|Phase 1||Phase 2||Phase 3|
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 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 1 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.
One genetic form of ALS is caused by mutations in a gene called “SOD1” (superoxide dismutase). If the toxic (mutated) SOD1 could be removed or neutralized, scientists predict that the disease could be slowed or halted. Such therapy would probably only be effective for the genetic forms of ALS caused by SOD1 mutations. Several strategies for reducing the levels of toxic SOD1 have been proposed and have undergone preclinical testing. MDA has invested more than $3.5 million on such approaches.
Importantly, MDA funded Timothy Miller at Washington University in St. Louis, Mo., who is collaborating with Isis Pharmaceuticals to develop compounds that would remove the toxic SOD1. These compounds, called “antisense oligonucleotides” (ASOs), bind to the messenger RNA made from the mutant gene, signaling it for destruction, thus preventing protein from being made. A phase 1 safety trial indicated that administering the SOD1 ASO to ALS patients is safe. As of August 2013, work is underway to improve the efficiency of the ASO, before proceeding to a trial testing whether the treatment can reduce SOD1 levels in the central nervous system. MDA is supporting a natural history study of SOD1 ALS to support further trials.
The ASO approach is also being contemplated for patients with ALS due to C9ORF72. That approach is currently in the preclinical phase but is likely to advance quickly if the SOD1 trial is successful.
An alternative MDA-sponsored strategy for lowering SOD1 protein is with the antimalarial drug, pyrimethamine. This drug is being tested in a phase 1/2 study that is recruiting SOD1 ALS patients as of August 2013.
Excitotoxicity is a process by which nerve cells are damaged by an excess of chemical nerve signals called neurotransmitters, such as glutamate and related compounds. People with ALS have excessive levels of glutamate in their blood and spinal fluid. Thus, compounds that reduce excitotoxicity are an attractive therapeutic strategy. Indeed, the only drug currently approved for ALS is riluzole (Rilutek), which, among other actions, decreases the release of glutamate. Riluzole only prolongs survival by an average of three months. However, a number of researchers are working to develop new anti-excitotoxic compounds that may have a greater effect. Some of these directly reduce glutamate levels, while others reduce excitotoxicity indirectly (e.g., by inhibiting enzymes involved in processing neurotransmitters). MDA has devoted almost $3 million toward strategies to reduce glutamate, or otherwise reduce excitotoxicity. A recent trial of ceftriaxone, a drug that reduces glutamate in animal models, was unsuccessful in ALS patients, but it was unclear whether the drug was able to reach the spinal cord in sufficient concentration to exert its effect.
Inflammation is a short-term protective response mounted by the immune system. Over longer periods, however, it can become damaging. Individuals with ALS have high levels of neuroinflammation, that is, inflammation of the spinal cord. Scientists have not settled on whether this inflammation protects neurons, harms them or does both at different times. One anti-inflammatory compound that has been tested in ALS clinical trials, minocycline, did not prove to be effective in slowing the disease, but other compounds are under investigation. MDA has funded over $3.6 million investigating compounds that might affect the neuroinflammation process. Multiple agents are being tested, including Gilenya (currently approved for multiple sclerosis and being tested by MDA-funded ALS TDI), tamoxifen (approved for breast cancer), and several experimental drugs. Acthar, a form of adrenocorticotropic hormone, is being developed by Questcor Pharmaceuticals and has entered phase 2 testing. NP001, from Neuraltus, targets immune system cells called macrophages in the blood and microglia in the central nervous system, causing them to switch from an active "attack" mode to a "protective" mode. This drug was not effective overall in a phase 2 trial, but patients on the higher dose appeared to show enough benefit to justify a larger trial, which is in the planning stages as of August 2013.
One hypothesis as to why cells die in ALS patients is due to a buildup of molecules called free radicals. Left unchecked, free radicals cause damage to a wide variety of other molecules in the cell, in a process called oxidation. Several pharmaceutical companies are investigating antioxidant molecules such as coenzyme Q10, edaverone and creatine as possible protectants against ALS-caused cell damage. Other companies are testing their own proprietary antioxidants for efficacy in ALS. MDA has funded almost $900,000 on projects pursuing this strategy. The most advanced trials of such compounds were phase 2 trials and showed limited effectiveness in isolation, but these compounds are often tested in combination with other drugs.
Histone deacetylase inhibitors (HDAC inhibitors) are compounds that inhibit a type of enzyme that turns off certain genes, thus keeping them available for protein synthesis. When those proteins are important for motor neuron health, inhibiting HDAC can be therapeutic. Some results in animal models suggest HDAC inhibitors may offer some benefit. MDA awarded over $100,000 for a clinical trial to test if an FDA approved HDAC inhibitor is safe in ALS patients, prior to studies to see if it is effective at slowing ALS. The study found that it was safe but was not large enough to determine if it was effective.
In many cases, a compound is discovered that has a beneficial effect on motor neuron survival, either in cell culture or an animal model, without it being clear how the compound exerts its effect. Many such compounds have been tested in clinical trials in the past, and have shown limited effect on the progression of the disease, but there is always hope in new compounds. Recently, dexpramipexole, from Biogen Idec, failed to show any benefit in a phase 3 trial, despite some hints of efficacy in a smaller phase 2 trial. Rasagiline, from Teva Pharmaceuticals, is currently in phase 2 testing. MDA has funded over $2 million in support of neuroprotective compounds.
