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The Huntington’s Disease Pipeline

Have you ever wondered how new medicines are discovered? The process of going from an important discovery in a science laboratory to a successful drug available to the public is complex, costly, and time-consuming. This process is often referred to as Research and Development, or the R&D pipeline. It has many stages that interact and feedback into one another, takes many years, and costs millions of dollars.

In a way, R&D is like searching for two separate needles in two separate haystacks. The process begins with a thorough search and identification of all the different biological pathways that are involved in the disease process. The goal is to identify one or more pathways that contain possible biological targets for treating the disease. After finding one or more targets, the next step is to find potential drugs that block or change how the target causes or contributes to disease; this can be done by either designing a drug based on knowledge of the target’s molecular structure and function, or by screening large libraries of chemicals and molecular compounds to find one.

A potential drug treatment may emerge from these extensive searches. However, this “candidate” drug is not yet available for treating patients. First, it must journey through more research, tests, and clinical trials before it is finally approved by the Federal government’s Food and Drug Administration (FDA). Only then, many years later (and after spending a lot of money!), might a new medicine be available to help patients with debilitating diseases. For every attempt, the probability of success is less than 1%. But thousands of scientists around the world are working hard to beat those odds every day, discovering new biological pathways to target and new chemicals to try for all sorts of diseases.


Let’s take a closer look at the steps of the R&D pipeline. Below is a brief overview of each stage, and you can read other sections of this article to get a more comprehensive look at that stage of the process and how it applies to HD research.

Basic Research:
Before scientists can even begin to think about finding treatments for a disease, they must have a good understanding of the biology and chemistry involved in the disease’s molecular pathways. Basic research tries to understand how certain biological and chemical imbalances cause disease. Scientists must investigate everything, from the genes and proteins involved, to clinical symptoms and disease progression.

Target Identification and Validation:
While gaining a thorough understanding of a disease through basic research, scientists also attempt to identify biological targets- usually genes or proteins – that trigger or contribute to a disease. A biological target is a good place to start looking for a treatment. There are numerous genes and proteins involved in most diseases- so how can scientists know if they have picked the right one to target? Researchers generally perform experiments on animal models to assess whether the biological target they have identified is crucial to the disease pathway.

Drug Optimization:
The next step is to find one or more drugs that might make a useful treatment. One way to find candidates is to search through, or screen, thousands of chemical compounds to identify potential drugs. Alternatively, if enough is known about the shape and function of the biological target, scientists may be able to design new molecules or drugs that change the way the target behaves in living cells and patients. As opposed to screening, this approach is often called “rational drug design.” A potential drug must interact with the chosen biological target, and modify it in a way that will cure the disease or decrease its effects.

Drug Development/ Pre-Clinical Animal Studies:
When a potential drug is discovered from a screen or rational drug design, it has much promise as a therapeutic drug. However, little is known about the safety and effectiveness of this so-called lead compound in animals or humans. All lead compounds must be thoroughly tested in at least two animal models to determine safe doses, understand side effects, and discover more about long-term toxicity.

Investigational New Drug (IND) Application:
After animal model studies have been completed, pharmaceutical companies must submit an IND application to the Food and Drug Administration (FDA) to continue drug development. If approved, it gives the pharmaceutical company permission to begin clinical trials which involve testing the potential drug in human participants. The IND application must include data from animal studies, information about the drug’s production, and a detailed proposal for human clinical trials. Unless the FDA specifically objects, an IND application is automatically accepted after 30 days and clinical trials can begin.

Clinical Trials: Phase I
Phase I clinical trials are also called “First-In-Man” studies. These studies are mostly concerned with safety, determining the maximum tolerated dose (MTD) of the drug in healthy volunteers that do not have the disease of interest. They also look for how the drug should be delivered (for example, by pill, injection, or IV fluid), how it is absorbed into different organs, how it is excreted from the body, and if it has any side effects. Approximately, 70% of potential drugs make it through this initial stage of testing.

