Reldesemtiv (formerly CK-2127107) is an investigational therapy that may improve muscle function and physical performance in people with spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS). It is being developed by Cytokinetics in collaboration with Astellas.
How reldesemtiv works
SMA is characterized by a loss of muscle strength due to the progressive death of motor neurons — specialized nerve cells that send signals that control muscle movement. As the motor neurons die, the signals telling the muscles to contract become gradually weaker. That decreases muscle force, leading to the many symptoms of SMA.
Muscles contract when the signals from the motor neurons cause calcium to be released inside muscle cells. Reldesemtiv works by slowing the rate of calcium release from a group of proteins called the regulatory troponin complex. In specific types of skeletal muscle fibers, the troponin complex sensitizes the long fibrous proteins that slide past each other when muscles contract or relax due to the calcium. By acting on the troponin complex, reldesemtiv is thought to lead to an increase in the capacity of skeletal muscles to contract, despite receiving reduced nerve signaling.
Reldesemtiv in clinical trials
Preclinical studies evaluated the effect of reldesemtiv on skeletal muscle function using two mouse models, one similar to SMA type 2, and the other to SMA types 3 and 4. Both mouse models had different levels of disease activity, measured by nerve dysfunction, muscle atrophy, and a decrease in maximum muscle force production. Results showed that treatment with reldesemtiv led to an increase in skeletal muscle force in response to nerve stimulation in both mouse models. They also showed that reldesemtiv had a calcium-sensitizing effect.
Reldesemtiv has been tested in healthy volunteers in five Phase 1 clinical trials, which assessed the safety, tolerability, bioavailability, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of the treatment. Results demonstrated that reldesemtiv was well-tolerated at single doses up to 4,000 mg.
The treatment also has been tested in people with SMA types 2, 3, or 4 in a Phase 2 clinical trial (NCT02644668) that enrolled 70 participants in the U.S. Patients were grouped according to whether or not they could walk. Participants received either ascending doses of reldesemtiv or a placebo twice a day for eight weeks.
The results of the trial, announced in June 2018, showed a statistically significant concentration-dependent increase from baseline in the six-minute walk test (6MWT), an exercise test of aerobic capacity and endurance. The study also showed statistically significant increases in maximal expiratory pressure (MEP), a measure of respiratory muscle strength. Adverse events were similar between patients receiving reldesemtiv and those receiving placebo. A sustained increase in both the 6MWT and MEP was observed four weeks after stopping reldesemtiv treatment.
Cytokinetics is preparing to conduct another Phase 1 trial in healthy volunteers to investigate whether the higher doses used in the Phase 2 trial result in higher levels of the medicine in the blood.
The U.S. Food and Drug Administration (FDA) granted reldesemtiv orphan drug status for the treatment of SMA in May 2017. In October 2018, Cytokinetics announced it would seek a type C regulatory interaction with the FDA for acceptability of the 6MWT as an endpoint for a potential registration program for reldesemtiv in patients with SMA. The FDA responded in June of 2019 that the 6MWT was an acceptable primary efficacy endpoint for registration. The agency recommended adding a more global functional scale such as the Hammersmith functional motor scale-expanded (HFMSE) as a secondary endpoint.
SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.