The ALS Association

Animal Models are Problematic but Crucial

By Richard Robinson

Science Writer

Third in a series of three articles

In late September 2007, The ALS Association brought together 30 scientists, clinicians, and industry researchers for a three-day conference on “Drug Discovery, Biomarkers, and Clinical Trials in ALS.” This is the third of three articles on that conference.

In the first two parts, we looked at the challenges facing ALS researchers in understanding the disease process, and how that information is used to search for drugs to alter the course of the disease. In the final installment of this series, we take a close look at clinical trial design and the use of biomarkers in ALS trials, two important factors for increasing the speed and decreasing the size of trials, both vital for quickening the pace of drug trials for ALS.

The ultimate goal of all research in ALS is to find treatments to slow or halt the disease. Once a candidate drug is identified, and preliminary tests in animal models indicate it may have promise, it enters a series of increasingly rigorous trials, first in animals, and then in humans, to test its safety and effectiveness.

“Preclinical” trials are performed in animals to test for safety. The United States Food and Drug Administration (FDA) usually requires that a new drug be tested in two different kinds of animals, such as mice and monkeys.

Clinical Trials: Safety First, then Efficacy

Following successful preclinical safety trials, the drug’s safety must then be tested in a “Phase I” trial in humans. In a Phase I trial, the drug is given to healthy volunteers, who are monitored carefully for signs of toxicity, especially of the heart or nervous system. “Safety always comes first for the FDA, even for a disorder such as ALS, where there are no significant treatments available,” according to Scott Wieland, PhD, of CytRx Corporation, which is developing a new treatment for ALS.

David Schoenfeld, M.D. (Harvard University) suggested that a meeting between the FDA and The ALS Association and other concerned groups might be useful to discuss how best to balance the need for careful safety studies with urgent need to speed drugs into clinical trials

On the other hand, said Wilson Bryan, M.D., a former FDA regulator and now an industry consultant, “Dealing with the FDA is probably the least challenging,” since there are so many other significant hurdles in this disease.

After a successful Phase I trial, a drug enters a Phase II trial, in which a small number of patients receive the drug, testing for safety at different doses, and perhaps getting a preliminary look at the drug’s efficacy (effectiveness at treating ALS). If that is successful, a Phase III trial follows, testing efficacy in larger numbers of patients. As the number of people enrolled in a trial grows, so does the cost.

Both Phase II and Phase III trials are double-blind, placebo-controlled trials, meaning some patients receive the active drug, while others receive a placebo, an inert substance. Neither patients nor researchers know who is treated with what. This avoids the “placebo effect” of a patient feeling better simply because he or she knows he is receiving treatment. This kind of trial is the “gold standard” for testing a new drug, and is an absolute requirement for FDA approval.

Can Changing Trial Design Speed Drug Testing?

Among the most significant hurdles in the design of a Phase III trial is finding an outcome measure that can quickly show whether a drug is working. Outcome measures are what researchers measure, such as prolonged survival or slower loss of strength. There are difficulties with both of these outcome measures. Strength fluctuates from month to month, so that only over many months can a clear effect of a drug be seen (or ruled out). Survival also requires very long trials. Researchers would like to be able to conduct much shorter trials, but shorter trials using these outcome measures must enroll many more patients, greatly increasing costs.

At the conference, researchers discussed at length two strategies that might help solve this problem. Changing the design of Phase II trials could require fewer patients while still providing valuable information. And “biomarkers” that reliably track disease progression without short-term fluctuations would allow shorter trials.

The trial design changes are somewhat complex, and require some training in statistics to fully appreciate. But the essential idea is this: A standard Phase II trial begins with the assumption that “this drug is no better than placebo,” and hopes the data will disprove it. The alternative design begins with the assumption that “this drug is better than placebo by some pre-set amount,” and hopes the data will support it. If they do, a Phase III trial may be warranted. If they don’t, further testing is futile. Because of this, the new trial design is called a futility study.

The advantage is that futility studies are faster and cheaper than standard Phase II trials. Bruce Levin, Ph.D. (Columbia University), who is an expert in the statistical analysis of clinical trials, pointed out that because of the differences in study design, a Phase II futility study requires less than half the number of patients as a standard Phase II trial.

Biomarkers to Track ALS

The second strategy for speeding trials, and the one in which interest is keenest, is to find alternative outcome measures that display a reliable change over much shorter time periods—a few months instead of a few years. Such a measure is called a biomarker. A biomarker could be a change in a substance in the blood, or a measurement of nerve cell function, or some other measurement that correlates with change in the disease itself. Finding a biomarker for use in ALS trials is a major challenge for researchers.

The payoff could be huge, according to Dr. Schoenfeld, who helps plan trials in many diseases. When reduced viral load was developed as a biomarker for response to anti-HIV drugs in treatment of AIDS, “it sped up drug development by orders of magnitude,” he said.

Several potential biomarkers caught the attention of researchers at the conference. The blood and brain fluids carry over two thousand compounds, many in very small amounts, which are generated through the normal metabolic processes that keep us alive. These metabolites differ from person to person, from day to day, and from health to illness. Bruce McCreedy, Ph.D. of the biotech firm Metabolon, Inc., reported some preliminary results showing that a small set of metabolites differ in people with ALS versus those who don’t have the disease. Metabolon, Inc. is currently investigating what these compounds are, and whether they can be used to track disease progression. A side benefit of this research may be that identifying these compounds can shed light on the ALS disease process itself. “One strength of this approach is to be able to ask questions about disease mechanisms,” Dr. McCreedy said.

Perhaps the most promising biomarker for tracking the degeneration of spinal cord motor neurons in ALS is motor unit number estimate (MUNE, pronounced “myoo-nee”). MUNE uses small electrodes to measure the number of axons stimulating a specific muscle. An axon is the long extension of a motor neuron that extends from the spinal cord out to the muscle. In ALS, motor neurons die, reducing the number of axons reaching the muscle. MUNE provides an accurate look at this ongoing process.

Most outcome measures in ALS, including strength, don’t fully reflect the disease process alone, because the patient compensates for lost motor neurons by recruiting remaining ones to accomplish a task, according to Jeremy Shefner, M.D. (SUNY Upstate Medical University). MUNE, on the other hand, directly reflects the decline in the number of motor neurons. “I think it has the potential to provide significant added information,” he said. “It could be a very powerful addition to our clinical armamentarium.” Because MUNE assesses primarily the loss of spinal cord motor neuron, biomarkers of degeneration in the brain of patients with ALS are also required. “Novel neuroimaging techniques identifying brain degeneration have the potential for tracking disease progression, possibly in future ALS clinical trials” commented Eric Pioro, M.D. (Cleveland Clinic).

As the conference wound to a close, researchers agreed that patients and families remain an important key to increasing the pace of clinical trials. “To conduct successful trials of potential new therapies, we will need the highest possible participation from the ALS community,” said Lucie Bruijn, Ph.D., science director for The ALS Association. “It is important to partner early on with patient groups to increase enrollment in these trials.”

“We accomplished a lot at this meeting, forging new partnerships and strengthening old ones,” Dr. Bruijn said. “Despite the many challenges, we are very optimistic that we are laying the groundwork for increasing the pace of clinical trials.”

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