Clinical Trials: Phase II
Once a safe dose of the potential drug has been found in healthy human participants, phase II clinical trials test it in participants with the disease of interest. Like phase I trials, these trials look for evidence of toxicity, and side effects, but they also look for evidence that the drug helps patients with the disease feel better in some way. These trials help to further refine the optimal dosage, in order to maximize beneficial effects and minimize harmful side effects.

Clinical Trials: Phase III
Phase III clinical studies are the most expensive, time consuming, and complex trials to design and run. They use a very large participant group, all of whom have the relevant disease condition. These studies determine if the drug’s benefits outweigh the risks (like side-effects and long term toxicity) in a larger patient group, and also compares the new potential drug with older, more commonly used treatments if any are already on the market.

New Drug Application (NDA):
The FDA must review results at the end of each phase to approve the drug before it can move into the next phase of trials. Once phase I, II, and III trials have all been successfully completed, the pharmaceutical company submits a New Drug Application (NDA) to the FDA. The results of all of the trials are given, as well as the results of animal studies, manufacturing procedures, formulation details, and shelf life. In short, they include everything that would be used to label the drug. If the FDA approves a company’s NDA, they can begin to mass produce and market the drug in the US. Pharmaceutical companies submit similar applications to authorities in Europe, Australia and elsewhere to market successful treatments there.

Clinical Trials: Phase IV:
Phase IV trials are done after a drug has been approved, officially manufactured, and put on the market. They are done to determine the absolute optimal dosages in case it needs to be refined, to look at the very long term safety and efficacy of a drug, and to discover any rare side-effects. Phase IV trials are also used to identify the potential for new indication studies, meaning that the same drug may be able to treat diseases other than the one for which it was initially tested.

Basic Research^

Basic research is concerned with understanding the background biology and chemistry underlying the mechanism of a disease. Scientists identify the genes, proteins, and specific types of cells involved in a disease and investigate how they contribute to the disease state. This type of science research is usually conducted in academic laboratories and research institutes around the world, and is less likely to take place in pharmaceutical companies. It is important to understand that basic science researchers focus their efforts on understanding the pathways and molecules involved in the disease- they don’t concentrate on finding a treatment. This information is then used by scientists in other research fields, such as drug discovery and therapeutics, to aid in the identification of drug targets and possible disease cures.

Usually, a research laboratory will concentrate on a few molecules or proteins in a disease pathway and try to discover as much as they can about those molecules. They may study the molecular structure of the molecule, how it usually functions in normal cells, and figure out what other proteins and genes it is related to or interacts with. Scientists will look at how their molecule (or molecules) of choice changes in diseased cells – if it works too much, stops working, or starts interacting with parts of the cell in a way that causes damage. All of this basic research helps to determine whether this molecule should be investigated as a biological target- the next step in the R&D pipeline. Although not all basic research directly contributes to a drug treatment, it all has the potential to, and so it is important to continue to strongly support basic science research programs to provide a solid foundation for drug development research.

Scientists often use model systems to study the genes and proteins involved in a disease. These can be in vitro, which is a useful way to isolate specific molecules and determine if they interact with one another in any way. Model systems can also be in vivo, which are more useful for studying specific molecules in the context of a disease, to see how they change a cell. In vivo model systems are also used to study the progression and development of a disease throughout an animal’s lifetime. The most common kinds of models include mice, yeast cells, worms, flies, rats, and human tissue culture.

HD and Basic Research

The HD community is doing a lot of basic research. We have much of this information located elsewhere on the HOPES site.

  • For more information on the kinds of institutions and programs that do HD research, click here.
  • For information on HD research going on here at Stanford University, click here.
  • To find out about the techniques that scientists use in basic HD research, click here.
  • To get an in-depth look at the day-to-day workings of a few research laboratories that conduct basic HD research click here.

Target Identification and Validation^

Basic research on the genes, proteins, and molecular pathways involved in a disease, may assist in the discovery of a biological target. Since there are many genes and proteins involved in most disease pathways, there needs to be a way to identify which ones would be worth targeting for creating a drug therapy. A biological target is a molecule that may hold the key to a disease- it may greatly contribute to, or possibly be the direct cause of a disease.

