Reldesemtiv (formerly CK-2127107) is an experimental treatment being developed by Cytokinetics in collaboration with Astellas. It is intended to improve muscle function and physical performance in people with diseases that cause muscle weakness and/or muscle fatigue, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).
How reldesemtiv 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 complex structures made up of multiple muscle fibers. These fibers contain sarcomeres, the basic mechanical unit that contracts to make the muscles work, and is activated by calcium. The release of calcium is triggered by signals from the nervous system — signals that 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 due to ALS.
Reldesemtiv in clinical trials
The safety, tolerability, bioavailability (the proportion of the therapy entering 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 were also tested in ALS patients in a Phase 2 clinical trial (NCT03160898). Researchers assessed the change from baseline after treatment with reldesemtiv 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. The study, called FORTITUDE-ALS, recruited 458 ALS patients at centers in the U.S., Canada, Australia, Ireland, Spain, and the Netherlands.
However, at the beginning of May 2019, Cytokinetics announced that reldesemtiv failed to reach statistically significant differences in SVC decline compared with a placebo after 12 weeks. But the company is still optimistic about the results and stated that it did notice differences between the treatment and placebo groups, which became larger over time. During the trial, the effects of three different doses of reldesemtiv were compared with a placebo. When each dose was compared separately to the placebo, there was no large enough difference in SVC. However, if all three reldesemtiv groups were combined, there was a 27% reduction in SVC decline compared with the placebo. When all treatment groups were grouped together, there was also a 25% reduction in the decline on the ALS functional rating scale-revised (ALSFRS-R). The ALSFRS-R measures how well ALS patients can perform certain daily activities.
In addition to ALS, reldesemtiv has been evaluated in a completed Phase 2 clinical trial in patients with SMA (NCT02644668), and a completed Phase 2a clinical trial (NCT02662582) in patients with chronic obstructive pulmonary disease. A Phase 1 trial (NCT03065959) in elderly participants with limited mobility was terminated following an interim analysis that suggested that reldesemtiv was not effective in improving muscle function in these patients.
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