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A new drug, CK-2017357, was reported to delay the onset and magnitude of fatigue in ALS patients.
DR. JEREMY SHEFNER described the research as “hypothesis-generating,” designed to generate ideas for more definitive trials in the future.
ORLANDO, FL—An experimental drug that increases the force of contraction of skeletal muscle may improve endurance in amyotrophic lateral sclerosis patients (ALS), according to a study presented here at the annual meeting of the ALS-MND Society in December. The drug does not have any effect on disease progression, but may allow patients, especially early in the disease, to better perform their activities of daily living.
“While it isn't a cure, it may be able to help with fatigue,” said Terry Heiman-Patterson, MD, professor of neurology at Drexel University College of Medicine in Philadelphia, who was not involved in the study. “Fatigue is a major concern for patients. If we can help with that, it means patients may get more done in a day.”
The drug, known as CK-2017357, increases the sensitivity to calcium of the troponin complex in fast skeletal muscle fibers. Binding of calcium to the troponin complex triggers muscle contraction. CK-2017357 is manufactured by Cytokinetics, a biotechnology firm located in South San Francisco, CA.
Lead investigator Jeremy Shefner, MD, PhD, said that previous studies have shown that, when delivered orally, the drug reaches a maximum serum concentration after three to five hours. It has no effect at maximal contraction force, when all available troponin complexes are already engaged. Instead, “it improves the force of muscle contraction at submaximal contraction forces, delaying the onset and magnitude of fatigue in animals and healthy humans,” said Dr. Shefner, professor and chair of neurology at Upstate Medical University of the State University of New York in Syracuse.
The importance for ALS patients, he said, is that “most movements are made with submaximal contractions. Very few activities of daily living are performed at maximal contraction. One could predict that increased endurance and decreased fatigue could result from a drug that increased force, and that this could improve function.”
To explore that question, Dr. Shefner led a 14-center, double-blind study in 67 men and women with ALS. Enrolled patients were on average 68 years old, with a vital capacity of approximately 80 percent of the predicted normal value. The average ALS Functional Rating Scale (ALS-FRS) score was 36 (of a possible 40 on this 10-item scale).
Each patient received a single dose of placebo, and 250 mg and 500 mg of the drug, given in random order separated by at least six days. Measurements of endurance, strength, safety, and overall benefit were performed at three, six, and 24 hours after each dose. “This was a hypothesis-generating study,” Dr. Shefner said, designed to generate ideas for more definitive trials in the future.
Strength was measured by hand-held dynamometer. Endurance was tested by asking patients to flex their shoulders and maintain the posture for up to two minutes, and by determining how long they could maintain 30 percent of their maximum hand grip strength. Pulmonary strength was tested by sniff inspiratory pressure, and pulmonary endurance by maximum voluntary ventilation. For the global assessment, both patients and investigators rated whether the patients were overall better, worse, or the same at each time point.
The pharmacokinetics were “very clean,” Dr. Shefner said, with peak plasma levels of the high dose almost exactly double those of the low dose for each time point. Tolerability was very good, with no serious adverse events related to treatment. Most adverse events were minor, with dizziness the most common and showing a clear dose-dependent increase. The dizziness was best described as “unsteadiness,” Dr. Shefner said, rather than vertigo, and was not accompanied by any change in blood pressure. “Whether this becomes more or less obvious with repeated dosing is something that needs to be investigated in future trials.”
There was a dose-related improvement in overall assessment, with both patients and investigators more likely to judge improvements when plasma concentration of the drug was highest. Six hours after treatment significantly more patients receiving high-dose CK-2017357 than placebo were judged improved by both patients and investigators.
At almost all time points, patients receiving active treatment showed greater endurance than those receiving placebo. This was most obvious for the weaker hand, Dr. Shefner said. The differences were not large for any one time point or any one muscle group, he said, “but I think the trend is more impressive than the individual results.”
Patients also seemed to benefit on pulmonary endurance, although the results did not reach statistical significance. “I don't want to make too much of it, but there is a trend to improvement” on this measure, he said. Measures of strength did not improve, and there was no clear benefit on other measures, including shoulder flexion endurance and the ALS-FRS. The lack of effect on the ALS-FRS was not unexpected, according to Dr. Shefner, since it is a gross functional scale, and not designed to register changes from a single dose of a short-acting drug. The data had not been fully analyzed at the time of presentation, “but thus far, none of them are showing a clear signal.”
“I think this is potentially an important and useful demonstration,” Dr. Shefner said. “What patients need to do is not function at maximum voluntary contraction levels, but to function in multiple ADLs [activities of daily living] at submaximal levels. An agent that helps that has the potential to be significantly beneficial for patients with ALS. These results are exploratory, but do support further evaluation, in particular for chronic dosing.”
A seven-day study in healthy volunteers has been done, Dr. Shefner said, with no safety concerns arising from chronic treatment.
Dr. Shefner cautioned that there is no reason to expect that the underlying disease course is modifiable by this treatment. In addition, more advanced patients may be too weak to benefit from an increase in submaximal contraction strength, since even at maximal effort, they are unable to perform many activities.
In almost any other disease, results this partial in extent and modest in size might be met with disappointment. But for ALS, there is little else to offer patients, said Dr. Heiman-Patterson of Drexel University.
“It's exciting that it showed anything,” she said, noting that currently, rest is about the only option for ALS patients with fatigue. “I think it is exciting that we may have something that can help.”
Larger trials will be needed before any conclusions can be drawn, Dr. Heiman-Patterson said, but it could be a potentially important treatment. “I suspect you would give this drug on a daily basis, to keep people as highly functioning as possible. That is the kind of question answered by a longer term trial.”Back to top