Validation of the molecule as a biological target usually requires answering two questions. The first asks if the target is relevant to the disease, by examining if a change in the biological target results in a change in the disease. If a certain molecule is produced in a mutated form, in abnormally high quantities, or abnormally low quantities in a disease, it is usually a good biological target. Secondly, if a biological target is proven relevant to a disease, it is then important to determine whether it is drugable – that is, can it be targeted or changed by treatment with a drug.

It is important to remember that validation occurs throughout many stages of the R&D pipeline, including the basic science research, the drug discovery, and the development processes. What may appear effective in a tissue culture model may not work in a mouse model. In each stage of testing or clinical trials, if evidence indicates that a biological target is either not relevant or not drugable, then development of the treatment will stop. The scientists and pharmaceutical companies must then go back to the drawing board. This occurs fairly often, making drug discovery and development a difficult, costly, and time-consuming process. It does not mean that scientists made a mistake earlier on in the process, simply that a different experiment revealed that the target would not be suitable for drug development after all.

HD and Target Identification^

A number of biological targets have been identified in the HD research field. First, there is the possibility that the altered HD protein itself may be a good target. It has been well-established as crucial to the disease, but it remains to be seen if it is drugable. Many animal models have shown that once neurodegeneration has begun, elimination of the altered HD protein halts the course of the disease (see Yamamoto 2000 in Cell, or click here for more information). At the same time, little is known about the normal function of the HD protein. We do know that huntingtin is critical for the creation and development of nerve cells, and that mice without the HD gene do not survive to birth (see Reiner 2003 in Molecular Neurobiology, or click here for the abstract.

In addition to the altered HD gene, many other genes, proteins, and molecular pathways have been identified as being involved in the HD disease pathway and its clinical symptoms. We know that molecules involved in energy production, apoptosis, and free radical damage (among others) contribute to HD. It is entirely possible that one of these pathways may have a good biological target that is drugable. For more information about many of the pathways and biological targets being currently examined and developed, click here.

Identifying and validating biological targets is a huge priority in the HD research community. Many basic research labs at universities and private institutions are devoted to this undertaking. The High Q foundation is a non-profit organization that works to bring together academia, industry, governmental agencies, and other funding organizations to identify and validate new therapeutic targets for HD. Recently, proteins like caspase-6 and Poly(ADP-ribose) polymerase (PARP1), have been identified as promising therapeutic targets.

Drug Optimization^

Once a biological target has been identified and has passed preliminary validation, the next step is to identify candidate drugs that can modify the target’s actions in living tissues and cells. One way of finding potential drugs is to screen through the thousands of available drugs and compounds to see if any interact with the target in the desired manner. When screening, it is important to consider if the desired effect of the drug is to inhibit or enhance the normal activity of a biological target. A thorough understanding of the target’s biochemistry can sometimes enable scientists to guess what kinds of drugs and chemical compounds will interact with it. This can lead to a narrowed, more efficient screen.

In a full-scale screen, there may be more than 10,000 different molecules to look through. Pharmaceutical companies use combinatorial chemistry and high throughput machines to screen chemical compound libraries, looking for interactions between a potential drug and the biological target. They continuously narrow down the drug candidates, refining the search and the criteria they are using until a likely group of compounds is identified. Scientists also have to verify that any candidate drugs are very specific to the biological target- meaning that they interact with only the target, and not any other important molecules in a cell. If a compound interacts with too many molecules in addition to the specific target, it will often cause problems independently of its work in curing the disease. In this case, the side effects it causes would not make it a suitable drug treatment.

After a high throughput screen, a group of chemical compounds may be identified as potential drugs. These compounds will then undergo further testing; scientists will often use biochemistry to modify one of the compounds- this process is called optimization. These modifications can increase the drug’s effectiveness and make sure it doesn’t target other proteins. After this process, one or two molecules will be put forth for drug development. The most promising one is called the “lead compound”, and another is designated as a “backup”.

