Tirasemtiv is an experimental therapy being developed by Cytokinetics for the potential treatment of amyotrophic lateral sclerosis (ALS). It is the first potential new treatment being developed for ALS in more than 20 years, according to the company.

How tirasemtiv works

The movement of skeletal muscles is controlled by the brain via signals carried by motor neurons (nerve cells). When the signal reaches the muscles, the movement of calcium ions from the nerve cell into muscle cell is stimulated. Inside the muscle cell, calcium binds to a protein called troponin, triggering a structural change in muscle filaments, causing them to contract.

ALS is a disease that damages motor neurons, which decreases the amount of nervous stimulation a muscle gets.

Tirasemtiv is a fast skeletal muscle troponin activator (FSTA). It increases muscle strength in people with ALS by making troponin more sensitive to calcium. When calcium floods into the muscle cells, troponin creates tighter bonds with calcium. This slows the rate of calcium release from troponin, which strengthens contractions and keeps the muscle from tiring as easily.

Tirasemtiv in clinical trials

Several early clinical trials have shown potentials benefit of tirasemtiv in patients with ALS.

A randomized, placebo-controlled Phase 2b trial called BENEFIT-ALS (NCT01709149) tested the safety, tolerability, and effectiveness of 12 weeks of tirasemtiv treatment in patients with ALS. Patients received either placebo and riluzole, or tirasemtiv and riluzole, up to the maximum tolerated dose of 250 mg tirasemtiv twice a day. Riluzole is a drug used to delay the progression of ALS.

The trial was completed in April 2014 and results published in 2016 showed that tirasemtiv slowed the decline of slowed vital capacity (SVC), a breathing test that reflects the strength of skeletal muscles used for breathing. The SVC has been shown to be an important predictor of disease progression and survival in patients with ALS.

Prompted by these encouraging results, investigators designed a multinational, randomized, placebo-controlled Phase 3 trial called VITALITY-ALS (NCT02496767) to test the ability of tirasemtiv to increase muscle strength in patients with possible, probable, or definite ALS.  The trial began in August 2016 and enrolled more than 700 patients at 81 centers in 11 different countries. The trial is ongoing, but no longer recruiting participants.

During the trial, all patients first receive 250 mg tirasemtiv per day for two weeks. After this two-week open-label period, patients are randomized to receive either placebo or one of three doses of tirasemtiv (250 mg per day, 375 mg per day, or 500 mg per day) for 48 weeks.

The main measure of effectiveness is the change in patients’ SVC after 24 weeks of treatment.  The trial is also assessing the effects of treatment on other measures of muscle strength.

Final results from the trial are expected in the last quarter of 2017. All patients who complete the trial have the option to continue to an open-label extension study called VIGOR-ALS (NCT02936635), which began enrolling patients in October 2016.

All patients enrolled in VIGOR-ALS receive 125 mg of tirasemtiv twice a day for four weeks, which is titrated to the maximum dose the patient can tolerate, up to a maximum dose of 250 mg twice a day. The clinical course of the patients who were treated with tirasemtiv in the VITALITY-ALS study is then compared to those who had been on placebo. The primary purpose of the VIGOR-ALS study is to assess the long-term safety and tolerability of tirasemtiv in patients with ALS.

Additional information

Tirasemtiv has been granted orphan drug designation and fast track status by the U.S. Food and Drug Administration (FDA), and orphan medicinal product designation by the European Medicines Agency (EMA) for the potential treatment of people with ALS, designations that help speed up the development and approval process of new treatments.


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