Reldesemtiv (formerly CK-2127107) is an experimental therapy being developed by Cytokinetics in collaboration with Astellas. It is intended to improve muscle function and physical performance in people with diseases associated with muscle weakness and/or muscle fatigue, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).

How it works

In ALS, the progressive loss of motor neurons or nerve cells involved in muscle control causes muscles to weaken and waste away (atrophy). This can result in problems with movement and breathing, and various other symptoms. Reldesemtiv is a type of fast skeletal muscle troponin activator (FSTA) that aims to slow the decline of muscle function in patients with ALS.

Muscles are a complex structure, made up of multiple muscle fibers. These fibers contain sarcomeres, the basic mechanical unit that contracts to make the muscles work, activated by calcium. The release of calcium is triggered by signals from the nervous system. These signals are reduced in conditions such as ALS.

Reldesemtiv is designed to bind to and slow the rate of calcium release from the troponin complex, a regulatory protein that plays an essential role in the contraction of fast skeletal muscle fibers. By doing this, the treatment boosts the sensitivity of the sarcomere to calcium, which should increase the ability of the muscles to contract despite reduced nerve signaling.

Reldesemtiv in clinical trials

The safety, tolerability, bioavailability (the proportion of the drug entering the circulation when introduced into the body), pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of reldesemtiv were evaluated in five Phase 1 clinical trials.

Results from one study, conducted in healthy volunteers, showed that reldesemtiv was well-tolerated with no adverse events and led to increases in the force of muscle contraction measured by nerve stimulation.

The effectiveness, safety, and tolerability of reldesemtiv in ALS patients are currently being tested in a Phase 2 clinical trial (NCT03160898). Researchers will assess the change from baseline in the percent predicted slow vital capacity (SVC), a measure of the strength of respiratory muscles as a predictor of disease progression and survival, and other measures of skeletal muscle function after treatment with reldesemtiv. The study, called FORTITUDE-ALS, is recruiting up to 445 eligible ALS patients at centers in the U.S. and Canada. More than 350 patients have already been enrolled, and initial results are expected in the first half of 2019.

In addition to ALS, reldesemtiv has been evaluated in a completed Phase 2 clinical trial in people with SMA (NCT02644668), and a completed Phase 2a clinical trial (NCT02662582) in patients with chronic obstructive pulmonary disease (COPD). A Phase 1 trial (NCT03065959) in elderly participants with limited mobility was terminated following an interim analysis that suggested reldesemtiv was not effective in improving muscle function in these patients.

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