In the past many drugs were discovered by trial and error, or by chance through a screen. More and more often now, scientists are using a process called “rational drug design” to design and create a lead compound, instead of finding one in a screen. In rational drug design, scientists use knowledge about the three dimensional structure of the chosen biological target’s active site to design a drug to specifically interact with it. This requires a good knowledge of chemical biology to synthesize molecules and modify their shape so that they may serve as a drug. While many techniques for rational drug design are still being developed, it seems like it will be a good way for scientists to produce targeted and effective drugs with few unwanted interactions or side effects.

HD and Drug Optimization^

The HD research community is helping to pioneer a new approach to drug development, using biotechnology in combination with traditional pharmaceutical approaches. In HD, every case has the same cause (the mutation in the HD gene), unlike diseases like Alzheimer’s disease, cancer, heart disease, and diabetes, which can be caused by a variety of different factors in individual patients. This allows HD researchers to use biotechnology to develop new treatments to target early disease time points, before the onset of symptoms, as well as treatments for particular symptoms. To learn more about the progression of HD and the onset of symptoms, click here Traditional pharmaceutical companies often develop treatments by modifying a relatively small number of existing drugs to target symptoms that are common in a number of different diseases. But the advent of new biotechnology approaches like those used by many HD researchers have recently started to force the pharmaceutical industry to look into finding other types of rational biological targets. Currently, pharmaceutical companies and biotechnology companies are forming partnerships to do just that.

There are many institutions and pharmaceutical companies devoted to HD drug discovery research. At Harvard Medical School, the Laboratory for Drug Discovery in Neurodegeneration (LDDN) is set up like a small biotechnology company. They have high-throughput screening robotics, a chemical compound library with nearly 100,000 different drugs, and staff and collaborators from all over Harvard University. Their goal is to find lead compounds and then hand them over to larger pharmaceutical companies for further testing and development. Since it doesn’t have investors to pay back like pharmaceutical companies often do, researchers have more freedom to pursue high-risk but high-payoff biological targets. Their projects focusing on HD involve screening their compound library for molecules that interact with and/or affect polyglutamine repeats polymerization, and kinases.

CHDI, Inc is a non-profit drug discovery and research organization based in Los Angeles, California. They are sponsored by the High Q Foundation a private philanthropic foundation that was established to bring together academia, industry, governmental agencies, and other funding organizations in the search for HD treatments. CHDI, Inc is a “dry” lab, meaning that rather than conduct experiments at their own facilities, they contract out projects to established laboratories that have the most relevant equipment, supplies, and scientists for the specific experiments. They collaborate with private and academic labs to do research on all aspects of drug discovery and development, from high throughput screening to preclinical development. One of their most recent projects is to partner with Amphora Discovery, a drug discovery and development company that has developed their own high throughput screening process, to find compounds that inhibit caspase-6 activity. For more on caspase-6, click here.

Medivation is a company dedicated to research and drug development in HD, Alzheimer’s disease and Prostate Cancer. They work with drugs from the pre-clinical stage through Phase II trials. One of their newest products is a drug called Dimebon, which is an antihistamine that is thought to alleviate symptoms and prevent progression of neurodegenerative diseases like Alzheimer’s and now is being tested for its effects in HD. For more information on Dimebon, please click here).

Drug Development/ Pre-Clinical Animal Studies^

Once a lead compound is identified, it must be tested for toxicity in animals. Scientists are usually required to test the lead compound in two types of animals, typically a rodent and a larger animal. It is important to note animal models are not used in these tests for toxicity, meaning that they do not have the relevant disease condition. While animal models are often used in basic research and in target identification, healthy animals are used in these studies so scientists can determine the baseline levels of toxicity. Researchers test many dosage variables of the compound by administering various concentrations to the animals, changing how often the drug is given (frequency), and how long the drug is administered for. The drug can be administered in a chronic regimen, meaning it is administered frequently to keep the concentration at a constant rate. Alternatively, it can be administered in an acute regimen, meaning that it is given in an initial high dose and then is eliminated from the body.

