TIRASEMTIV, CK-2017357 (CYTOKINETICS)
Based on data provided by the Principal Investigator, Dr Jeremy Shefner of SUNY Upstate Medical University, Syracuse, NY, at both the American Academy of Neurology and MNDA ALS/MND Annual Symposium, Tirasemtiv activates the fast skeletal muscle troponin complex and thereby increases the sensitivity of the sarcomere to calcium, resulting in increased skeletal muscle force and slowing of time to muscle fatigue. These actions appear to have positive effect on functional ability as measured by the ALSFRS-R as well as other measures of neuromuscular endurance. A double blind, placebo controlled Phase IIB Clinical Trial for 400 persons is being conducted at 50 US/Canada sites and 20 European sites, with a 3 month duration of treatment. We urge your immediate investigation and hopeful enrollment. More complete information is available at the Clinical Trials website.
Cytokinetics (CK-2017357)- Identifier Number NCT01378676*
This clinical trial is in Phase IIa. It is a double-blind, randomized, placebo-controlled two-center study which means that you may or may not receive the actual medication. There are four groups of patients, each receiving either the full dosage, partial dosage or placebo. The trial lasts for only 21 days, but participants must return to the study site on the second, eighth and fifteenth days and a final followup visit seven days after their last dose. With only two sites at this time, location is important. This trial is measuring both safety and dosage.
Why this trial is notable
The Principal Investigator, Dr Jeremy Shefner, Professor and Chair of Nerology, of SUNY Upstate University, Syracuse, is a highly rated ALS clinician-researcher at an esteemed institution. CK-2017357 appears to be a fast-acting, symptom-relieving pharmaceutical compound that is in line with the current trend of ALS research to effectively treat symptoms first and perhaps find the "cure" through stem cell technology or gene therapy. In its early trial stages, the compound has performed admirably and is indicated to be safe. The inclusion criteria is liberal compared to several other current trials. Cytokinetics, while a young company, has demonstrated intelligence, purpose and continuity in their research and development of pharmaceuticals and they appear to have a commitment to ALS.
Issues of concern
Although this clinical trial is now expanded to nine sites, it remains at 24 subjects. This suggests the greater likelihood of participation in a Phase III Clinical Trial.
Trial Principal Investigator statement
“CK-2017357 is a fast skeletal muscle activator that, in animal models, improves amount of force generated by muscle in response to nerve activity. In preclinical studies, maximum muscle strength is not improved, but muscles are less fatigueable. A drug with a direct effect on muscle is not likely to change the underlying course of disease in people with ALS, but could provide important functional benefits.
The initial trial of CK-2017357 in ALS took advantage of the fact that the drug is rapidly absorbed after oral administration, and that its effects can be observed very shortly after the drug is taken. Subjects were given a single doses of CK-2017357 at 250 mg, 500 mg, or were given a placebo pill. Since the drug is eliminated from the body fairly quickly, subjects in this study were given 3 doses, one of placebo and one of each dosage strength of CK-2017357. The doses were separated by about a week, with the order randomly determined for each subject. For the 24 hours after each dose, many safety measures were obtained, as well as several assessments aimed at determining whether muscle function was improved. In addition, subjects were asked whether they felt better, worse, or the same at specific time points. In all, 67 subjects participated in this trial.
The results of this early phase trial were encouraging in many ways. Perhaps most striking was the fact that both subjects and investigators rated subjects to be improved in a dose dependent manner, meaning that more subjects were judged to be better on the low dose than placebo, and more on the high dose than on the low dose. Certain measures of breathing function also appeared to be improved, as did muscle endurance. While encouraging, it is important to remember that this is a preliminary study, based on the responses of subjects to single doses of medication. A longer, repeated dose study is now underway.”
Jeremy M Shefner, MD, PhD