The ALS Association

Ice Bucket Challenge Progress

ALS Association’s Drug Company Working Group Discusses Dexpramipexole, Tirasemtiv and Biomarkers

April 15, 2013

In March, The ALS Association convened its Drug Company Working Group to review recent trial results and discuss new developments in the search for treatments for ALS. The meeting was held during the Annual Meeting of the American Academy of Neurology in San Diego. The group comprises a rotating mix of representatives from industry, academic medicine, government research, and other disease-focused nonprofit organizations, all dedicated to developing new treatments for ALS.

Steve Gibson, Chief of Public Policy at The Association, provided the opening remarks and noted that there were significant opportunities for ALS including the National ALS Registry and the ALS Research Program at The Department of Defense.  Lucie Bruijn, Ph.D., The Association’s Chief Scientist who organized the scientific program, noted that tremendous progress in understanding ALS has been made during the past two decades since the group first met, with new genes and new understanding of degenerative pathways now being explored for therapy development.

Doug Kerr, M.D., Ph.D., Medical Director of Neurodegeneration and Translational Neurology at Biogen Idec, led off the discussion with a report on the outcome of the EMPOWER trial. This trial was a Phase 3 study of dexpramipexole in almost one thousand ALS patients. Dr. Kerr expressed disappointment in the outcome of the trial, a feeling shared by the ALS community as a whole. But, he said, all parties recognize that developing treatments for neurodegenerative disease “is very tough. But this does not deter us—we are in it to stay,” he said.

The trial compared twice daily administered dexpramipexole to placebo. Patients enrolled on average 15 months after diagnosis. Three quarters were taking riluzole. After 12 months of treatment, there was no difference between treatment arms in either deaths or time to reach a vital capacity of 50% predicted. There was also no difference when patients were subdivided and analyzed by various criteria, including bulbar versus limb onset, rate of progression before treatment, on or off riluzole, and several other factors. “We looked hard, and we haven’t seen any effect,” Dr. Kerr said. “We must conclude the drug failed to demonstrate efficacy on primary, secondary, and other measures, in one of the largest trials in ALS.”

Despite that disappointment, there were some important lessons learned from the trial. A new measure of drug benefit was tested and found to be robust enough for use in future trials. A new system for identifying ALS at its earliest stages should make much earlier diagnosis possible in the future. And differences between patients on and off riluzole supported the survival benefit of that drug in a trial that was more sophisticated than the one that led to its initial approval.

For the future, Dr. Kerr stressed the importance of developing biomarkers to track drug response and disease progression, in order to better evaluate the results of smaller trials and avoid the time and expense of larger ones with drugs of unknown promise. “Those types of decisions can be made when you have relevant biomarkers,” he said.

On that topic, Rita Sattler, Ph.D., of Johns Hopkins University, reported the latest on her work developing an imaging biomarker for ALS. She and her colleagues are focused on revealing the levels of a protein in the central nervous system called the glutamate transporter, known formally as EAAT2. A large body of work has shown that this transporter is essential for the health of motor neurons and that its level decreases in ALS. That makes neurons more vulnerable to overexcitation, which can lead to death of the neuron. Dr. Sattler wants to be able to see how much transporter is in the nervous system by using PET imaging, a type of neuroimaging that can display rich pictures of the inside of the brain and spinal cord. Making those images requires a marker molecule that binds to the transporter. She reported to the group that she and her colleagues are currently fine-tuning the marker and plan to proceed to clinical trials shortly.

James Berry, M.D., of Massachusetts General Hospital, described work on a set of immune system cells that may serve as biomarkers for disease progression. The cells are called monocytes, and they move between the blood stream and the central nervous system. One type of monocyte, called M1, damages neurons when it enters the CNS, through the process called neuroinflammation. Working with Howard Wiener, M.D., and Oleg Butovsky, Ph.D., of Harvard Medical School, he is trying to determine if the level of M1 cells correlates with progression of the disease. He is also investigating the cellular events that activate M1 cells as a possible target for therapy.

Progress on Tirasemtiv
Tirasemtiv is an experimental drug that helps muscles deliver more power for a given level of contraction. This would be valuable in ALS because it would allow a patient to perform activities of daily living more easily and for longer in the disease process. A single dose of the drug has been shown to be effective in ALS patients. Jeremy Shefner, M.D., of SUNY Upstate Medical University in Albany, N.Y., described the results from a trial of longer duration and higher doses. He reported that a two-week trial of tirasemtiv in 50 patients indicated that the treatment was safe. Dizziness was the major side effect and resolved in most patients before the end of the trial. Treatment increased muscle strength and maximum voluntary ventilation (a breathing measure). Patients taking riluzole were instructed to reduce their dose because tirasemtiv increases the blood level of a give dose of the drug.

Dr. Shefner is now leading a new trial, which will enroll 400 patients at multiple sites in the United States and Canada. Patients will be randomized to receive tirasemtiv or placebo for three months. Those interested in the trial can learn more at or by contacting Jinsy Andrews, M.D. (650-624-2929, or

“The field of ALS treatment research is moving very fast,” Dr. Bruijn said. “Gone are the days when basic and clinical scientists were isolated from each other. It is now a back-and-forth relationship, which speeds the development of new treatments. While we were all disappointed in the results from the dexpramipexole trial, we will use those results, and progress on new biomarkers, to design better trials and test new therapies in the future.”

Powered by Blackbaud
nonprofit software