Essentially, these studies are looking for the best treatment regimen with the least amount of toxic side effects. This is the therapeutic window, the dosage range in which the benefit of the drug outweighs its toxic effect. Throughout drug development and animal testing, researchers are also investigating the pharmacokinetics and pharmacodynamics of the lead compound.

Pharmacokinetics essentially looks at what the body does to the drug, and usually is characterized by the ADME, or absorption, distribution, metabolism, and excretion of the compound. Pharmacodynamics looks at what the drug does to the body. This looks at the dose-response relationship, and what effect the drug has on each of the major organs within the animal. It looks for any evidence that the drug is mutagenic (causes DNA mutations), carcinogenic (causes cancer), or teratogenic (causes problems with fetal development). Researchers also look for any long term or delayed effects in the animals.

HD and Pre-Clinical Development^

There is a good deal of research in the HD community devoted to drug development, although more biological targets are needed for the field to grow much more. Among its many activities in drug discovery and development, CHDI, Inc has recently contracted with Edison Pharmaceuticals, Inc to develop new formulations of Coenzyme-Q10 that will act as more targeted forms. For more information on Coenzyme-Q10, click here.

VistaGen Therapeutics, Inc., a pharmaceutical company devoted to the discovery and development of small molecule therapies using stem cell technology has recently been awarded a grant from the NIH to do pre-clinical development of AV-101. This is a drug candidate with the potential to reduce the production of quinolinic acid, a neurotoxin produced in the brain that is believed to be involved in HD.

Clinical Trials: Phase I^

A clinical trial is an important experimental technique for assessing the safety and effectiveness of a treatment. The most important purpose of a phase I clinical trial is to investigate the safety of a potential drug in humans, but it is also used to examine the pharmacokinetics and find the maximally tolerated dose.

For almost all phase I clinical studies, the participants should be healthy males and females from ages 18-40 who are not taking any additional medication. Usually, 20-100 participants are used in these studies. These trials are uncontrolled, meaning that all participants are given the drug. Each participant serves as their own control, because their health before and after the drug treatment is assessed and compared.

When beginning a phase I trial, researchers have to start with a certain dosage, look at its effects, and then slowly scale it up until they reach what they feel is the dose-limiting toxicity. This is the dosage at which side-effects are severe enough to prevent the participants from benefiting from the treatment. The dose previous to this one is considered the maximally tolerated dose, and is used in phase II clinical trials.

Furthermore, the toxicity of the drug and its effects on each of the major organs is carefully studied at each dose level. The pharmacokinetics of the drug- how much a change in dose affects the distribution, absorption, and elimination of the drug from the body- is examined as well. Participants are usually observed until several half-lives of the drug have passed. Essentially, by the end of a phase I clinical trial, researchers should have a recommended dose to use in phase II trials, a good idea of the pharmacokinetics of the drug, and notes as to any benefits they may have seen in the participants. Approximately 70% of drugs tested in phase I trials make it to phase II. Potential drugs that fail in phase 1 trials, usually do so because too many harmful side effects are produced that outweigh the benefits to justify using it as a kind of treatment.

HD and Phase I Clinical Trials^

There are currently many clinical trials being conducted to study potential treatments for HD. Because the HD community is relatively small, it is possible to have good communication and coordination between researchers all over the world. The Huntington Study Group has been organizing and conducting clinical trials for HD since 1993. The HSG is a non-profit organization that is composed of physicians and health-care providers from around the world. They support open communication across the scientific community and full disclosure of all clinical trial results to the public.

Encouragingly, many clinical trials for potential HD therapies in progress at the time of writing have moved from phase I into phase II and III. As of March 2007 the University of Iowa is conducting a Phase I trial on a selective serotonin reuptake inhibitor (SSRI) called citalopram. For more information on this trial, please click here The National Center for Complementary and Alternative Medicine (NCCAM) has completed a phase I trial with an amino acid derivative called creatine for patients with HD. However, because it is thought that creatine will be more effective when used in combination with other drugs, additional research will first determine what other drugs it should be paired with before it is tested in phase III trials.

