HD research news - medical research into treatment & prevention

Bringing a drug to market in Huntington's disease

January 2005

Now is an extremely exciting time in the Huntington's research world - new discoveries are made on a weekly basis from all corners of the world, each one providing a better understanding of HD and bringing us a bit closer to a treatment that will have an impact on Huntington's disease. Nowhere is this excitement more visible than in the area of clinical research.

We continually hear about prospective compounds that may be used eventually for the treatment of HD. It's extremely encouraging for those in the Huntington's community.

But what exactly is involved in clinical research? How long after a drug is identified as a potential therapeutic compound can we actually expect an announcement that a treatment has been developed? Dr. Lynn Raymond, a neurologist at the University of British Columbia, is frequently asked this question by her patients who participate in an HD clinic. Here's the information she provides on bringing a drug to market in Huntington disease:

There are basically six steps involved in the clinical trial process:

Step 1 - Preclinical: Data is used to identify candidate drugs or nutritional supplements for testing in humans. This data is collected from in vitro research (neurons from the animal brain grown in culture dishes or test tube experiments); and through testing in animal models, like mice and fruit flies.

Step 2 - Moving to clinical trials: Based on the results of experiments, in step 1, we generate a consensus among the research community (basic scientists and clinical researchers) as to which drugs are the best candidates to bring forward to human clinical trials. This is the focus of the SET-HD project.

Step 3 - Tolerability test: The first phase is to test the drug in non-HD-affected volunteers to look for side effects. If the drug is already on the market for other purposes, this step can be bypassed.

Step 4 - Short trial in subjects with early HD: This trial usually takes several weeks and involves a small number of participants - usually less than 60 people. The drug is tested against a placebo - a "sugar pill" with no medicinal properties - and the test is both randomized and double-blind. That means that neither the researchers nor the participants know who is taking the actual drug and who is taking the placebo. The main outcome of this step is to measure side effects, including, behavioural and chemical side effects. Change in symptoms over this short period may also be measured.

Step 5 - Medium-length "futility" study in subjects with early HD: This step takes about 18 months, and involves a medium number of subjects (usually about 200). Again, the study involves both the actual drug and a placebo, and is both randomized and double-blind. An outcome measure is the rate of progression, and there are two possibilities for the outcome:

1) The drug has a large effect (either to increase or decrease the rate of progression) and the result is statistically significant - in this case, a decision can he made regarding the drug's usefulness as a therapy in HD; or

2) There is a trend toward change in rate of progression that is not statistically significant because of the small effect of the drug in a relatively low sample size and short trial. Drugs that give the second result may move forward to step 6.

Step 6 - Full-length efficacy trial in subjects with early HD: This trial can take up to 3-5 years. A large number of subjects are involved (at least 500) and again, the study involves both the drug and a placebo, and is randomized and double-blind. The study is designed to detect a statistically significant, relatively small effect of the drug to slow the progression of HD.

There are other key points to understand regarding the search for a treatment for HD:

• The first round of drug testing is always done in symptomatic individuals, because we have no markers yet to follow in asymptomatic, gene-positive individuals to judge the efficacy of a drug. PREDICT-HD is underway to determine markers that will allow drug testing to delay onset of disease in this population.

• Drug testing is in symptomatic individuals in the early stages of HD because in later stages, progression is no longer linear with time.

• Randomized, placebo vs. drug trial is the only way to be sure a drug is actually effective, because taking a "sugar pill" and being closely monitored by HD experts can produce physiological effects that result in improved clinical status.

Steps 4 - 6 require large amounts of money, and raising funds for these trials (e.g., preparing a proposal to submit to a funding agency, undergoing the review process, making revisions to the protocol, etc.) can take a year or two.

• First published in Horizon, Summer 2004 Edition