The Search for Biomarkers to Speed Drug Discovery

Developing biomarkers for ALS has emerged as one of the most urgent needs in the search for effective treatments. According to Gilmore O’Neill, M.D., of Biogen Idec in Massachusetts, who took part in the Biomarker Development session at the ALS Association’s Drug Discovery Workshop in Washington, D.C., “The earlier you confirm or refute the biological hypothesis underlying a new drug, the better,” since decisions about investing time and money in further development can be made early on. Having a good biomarker goes a long way to aid that process.

A biomarker is any measurement, such as a blood test or imaging result that tracks the disease process and the effects of treatment. Cholesterol is a biomarker for heart disease, for instance, because its level correlates with the risk for the disease. Currently, The ALS Association is funding research to develop biomarkers for diagnosis, disease progress, and response to therapy.

Biomarkers are especially important for therapy development, according to several speakers at the workshop, because they allow researchers to determine if a new treatment is having the intended biological effect. The existence of a reliable progression biomarker can influence a pharmaceutical company’s decision whether to invest the millions of dollars needed to support a large clinical trial.

“There are three possible outcomes of clinical trials,” Dr. O’Neill said. A positive trial, in which the drug has a beneficial effect, is what everyone hopes for. But a negative trial, in which it is decisively shown that the treatment did not have the desired biological effect or that it had the effect but didn’t help the patient, is also valuable. The worst outcome is failure or absence of certainty. Biomarkers can help avoid that uncertainty. “It takes a long time to develop a good biomarker, but the return on investment is good, especially compared to the investment in a clinical trial.” Because of that,” he said, “a good biomarker improves your portfolio when you approach funders,” such as pharmaceutical companies.

The ALS Functional Rating Scale (ALSFRS) is currently the most important validated biomarker used in ALS trials, but its results may be variable based on the daily fluctuations in a person’s energy level or general health. Two electrical tests are as reliable as the ALSFRS, according to Jeremy Shefner, M.D., of SUNY Upstate Medical University in New York. Electrical impedance myography (EIM) and motor unit number estimation (MUNE) are painless, quick to administer, and can be used to track progression. Because they are less susceptible to fluctuation, fewer patients are needed for clinical trials in which these are the main outcomes being tracked.

One characteristic of ALS disease development is loss of a protein in the brain and spinal cord called EAAT2, which prevents toxic build-up of glutamate. Most ALS patients have severely reduced amounts of this protein, and lab models suggest that increasing it may be therapeutic. A clinical trial of Ceftriaxone, which elevates the protein, is currently underway. Rita Sattler, Ph.D., of Johns Hopkins University in Baltimore, Maryland, John Gerdes Ph.D. and Richard Bridges, Ph.D., of the University of Montana, and Henry Van Brocklin, Ph.D. of University of California, San Francisco have collaborated on the discovery and development of a PET ligand that tags the EAAT2 glutamate transporter, which they are developing as a potential therapeutic biomarker for treatments that increase the level of the transporter. Rodent testing is completed with primates to follow. The team hopes to test the imaging agent in humans in 2013. Even if Ceftriaxone itself is not beneficial in ALS, determining whether the drug raises EAAT2 in patients would be an important test of the glutamate toxicity hypothesis of the disease.

Robert Bowser, Ph.D., of the Barrow Neurological Institute in Phoenix, Arizona, has been searching for a “protein signature” of ALS in the cerebrospinal fluid (CSF), the fluid within the central nervous system that helps nourish the brain and spinal cord. “There are more than 4,000 proteins in the human CSF,” he said, making it a real challenge to find the best proteins to track. Dr. Bowser pointed out that quality control measures are also a challenge since CSF must be removed and stored in the same way each time in order to be able to compare results between samples.

Using a set of lab techniques that separate and identify the proteins, and then a set of computer tools to analyze the data, Dr. Bowser has begun to develop a biomarker that reliably distinguishes ALS patients from healthy controls. A critical difference between the two groups is the ratio of two proteins, called phosphorylated neurofilament and complement 3. This may be helpful for diagnosis.

Finding a CSF biomarker for disease progression will require collecting multiple samples from individual patients over time, work that is ongoing, according to Dr. Bowser. “Heterogeneity in the ALS patient population is a challenge,” he said.

The long-term goal of all these projects is to develop ways to more quickly and accurately determine a patient’s response to therapy, in order to test new therapies more quickly and reliably, said ALS Association Chief Scientist Lucie Bruijn, Ph.D., who organized the meeting.