For information about clinical trials in every phase, the NIH runs a database that compiles all known trials in the country. For their list of trials related to HD, click here. Finally, there are ways for HD patients and their families to get involved with clinical trials for potential HD treatments. Huntington’s Disease Drug Works is a program designed to facilitate communication between HD patients and their families, and the scientists and doctors conducting the latest research on Huntington’s disease. Their hope is to speed up research and reduce the time it takes to set up a clinical trial. Through their website, you can find ways to enroll in a trial as a participant, or volunteer to help out those who do participate.

Clinical Trials: Phase II^

The main purpose of phase II is to gather preliminary evidence as to whether the potential drug helps participants with the relevant disease. Phase II trials are also used to determine the common short-term side effects and risks associated with the drug in patients with the relevant disease. The participants in these studies, anywhere from 100-300 affected individuals, are usually closely monitored. Rare side effects will probably not be seen because the phase II participant population is too small.

Phase II trials are sometimes randomized, which means that half the participants in the study are chosen at random to receive the old or “standard” treatment, and half are chosen to receive the new treatment. Furthermore, these trials are often double-blinded, which means that neither the participants nor the clinical researchers know who has gotten which treatment. This eliminates bias on the part of the researchers, both in terms of deciding who would get the new treatment, and in observing or measuring the results.

A successful phase II trial is necessary to convince the scientists and physicians conducting the clinical trials that it is worthwhile to move into a phase III trial, which is very costly and time-consuming. Scientists must look at various measurable factors (outcomes) to decide whether the phase II trial was successful. If the drug being tested seemed to reduce or improve symptoms, nerve cell loss, tumor size, blood pressure, or any other relevant outcome in comparison with the control group, they will consider proceeding with a phase III trial.

A phase II trial can take up to two years, and even if successful, does not guarantee that a phase III trial will also be successful. It is important to note that only about 30% of all potential drugs make it through phase I and phase II trials. Even if the drug does make it this far, many problems may become evident once it is used in a larger participant population. This uncertainty is simply one of the many risks that all drug developers and clinical researchers take during research and development.

HD and Phase II Clinical Trials^

A few different HD treatments are being studied in phase II trials as of April 2007. The Huntington’s Study Group is sponsoring a trial to look at the long-term safety and efficacy of minocycline in reducing symptoms for patients with HD. This phase II study is being conducted at multiple centers across the US, and is enrolling about 100 participants. For more information on this study, please click here.

Another phase II trial is being conducted at the University of Iowa to examine the effects of atomoxetine on daily activities such as attention and focus, thinking ability and muscle movements in subjects with early HD. This treatment is mostly aimed at relieving the cognitive symptoms of HD, and the drug has been successful in treating similar symptoms in patients with ADHD. The trial is currently recruiting participants; for more information, please click here.

It is important to remember that only a small percentage of all clinical trials are successful. In 2001, a phase II trial was conducted to test the effectiveness of the drug amantadine for the treatment of chorea associated with HD. Amantadine blocks the action of glutamate, which is thought to be implicated in HD toxicity. For more information on the role of glutamate in HD, please click here. The drug has had some success in relieving symptoms in patients with Parkinson’s disease. However, the phase II clinical trial indicated that, in fact, amantadine had little effect on Huntington’s chorea, and so it was not continued into a phase III trial. For more information on this trial, click here.

