April 03, 2013

San Diego, California — The investigational drug tirasemtiv (Cytokinetics), which is being studied for the first indication of amyotrophic lateral sclerosis (ALS), may also have a role in myasthenia gravis, preliminary data suggest.

Presenting the initial data in patients with myasthenia gravis, Donald B. Sanders, MD, founder of the Duke Myasthenia Gravis Clinic, Durham, North Carolina, said, "These results suggest that tirasemtiv improves function in myasthenia gravis and they will be used to support further development of tirasemtiv in neuromuscular diseases."

"Almost all drugs used in myasthenia gravis are immunologics, such as prednisolone, azathioprine etc. But tirasemtiv is a symptomatic therapy could improve strength in patients who don't respond to other treatments or in whom they are contraindicated," Dr. Sanders commented to Medscape Medical News.

He added, "This was a pilot study to see if we could find a signal of efficacy. We did see such a signal. It could be particularly valuable in the subgroup of patients who have congenital myasthenic syndromes for whom there are few therapies available. It could also have a role in other neuromuscular diseases that cause weakness."

The results were presented here at the recent American Academy of Neurology (AAN) 65th Annual Meeting.

Activates Skeletal Muscle Troponin

The drug is said to selectively activate the fast skeletal muscle troponin complex by increasing its sensitivity to calcium, thereby increasing skeletal muscle force in response to neuronal input and delaying the onset and reducing the degree of muscle fatigue.

Dr. Sanders noted that single doses have been shown to increase skeletal muscle strength and endurance in healthy volunteers, in patients with ALS, and in patients with calf claudication. In a passive transfer rat model of myasthenia gravis, tirasemtiv decreased muscle fatigability and increased muscle force and grip strength.

In the current study, which had a double-blind, randomized, 3-period crossover design, 32 patients with generalized myasthenia gravis with a Quantitative Myasthenia Gravis (QMG) grade of 2 or 3 in 2 or more muscles received single oral doses of placebo, 250 mg of tirasemtiv, and 500 mg of tirasemtiv in random order and approximately 1 week apart.

The main objectives of this trial were to assess the effects of tirasemtiv on various measures of skeletal muscle strength and fatigue, including measures of pulmonary function.

At 6 hours after dosing, dose-related improvements in the QMG score (a validated index of disease severity) were seen with the drug.

Table 1. Changes in QMG Score With Tirasemtiv versus Placebo

Dose Change in QMG Score P Value (vs Placebo)
250 mg –0.49 .02
500 mg –0.99 .02


In a responder analysis, twice as many patients improved by 3 points or more 6 hours after dosing with 500 mg of tirasemtiv compared with 6 hours after placebo (12 vs 6; P = .098). In addition, the percentage predicted forced vital capacity (FVC) increased relative to placebo.

Table 2. Increase in Predicted FVC vs Placebo

Dose Increase in Predicted FVC P Value (vs Placebo)
250 mg 4.5 .034
500 mg 7.0 .0012


The drug was said to be well tolerated, with no serious adverse events occurring. The most commonly reported adverse event in this trial was dizziness, which was mild in all but 1 case that was classified as moderate.

Tirasemtiv is being developed first for ALS, for which it is being investigated in a phase 2b study in 400 patients.

American Academy of Neurology (AAN) 65th Annual Meeting. Emerging Science Abstract #009. Presented March 20, 2013.