Last updated Nov. 15, 2022, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD
What is reldesemtiv for SMA?
Reldesemtiv (formerly CK-2127107) is an investigational oral therapy designed to increase muscle strength that Cytokinetics is developing as a potential treatment for spinal muscular atrophy (SMA). As a muscle-directed therapy, reldesemtiv doesn’t target SMA’s underlying cause — reduced production of the SMN protein — and is therefore meant to complement disease-modifying therapies (DMTs), which work by raising SMN levels.
Cytokinetics is also evaluating reldesemtiv as a treatment for amyotrophic lateral sclerosis, another progressive neuromuscular disease.
Reldesemtiv received orphan drug designation in both the U.S. and European Union for SMA. This status is meant to accelerate the therapy’s development and regulatory review, and provide long marketing exclusivity periods upon approval.
A previous collaboration between Cytokinetics and Astellas to advance the development of reldesemtiv ended in late 2021.
How does reldesemtiv work in SMA?
SMA is characterized by muscle weakness and wasting due to the progressive death of motor neurons, the specialized nerve cells that control voluntary movement. As motor neurons die, the signals they send that tell muscles to contract become weaker, ultimately reducing the force of muscle contractions.
When a muscle cell contracts, the biomechanical process is driven by a release of calcium inside the muscle cell. Reldesemtiv is an orally available, second-generation fast skeletal muscle troponin activator (FSTA) that works by selectively slowing the rate of calcium release from a protein complex called the troponin complex in fast-twitch muscle fibers. Fast-twitch muscle fibers allow faster voluntary movement of short duration and are more susceptible to damage in SMA.
By increasing calcium sensitivity in these muscle fibers, the therapy is designed to boost their capacity to contract, despite receiving weaker nerve stimuli due to the SMA-associated progressive loss of motor neurons.
In two mouse models of SMA — one similar to type 2 disease, and the other to the milder type 3 and type 4 — reldesemtiv was shown to have a calcium-sensitizing effect and to increase skeletal muscle force in response to nerve stimulation. It’s also been shown to further improve muscle function when added to SMN-targeting treatments such as Spinraza (nusinersen) in mouse models.
How will reldesemtiv be administered in SMA?
In a clinical trial testing the therapy in SMA, reldesemtiv was administered as an oral liquid at doses of 150 or 450 mg twice daily.
Reldesemtiv in SMA clinical trials
Multiple studies that included more than 100 healthy volunteers showed reldesemtiv was generally well tolerated at doses up to 4,000 mg and effectively increased muscle response to nerve stimuli in a dose-dependent manner.
These promising data prompted the launch of a hypothesis-generating Phase 2 trial (NCT02644668) that evaluated the therapy’s safety, pharmacokinetics (the movement of a compound into, through, and out of the body), and effectiveness against a placebo in 70 people, ages 12 to 72, with SMA types 2, 3, or 4.
None of the patients, recruited at sites across North America, previously received Biogen’s Spinraza (nusinersen), the first approved DMT for SMA and the only one available at the time. They were randomly assigned to receive an oral liquid of either one of two doses of reldesemtiv (150 or 450 mg) or a placebo, taken twice daily for eight weeks (about two months).
Results showed reldesemtiv led to significant increases in the distance that ambulatory participants could walk in six minutes, a common measure of muscle endurance. Measures of the strength of muscles used to breathe also showed significant improvements after eight weeks on reldesemtiv.
Greater benefits in these scores were observed with the therapy’s higher dose and the improvements were sustained for at least one month after the last dose. Other assessed measures of motor skills, lung function, and muscle strength did not show statistically significant changes.
Common side effects of reldesemtiv
In a clinical trial that tested the therapy in people with SMA, the most commonly reported side effects of reldesemtiv were:
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