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Report from the Drug Company Working Group Meeting: New Ideas, Opportunities and Trial Results

May 14, 2014

New disease models, new therapeutic targets, and new trial results were the highlights of this year's Drug Company Working Group meeting, sponsored by The ALS Association. The group included more than 60 attendees from pharmaceutical companies, biotechs, government agencies, and academic medicine, exchanging ideas and data to advance the development of treatments for ALS.

“It's a particularly exciting time for ALS, both for the diversity of the research and the diversity of the people here,” said Association Chief Scientist Lucie Bruijn, Ph.D., M.B.A., who hosted the meeting together with The Association’s Public Policy Department.

Stem Cells for Research, and Perhaps for Therapy
Nicholas Maragakis, M.D., from Johns Hopkins University, provided an update on the use of induced pluripotent stem cells (iPS cells), derived from skin cells of individuals with ALS. These cells can be maintained in cell culture and used to make neurons, glial cells (another central nervous system cell), or other cell types, for drug discovery or study of disease mechanisms. “This is both exciting, and sobering, as there is a lot of work yet to be done,” he said.

At Johns Hopkins, researchers have developed more than 50 cell lines, including from those with sporadic and familial forms of ALS. A “key question,” he said, is how well the cells recapitulate aspects of ALS. Recent work suggests they can display meaningful features of the disease, including development of multiple types of problems seen in neurons and glia from people with ALS. These cells are now being used to understand more about the ALS disease process.

While there is a great deal of interest in the idea of using stem cells for therapy, Dr. Maragakis noted the hurdles are high. Using them to replace dying neurons is probably the least likely strategy, at least in the near term, since it requires implanted cells to grow very long distances and make new connections, both of which have proved frustratingly difficult in all forms of transplantation experiments.

Implanted cells may be able to release growth factors and other neuroprotective molecules to aid the body's own neurons, and that idea is being tested by multiple groups, including one Dr. Maragakis contributes to. “The jury is still out” on these approaches, he said, with good safety results so far in human trials, but no evidence yet that the treatment can help slow the disease. Experiments are ongoing, and tests in new models are continuing to determine the most effective approaches.

Understanding the C9orf72 Gene
Robert Baloh, M.D., Ph.D., of Cedars-Sinai Medical Center in Los Angeles, gave the group an update on efforts to understand the effects of the C9orf72 gene mutation, the single most common genetic cause of ALS. A major question is whether, and to what extent, the problems caused by the mutation are due to loss of the normal protein it encodes, or to new toxic functions arising from the mutation, since that will help determine the best therapeutic strategy. A major stumbling block to date has been lack of knowledge of the gene's normal function. New results indicate it helps regulate movement of materials within membrane-bound “vesicles,” or little transport packages, within neurons. Loss of this function can have important consequences. “This suggests that loss of function could cause disease,” Dr. Baloh said.

But multiple results indicate that the highly expanded RNA that is formed from the mutation leads to several potentially toxic new functions in the cell, including formation of RNA aggregates that bind cell proteins, and creation of unusual protein-like molecules (called RAN peptides) that may also cause problems.

All these potential disease mechanisms are being explored in iPS cells derived from people with ALS due to the C9orf72 mutation. Progress is also being made in developing therapies targeting the mutation, using “antisense” RNA to bind to and disable the expanded RNA.

Attacking Inflammation in a New Trial
Inflammation is the immune response that causes an infected cut to become red and tender. Inflammation gone awry causes rheumatoid arthritis and is believed to play a role in ALS as well—probably not at the very start of the disease but in later stages, worsening the initial damage and possibly setting up a vicious cycle that contributes to disease progression.

That has led researchers to wonder whether reducing inflammation might be a valuable treatment strategy, explained Shafeeq Lahda, M.D., of Barrow Neurological Institute in Phoenix, who is leading a pilot trial of the drug tocilizumab, an approved arthritis treatment.

The drug influences microglia, cells in the central nervous system that can play two different roles. In one state (called M1), they are neurotoxic, while in the other (M2), they are neuroprotective. Tocilizumab interacts with microglia to convert them from the M1 to M2 state. In a recent small, open-label trial in eight people with ALS, there was some evidence that the drug may be able to reduce neuroinflammation.

But many questions remain, and the goal of Dr. Lahda's study will be to answer some of them. Among the most basic is whether the drug, which is given by injection, can reach the central nervous system. He and his colleagues will be looking at that, as well as whether short-term treatment can reduce peripheral signs of inflammation, as measured by blood tests. If these tests are positive, and the treatment proves safe, it could set the stage for a larger trial to determine whether the drug can slow progression of the disease.

Latest Data on Tirasemtiv Indicates Promise, Problems
Tirasemtiv is being developed as a symptomatic treatment for ALS. The drug increases the force of muscle contraction, especially at low levels of muscle stimulation, allowing a person with ALS to perform activities of daily living with less effort. Results from short-term trials have looked promising, although side effects have prevented some people from continuing on treatment.

BENEFIT-ALS, a Phase IIb, multi-national, double-blind, randomized, placebo-controlled, clinical trial designed to evaluate the safety, tolerability and efficacy of tirasemtiv in people with ALS has recently been completed. Andrew Wolff, M.D., Chief Medical Officer of Cytokinetics, the developer of the drug, gave the group an overview of the results.

The trial enrolled 711 people with ALS. All subjects completed one week of open-label treatment to screen out those who could not tolerate the drug, mostly due to dizziness. The 605 individuals remaining were randomized to receive placebo or tirasemtiv. The dose of drug was increased within the limits of tolerance, up to a maximum of 500 mg per day. About half of the group receiving tirasemtiv was able to tolerate the maximum dose.

Score on the ALS Functional Rating Scale (ALSFRS) was the primary measurement in the trial. There were many secondary measurements, including several different tests of breathing, muscle strength and endurance.

One of those, called the “slow vital capacity,” which is related to normal low-volume breathing, declined less for those taking tirasemtiv than for those taking placebo, at each of the times it was tested throughout the 12-week study. Muscle strength was also significantly better for those taking tirasemtiv. However, several other measures of breathing function were not different, and there was also no difference between the two groups on the ALSFRS, which combines multiple measures of function.

Nausea and other gastrointestinal disturbances were common among those receiving tirasemtiv, as was dizziness (despite the initial screening), and these were important contributors to a higher level of drop-outs among participants versus those receiving placebo.

Dr. Wolff indicated that there is much more analysis of the data still to come, but the earliest analyses suggest that the gastrointestinal side effects may have contributed to the apparent lack of superiority of tirasemtiv. He said that those individuals who reported the most GI disturbance also lost the most weight during the study, and this may have limited their ability to achieve the highest dose and contributed to the lack of benefit in these subjects. In those who did not lose weight on tirasemtiv, ALSFRS scores improved during the trial.

Further analysis of the results are in the works, and will inform decisions about future development of the drug, which will likely include modifications to the study design in the event of a larger Phase 3 trial. There is clearly interest in the ALS community for pursuing development. As lead investigator Jeremy Shefner, M.D., pointed out, “This is the most positive therapy trial in ALS since riluzole.” Future modifications may include addressing nausea and weight loss with adjunctive therapies.

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