective factors such as vascular endothelial growth factor (VEGF) through gene therapy to preserve existing neurons. These programs are still in the preclinical stage. MDA has invested $1.6 million toward the development of gene therapies for SMA.
Several biotechnology companies are pursuing stem cell therapies for SMA. California Stem Cells, previously supported by MDA for research on ALS, has the most advanced program. An Investigational New Drug filing has been placed on hold by the Food and Drug Administration, but the company is keeping the program active. Stem cells might be expected to offer existing neurons protection from degeneration. A major challenge facing stem cell approaches is sufficient delivery of the cells to the parts of the body where they are needed. MDA has invested $700,000 on stem cell therapies specific for SMA, and has provided further support on stem cell approaches for ALS, which may also be applicable to SMA.