Reldesemtiv (formerly CK-2127107) is an investigational therapy that may improve muscle function and physical performance in people with spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). It is being developed by Cytokinetics in collaboration with Astellas.

How reldesemtiv works

Reldesemtiv works by slowing the rate of calcium release from the regulatory troponin complex — a group of proteins that play an important role in muscle contraction. 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 to calcium. By acting on the troponin complex, reldesemtiv is thought to lead to an increase in the capacity of skeletal muscles to contract.

Reldesemtiv in clinical trials

Preclinical studies evaluated the effect of the therapy on skeletal muscle function using two mouse models, one similar to SMA type 2, and the other similar 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. The results also showed that reldesemtiv had a calcium-sensitizing effect.

Reldesemtiv has also been tested in healthy volunteers in 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 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 and received either ascending doses of reldesemtiv or a placebo twice a day for eight weeks.

Results of the study were announced in June 2018 and 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 on the placebo. A sustained increase in both the 6MWT and MEP was observed four weeks after stopping reldesemtiv treatment.

Other details

The U.S. Food and Drug Administration granted reldesemtiv orphan drug status for the treatment of SMA in May 2017. In October 2018, Cytokinetics announced it would be seeking a type C regulatory interaction with the FDA regarding the acceptability of the 6MWT as an endpoint for a potential registration program for reldesemtiv in patients with SMA.

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