For more in-depth information regarding the drugs in development for ALS, please visit the ALS Drug Development Database.
|Phase 1||Phase 2||Phase 3|
* MDA Contibution
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.
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).
An observation in ALS is that protein aggregates, or clumps, form in the cells of people with ALS, and these aggregates contain a protein called TDP-43. Some genetic forms of ALS are caused by mutant forms of TDP-43. 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.” Arimoclomol, from CytRx, is the most advanced drug in this class, and is being tested in a placebo-controlled phase 2-3 trial.
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. 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 2 trial where neural stem cells were safely implanted into the spinal cord in ALS patients at increasing doses. The trial was not designed to test efficacy, but a new trial currently being planned will do so. Israeli company Brainstorm is also currently conducting a Phase 2 trial in the U.S. for its stem cell therapy called NurOwn. In addition to BrainStorm Cell Therapeutics and Neuralstem, another biotechnology company called Q Therapeutics announced that they have received approval by the FDA to test their unique stem cells in ALS patients. These stem cells, called glial-restricted progenitor cells, have shown promise in slowing the disease progression in rodent models of ALS.
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 (inflammation of the brain and 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. Multiple agents are being tested, including Gilenya (currently approved for multiple sclerosis and being tested by ALS TDI), NP001, and Ibudilast. 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.
ALS patients lose strength as the disease progresses. Although increasing strength targets the muscle instead of the nerves, it could improve the quality of life for ALS patients. 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. 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 has completed a Phase 2 clinical trial with plans to start a Phase 3 trial soon.
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 antioxidants such as creatine and tamoxifen as possible protectants against ALS-caused cell damage. Other companies are testing their own proprietary antioxidants for efficacy in ALS. The most advanced trials of such compounds were phase 2 trials showing potential benefits when these compounds were tested in combination.
ALS often results in breathing difficulties. Diaphragm pacing tests whether electrical stimulation of the diaphragm (the main breathing muscle in the chest) is of benefit to people with ALS. It is unknown whether treatment of breathing muscle weakness with electrical stimulation of the diaphragm muscle could slow the progression of the disease. An ongoing phase 2 clinical trial is testing to determine whether diaphragm pacing can improve breathing function or prolong life span in people with ALS.
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. Drugs are in development to target anti-apoptotic pathways within the neuron. A drug called rasagiline, which is thought to be neuroprotective and anti-apoptotic, is currently being tested in a Phase 2 clinical trial in ALS patients.
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; however, some recent studies indicate SOD1 may also be involved in other forms of ALS. Several strategies for reducing the levels of toxic SOD1 have been proposed and have undergone preclinical testing.
Importantly, Isis Pharmaceuticals is developing 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. Work is underway to improve the efficiency of the ASO, before proceeding to a trial to test whether the treatment can slow ALS disease progression. MDA is supporting a natural history study of SOD1 ALS to support further trials.
The ASO approach is also being contemplated for patients with C9ORF72-related ALS. 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 currently being tested in a phase 1-2 study.
Recent studies have indicated that ALS patient neurons are “hyperexcitable” meaning that they can fire too easily. This over-activity of neurons has been observed in ALS patients as well as in neurons created from the stem cells of ALS patients. In studies focusing on patient-derived neurons from stem cells, researchers found that a drug called retigabine (or ezogabine) was able to help calm the excitable neurons in a dish. Retigabine is already approved for the treatment of epilepsy and is marketed by GlaxoSmithKline (GSK). A phase 2 trial will begin soon to test whether retigabine can stop the hyperexcitability of neurons in ALS patients.
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 a toxic form of the protein, not a non-functional form of the protein. Therefore, researchers have looked toward other genes to deliver. Some of the genes being considered are growth factor genes which may help protect existing neurons. Although some growth factors have failed in clinical trials, the advantage to using gene therapy is that the growth factor would be continually produced at the site where it’s needed. Additionally, researchers have tried other genes including those that were shown to suppress SOD1 and lead to increased life span in the SOD1 rodent model of ALS. Gene therapy strategies for ALS caused by TDP-43 or FUS are also being explored. These include the delivery of genes involved in RNA surveillance, since this mechanism may be involved in these forms of ALS.
In 2011, researchers identified the most common genetic cause of ALS known to date in a gene called C9ORF72. Two independent studies found that abnormalities called “expansions” — comprised of extra DNA — can exist in this gene, when flawed. These C9ORF72 DNA expansions are now known to be the most common inherited cause of familial ALS and are also found in some sporadic ALS patients. Since the identification of the C9ORF72 DNA expansions, scientists have been working diligently to come up with therapies to help patients with this form of ALS. One approach in development involves antisense oligonucleotides, which are small pieces of DNA that can bind to and block the C9ORF72 expansion. In patient cells containing the C9ORF72 expansion, antisense oligonucleotides were able to ameliorate several pathological features of toxicity. Another approach is the development of small molecules which can bind and inhibit the C9ORF72 DNA expansion, a method which has also shown promise in studies using patient cells.
Although motor neurons are the cell type that dies in ALS, researchers have shown that other non-nerve cell types in the brain and spinal cord are also involved in the disease process. One of these cell types — the oligodendrocyte — helps insulate and support motor neurons. Recent studies have shown that oligodendrocytes may also become dysfunctional and die during the course of ALS, which could contribute to motor neuron death. Therefore, scientists are working on developing different methods to help stop or slow this oligodendrocyte loss with the hope that motor neurons will be saved as well. ALS-TDI is in the preclinical stages of testing a drug that may improve an insulating material on these cells called myelin. Additionally, researchers have found that a specific protein in oligodendrocytes called MCT1 is decreased in ALS patients. This protein is important for shuttling supportive nutrients between motor neurons and oligodendrocytes. Drugs are currently in development to try to increase MCT1 which would hopefully allow more nutrients to get to motor neurons from oligodendrocytes.
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