|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.
One strategy in development for SMA is using antisense oligonucleotides to cause more full-length SMN production from the SMN2 gene. The SMN2 gene is similar in structure to the SMN1 gene. However, most of the protein made from the SMN2 gene is short and not functional. Antisense oligonucleotides can alter how SMN2 RNA is put together to increase the amount of full-length, functional SMN that is produced. In 2010, MDA-supported scientists announced that mice with an SMA-like condition showed a "robust and long-lasting increase" in full-length SMN protein in their spinal cords and in the motor neurons themselves after experimental antisense treatment. Based off of laboratory research findings, ISIS Pharmaceuticals is developing an antisense oligonucleotide therapy called ISIS-SMNRx, which is currently in clinical trials. The antisense oligonucleotide has been administered in several trials to SMA patients including those with types 1, 2 and 3 SMA. Thus far, ISIS-SMNRx appears to be safe and well-tolerated and has shown encouraging results in some SMA patients in phase 2 trials. ISIS Pharmaceuticals is currently testing this drug in phase 3 clinical trials.
Motor neurons are the nerve cell type that degenerates in SMA, leading to muscle weakness and paralysis. While some research is focused on strategies to increase SMN levels to help motor neurons, other scientists are focusing on broad neuroprotection. This research aims to prevent motor neurons from becoming dysfunctional and dying rather than altering the genetics of the SMN genes. Neuroprotective strategies could likely be used in combination with other drugs that address the underlying genetic problem in SMA.
In 2007, the French company Trophos identified a novel compound called olesoxime (TRO19622), which was able to protect motor neurons from death in a dish. Since then, olesoxime has been tested in SMA patients in clinical trials with encouraging results. A phase 2 trial conducted on types 2 and 3 SMA patients in Europe showed that olesoxime preserved motor function and seemed safe and well-tolerated. Trophos, which was acquired by Roche in 2015, has planned to file a New Drug Application (NDA) with the FDA in the US in order to move olesoxime forward.
Several research strategies involve manipulating the genetic instructions provided by the SMN2 gene so that more full-length SMN protein can be made. The SMN2 gene is similar in structure to the SMN1 gene. However, most of the protein made from the SMN2 gene is short and not functional. This research approach uses small molecule drugs that target the SMN2 gene to change how the SMN2 RNA is put together, with the goal of increasing full-length, functional SMN or increasing the overall level of SMN through other means.
Groups of pharmaceutical companies are testing different drugs that act through this approach in SMA patients. Novartis is beginning a phase 2 trial in type 1 SMA patients to test their drug called LM107. Additionally, Roche together with PTC Therapeutics, initiated a phase 2 clinical trial to test their drug, RG800, in SMA patients. With MDA support, a company called Repligen has developed an experimental compound called RG3039 (also called quinazoline), which is designed to interfere with an enzyme and thereby increase production of full-length SMN protein from the SMN2 gene. This drug is currently being tested in a phase 1 clinical trial in healthy volunteers.
Other companies developing drugs to increase the production of full-length SMN currently are in the preclinical development stage. Paratek Pharmaceuticals is working on a small molecule compound, similar to an antibiotic called tetracycline, which can increase SMN levels. Additionally, the California Institute for Biomedical Research (CALIBR) is in the process of optimizing drugs that upregulate SMN levels through a different mechanism than RNA splicing.
One research strategy to treat chromosome 5-related SMA types 1 through 4 is based on transferring SMN1 genes into the body to raise the level of full-length SMN protein. In a 2010 U.S. experiment, very young mice with an SMA-like disease received intravenous injections of genes containing instructions for the SMN protein, packaged inside modified type 9 adeno-associated viruses (AAV9 vehicles). The AAV9 vehicle reached its target — motor neurons in the spinal cord — and increased levels of SMN protein were subsequently found in the animals' brains, spinal cords and muscles. The mice showed dramatic improvement of motor function and brain-to-muscle signaling, and a significant increase in survival. This same gene delivery method later was successfully used in a monkey, although the monkey didn't have an SMA-like disease. A similar method was used in a pig model of SMA as well, providing promising results.
The biotechnology company AveXis is developing this gene therapy approach for use in SMA patients. A phase 1 clinical trial testing whether intravenous delivery of AAV9-SMN could help type 1 SMA patients is ongoing.
Motor neurons are a specialized type of nerve cell that dies in SMA patients. These motor neurons are the wires that connect the brain and spinal cord to the muscles, and their death leads to muscle weakness and paralysis in SMA. One approach researchers are pursuing for SMA focuses on protecting muscles from paralysis and increasing the strength of muscles. Although this approach does not fix the underlying genetic problem in SMA, drugs that enhance muscle function could likely be used in combination with other therapies which act on the SMN genes.
Cytokinetics is developing drugs that increase the ability of the muscle to contract. These drugs have shown early promise in patients with a similar motor neuron disease called ALS. Together with Astellas, Cytokinetics is developing a similar drug called CK-2127107 for SMA. This drug has been tested in a phase 1 clinical trial in healthy volunteers, where it proved to be safe and able to increase muscle force. Cytokinetics is planning to test CK-2127107 in a phase 2 clinical trial in SMA patients.
The human genome is largely made up of sections of DNA that do not directly translate into proteins. Long non-coding RNAs (lncRNAs) are a recently identified type of RNA that are not translated into protein but can have significant impacts on gene regulation. These lncRNAs can specifically inhibit the expression of a gene, and SMN-associated lncRNAs have recently been identified. Researchers are currently testing whether antisense oligonucleotides can be designed to specifically block lncRNA from regulating SMN expression. The lncRNA in this sense serves as the “brake” for SMN gene expression, and the antisense oligonucleotide would act to relieve this “brake,” with the goal to increase SMN levels.
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