November 27, 2007 

ALS Researchers Exchange Information on Clinical Trials

First in a series of three articles

In late September 2007, The ALS Association brought together 30 basic scientists, clinicians, and industry researchers for a three-day conference on “Drug Discovery, Biomarkers, and Clinical Trials in ALS.” “We hope that by bringing together these diverse groups of scientists, all of whom are dedicated to finding a cure for ALS, we will speed up the process of drug discovery and clinical testing,” said Lucie Bruijn, Ph.D., science director and vice president for The ALS Association.

The conference was held as part of The Association’s workshop program, which brings together scientists from diverse areas to help spur research and define new directions in understanding ALS. The topic of this workshop was inspired by The Association’s TREAT ALS (Translational Research Advancing Therapy for ALS) program, designed to accelerate the development of ALS treatments.

The meeting was held at the Banbury Center, part of the prestigious Cold Spring Harbor Laboratory on Long Island. “It is a great venue away from everything else to focus on the topic at hand,” Dr. Bruijn said. The Center specializes in bringing together top-notch scientists for frank and open discussions of cutting-edge research, and this meeting was no exception.

That openness was evident throughout the meeting, as researchers shared unpublished data and planned new collaborations. As just one example, Michael Strong, M.D. (London Health Sciences Centre, Ontario), presented new findings on the ALS disease process generated in his lab less than a week before the meeting.

“Information sharing is one of the keys to speeding drug development,” according to Petra Kaufmann, M.D., a participant and clinical researcher at Columbia University. Talk went on during the day-long meeting sessions, over coffee, all through dinner, and into the evening, as researchers examined every angle of the challenge—how to find and bring forward new drugs that hold promise for treatment of ALS.

Clinical Trials and the Importance of Biomarkers

There have been 25 large-scale clinical trials in ALS in the past 10 years, according to Merit Cudkowicz, M.D., of Harvard Medical School, who presented an overview to the group. There are 10 additional trials in progress, in Europe and the United States, and five more will start soon. From all these trials, only one drug—riluzole—has been proven effective and has been approved for use by the Food and Drug Administration (FDA). Some drugs, including talampanel, IGF-1 and tamoxifen have shown some initial promising results, and need to be studied further in larger trials. Others, including minocycline and celecoxib (Celebrex�) have not demonstrated any benefit, disappointing both patients and researchers.

“We’ve gained experience in the last decade of trials,” Dr. Cudkowicz said. We’ve tried a variety of trial designs and different outcome measures, and learned from these how to do better trials in the future.” Outcome measures are what researchers measure, such as prolonged survival or slower loss of strength, to tell whether a drug is having an effect. Also, by following so many patients so carefully over time, researchers have developed a very good picture of ALS progression, which can be used in the future to help assess the effects of potential treatments.

Several challenges have been identified in the carrying out of these trials which must be addressed going forward. Chief among them is recruiting enough patients. “You can’t tell if a drug works with 100 people,” Dr. Cudkowicz said. There are two major reasons large numbers of patients are needed. First, ALS is a heterogeneous disease, with different patients being affected in different ways, and progressing at different rates. This can hide small but significant treatment benefits, unless the number of patients is very large. A key goal for researchers is to understand these differences between patients, and to test whether some subtypes of ALS may respond better to specific treatments than others.

The second reason large numbers of patients are needed is that it may take many months for a particular drug to show any benefit using the most common outcome measures—survival and decline in function. For many different reasons, patients drop out of long trials (not just in ALS, but in trials of all diseases), meaning large numbers are needed at the start to have enough for analysis at the end. Therefore, Dr. Cudkowicz said, “our challenge is to get broader participation and involvement in the clinical trials process.”

It may also be possible to reduce the number of patients required, at least for initial studies, by changing the standard trial design, according to information presented by Bruce Levin, Ph.D. (Columbia University), an idea met with strong interest among many of the clinicians in the discussion. These alternative trial designs are currently being investigated and formed the basis of the recent study funded through TREAT ALS. (see )

At the same time, a key goal is to develop alternative outcome measures that are able to identify whether a treatment has an effect 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 to reliably track the response of ALS to treatments is a major challenge for ALS researchers, and was a major topic of discussion at the Banbury conference.

The Importance of Collaboration

A major goal of the Banbury conference was to forge links between the many groups that have an interest in finding treatments for ALS. Prominent among these is “Big Pharma,” the nickname for the largest pharmaceutical companies. While the market for a successful ALS drug will never be as lucrative as for a blockbuster drug like Viagra or Prozac, “Big Pharma is waking up to the possible value of small disorders with no current treatments,” according to John McCall, Ph.D. a consultant to the industry. In other words, Big Pharma is interested.

At the same time, a constellation of smaller groups, dedicated to promoting research in other neurodegenerative diseases, are also offering their expertise to benefit understanding and treatment of ALS. These include spinal muscular atrophy and Huntington’s disease (HD). A key effort in HD is being led by Cure Huntington’s Disease Initiative (CHDI), a private foundation operating as a biotechnology firm that focuses exclusively on Huntington’s disease. “We are time-motivated, not profit-motivated,” said Robert Pacifici, Ph.D. Chief Scientific Officer, a sentiment shared by other disease-focused organizations. The CHDI program of drug discovery and preclinical testing is a direct inspiration for The Association’s TREAT ALS program, and Dr. Pacifici serves on the TREAT ALS steering committee.

Working together will all these groups, and drawing on the expertise of the full range of experts in these diverse fields, The ALS Association hopes to speed up the rate at which new drugs can be tested in ALS patients.

In the next two parts of this article, we will look closely at two major challenges to accelerating the pace of clinical trials. First we will look at animal models and the drug discovery process—how models of ALS can be used to identify targets, and then how drugs can be found that aim at these targets. Key questions here are how good are the animal models, and how can they be made better? Second we will return to the question of biomarkers, why they are so important for drug trials, how they can be deployed, and what they may tell us about the disease process itself.

See also:

Article 2: Drug Discovery in ALS: Animal Models are Problematic but Crucial 
Article 3: Speeding ALS Clinical Trials with New Trial Designs and Biomarkers