Apoptosis is a biochemical program within a cell that causes it to self-destruct after it has received specific signals that target it for destruction. There is some evidence that this program may be affected in ALS, such that motor neurons start this cell death program. Several researchers have investigated compounds thought to prevent cell death, which would be expected to promote survival of neurons. MDA has funded more than $1 million on studies of such compounds. One agent, called tauroursodeoxycholic acid (TUDCA), is being tested in a small trial.
A relatively recent observation in ALS is that protein aggregates, or clumps, form in the cells of people with ALS, and these aggregates contain a protein called TDP43. Some genetic forms of ALS are caused by mutant forms of TDP43. Therefore, a new therapeutic focus is on breaking up these protein aggregates, usually using “chaperone” molecules. These may be artificial chaperones such as arimoclomol, or may work by increasing naturally occurring chaperones such as “heat shock proteins.” A company called Nexgenix is pursuing a potential therapy that appears to upregulate a suite of different heat shock proteins. This strategy is currently in preclinical testing for ALS. Coyote Pharmaceuticals is developing a small-molecule inducer of heat shock proteins for use in ALS. Arimoclomol, from CytRx, is the most advanced drug in this class, and as of August 2013, is enrolling patients for a placebo-controlled phase 2/3 trial. MDA has funded more than $2 million to projects investigating compounds that affect aggregation.
Growth factors such as Neurturin, brain derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF) have been proposed as therapeutics for ALS based on their ability to enhance nerve cell growth and survival. Many of these have shown promise in animal and cell-based models of the disease. Early clinical trials of such therapies showed little effect in patients. However, it is unclear whether this was because the growth factors had no effect, or if they were not getting into the central nervous system, where they needed to be in order to be effective. There is still significant interest in this strategy. Research is aimed at delivery of either the proteins themselves or other compounds that could elevate levels of the patient’s own growth factors. MDA has targeted more than $1.3 million on drugs in this class. The most advanced compounds currently in development involve VEGF, and are in phase 2 trials. The company Sangamo Biosciences is developing SB-509, a zinc finger protein transcriptional activator (ZFP-TF) of the vascular endothelial growth factor (VEGF). They have shown that administration is safe, and they have reported signs of efficacy, although this data has not been peer-reviewed.
An alternative strategy, reducing nerve growth inhibitors, is being tried by GlaxoSmithKline, with a drug called ozanezumab. This monoclonal antibody inactivates one such inhibitor called neurite outgrowth inhibitor A (Nogo-A). The hope is that ozanezumab will block Nogo-A, thereby allowing nerve cells to regrow. As of August 2013, this study was recruiting patients in Europe and Canada, though not in the United States, for a placebo-controlled phase 2 trial.
Growth factors also may be delivered by gene therapy or cell transplantation (see below).
Several different gene therapy strategies have been proposed for ALS. In gene therapy, a new gene is delivered to the body, and then used by the body’s own cells to produce a protein. Gene therapy can be used to replace a defective gene in inherited diseases, but this is generally not helpful in ALS. Even the SOD1 familial form of ALS is caused by toxic form of the protein, not a non-functional form of the protein. Therefore, researchers have looked toward other genes to deliver most often growth factor genes to help protect existing neurons. Gene therapy research is still in its infancy, and the process to develop such therapies is slow. MDA has invested over $2.4 million into such research, and the most advanced therapeutics have shown significant improvements in animal models of the disease.
Stem cell therapies have been portrayed in the popular media as having enormous therapeutic potential. Stem cells may be implanted directly, or may be manipulated in the lab to become various types of cells that may then be implanted to deliver a therapeutic effect. It is unlikely that stem cell therapy will be used to replace motor neurons in the near future, since after implantation, the new neuron would have to grow over very long distances (up to several feet) to reach its target muscle. That type of growth has not yet been seen in any model of any neurologic disease. One promising alternative is to convert stem cells into cells that support neurons, including cells that make and secrete growth factors.
Neuralstem has successfully completed a phase 1 safety trial of neural stem cells implanted into the spinal cord in ALS patients. Results indicated that the implanted cells made contact with the host motor neurons and expressed neurotrophic growth factors. The trial was not designed to test efficacy, but a new trial currently being planned will do so. Israeli company Brainstorm also is planning on initiating safety trials in the U.S. for its stem cell therapy soon. Overall, MDA has invested over $2 million on this approach.
ALS patients lose strength as the disease progresses. Although increasing strength will not necessarily prolong survival, it could improve the quality of life. Therefore, several compounds under development are targeted at increasing muscle strength directly, either by increasing muscle size or by increasing the force that can be generated by muscle. MDA has invested more than $100,000 on this strategy for ALS. In addition, many compounds under development for the muscular dystrophies, if proven effective, also may increase strength in people with ALS. The most advanced strategy of this kind is Cytokinetics’ tirasemtiv, which is progressing to a large phase 2 clinical trial, after successful completion of a smaller trial.