Clinical Trials: Phase III^

Phase III trials serve as the definitive experiment to determine if a potential drug is effective and should be available for routine use in patients. If there is no treatment available for the disease in question, a phase III trials tests the effectiveness of a new drug against a placebo or no treatment. When there are established treatments, the point of a phase III trial is not to test the effectiveness of a potential treatment, but to test if it is more effective than the established treatment. This is always done by comparing two treatments- usually, the new treatment with a standard one. Sometimes trials use the same type of drug for both categories, but compare a new dosage regiment with an old one. Like phase II trials, all participants have the relevant disease. Phase III trials typically enroll large participant groups, anywhere from 1000-7000 people. It is important to have a large group so that researchers can identify any benefits or side-effects, no matter how small they are. Like phase II trial, phase III trials are randomized.

Designing and conducting a phase III clinical trial is very difficult. It is very time-consuming and costly, and it must be done carefully to ensure valid results. Data analysis is very complex, especially when researchers are not simply looking for changes and effects that are very concrete and easily measurable, like the number of people who survived. Researchers often look for changes that can be measured on a scale, like the improvement of symptoms. These can be difficult to judge and compare between patients being treated with the potential new drug and those patients treated with an existing drug. However they are important to analyze and understand so that the benefits of the new potential treatment can be determined. It is also important that researchers recognize any significant differences in response between genders or ethnic groups.

HD and Phase III Clinical Trials^

As of April 2007, several phase III clinical trials are in progress, testing new treatments for HD. Enrollment was completed in August 2006 for a trial sponsored by the Huntington Study Group testing the effects of ethyl-eicosapentaenoate (ethyl-EPA) on HD chorea. Ethyl-EPA is thought to keep nerve cells healthy, inhibit apoptosis, and reduce free radical damage. The trial itself is underway, and is composed of at least two 6-month phases, and is slated for completion in September 2007. For more information on this study, please click here

A phase III trial has just finished recruiting participants for a three year study on the long term effects of the drug riluzole. Riluzole has been used to slow the progress of amyotrophic lateral sclerosis, a related neurodegenerative disorder. This study is sponsored by Sanofi-Aventis, and is testing whether riluzole has long term effects on HD chorea and on total functional capacity (TFC) of affected patients. For more information on riluzole, click hereand for more information on this clinical trial, please click here

Prestwick Pharmaceuticals has recently completed a phase III trial using tetrabenazine to treat HD chorea. Tetrabenazine is thought to reduce the amount of dopamine in nerve cells, and this may reduce the severity of chorea. Tetrabenazine is also used to treat chorea in other neurodegenerative disorders. Initial results have shown that it is better than a placebo. Prestwick filed an application with the FDA to market tetrabenezine, and in April 2006 received a letter from the FDA stipulating the conditions which they must meet to make it an available treatment. The FDA also designated tetrabenazine a fast track product because there are no other drugs available in the U.S. to treat chorea. However, Prestwick’s formulation is already marketed in at least 8 countries outside of the US, including Canada.

Clinical Trials: Phase IV^

Phase IV trials are conducted once a new drug has been approved for marketing and is available for prescription by doctors. Occasionally, government authorities (usually the FDA) may require a pharmaceutical company to do a phase IV study, while sometimes these studies are voluntarily conducted. A company might want to know more about the side effects and safety of the drug, or how the drug works in the long term. They also look at how the drug impacts the average participant’s quality of life. Many phase IV trials are also used to determine the cost-effectiveness of the treatment, and compare it to any alternatives available.

Many drugs have very rare side effects that only appear in 1 of every 10,000 participants, or less frequently. Because phase III clinical trials have only a few thousand subjects and only last for a couple of years, these side effects may not show up in the earlier trials. Phase IV trials are particularly useful in helping to discover and monitor these rare side effects. They are also used to look at the effects of the drug in specific sub-categories of the participant population, such as children and the elderly. If many unexpected and severe side effects are detected in the phase IV trials, the drug can be withdrawn or restricted, despite its earlier approval from the FDA.

Additionally, phase IV trials might discover that the drug can be used to treat conditions other than the ones it was originally intended for. If the drug seems promising as a new treatment for a different condition, a pharmaceutical company can take the drug back to phase III clinical trials (called a new indication study) to get approval for multiple uses.

For Further Reading^

-J. Seidenfeld, 5/19/07