Tirasemtiv is an experimental therapy that was being developed by Cytokinetics for the potential treatment of amyotrophic lateral sclerosis (ALS). Although it was shown to decrease muscle fatigue and increase skeletal muscle force in preclinical studies and early clinical trials, the development of the treatment was suspended owing to the absence of any benefits in late clinical trials.

How tirasemtiv works

Tirasemtiv is a fast skeletal muscle troponin activator (FSTA), i.e., it binds and activates a protein called troponin that is found in voluntary muscles.

The brain controls the movement of voluntary muscles via signals carried by the motor neurons, which stimulate the movement of calcium ions from the nerve cell into the muscle cell. These calcium ions bind to troponin, triggering a structural change in muscle filaments and causing them to contract. In ALS patients, motor neurons degenerate, and this decreases the amount of nervous stimulation a muscle gets.

Tirasemtiv was thought to increase muscle strength in people with ALS by making troponin more sensitive to calcium. It was thought that tirasemtiv would cause troponin to create tighter bonds with calcium, slowing the rate of calcium release, and therefore strengthening muscle contractions and keeping the muscle from tiring easily.

Tirasemtiv in clinical trials

Several early clinical trials showed promising results 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 a placebo and riluzole, the first treatment approved by the U.S. Food and Drug Administration for ALS, or tirasemtiv and riluzole, up to the maximum tolerated dose of 250 mg tirasemtiv twice a day. 

The trial was completed in April 2014. The results, published in 2016, showed that tirasemtiv slowed the decline of slowed vital capacity, a breathing test that reflects the strength of skeletal muscles used for breathing. Slowed vital capacity is known 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 effectiveness of tirasemtiv in increasing 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.

During the trial, all patients first received 250 mg of tirasemtiv per day for two weeks. After this two-week open-label period, patients were 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.

Results showed that tirasemtiv treatment did not improve muscle strength and there was no change in patients’ slowed vital capacity after 24 weeks of treatment. Instead, patients experienced non-serious adverse events such as dizziness, fatigue, and nausea. These negative results led to the company suspending the development of tirasemtiv.

The patients who completed the trial had the option to continue in an open-label extension study called VIGOR-ALS (NCT02936635), which began enrolling patients in October 2016. However, due to the suspension of tirasemtiv development, further treatment has been discontinued

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