Reldesemtiv for SMA

Last updated Aug. 15, 2024, 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 that was being developed as a potential treatment to increase muscle strength in people with spinal muscular atrophy (SMA).

The therapy’s developer, Cytokinetics, was also investigating reldesemtiv as a potential treatment for amyotrophic lateral sclerosis (ALS), a neurological disorder that, like SMA, leads to symptoms including muscle weakness and wasting.

Although reldesemtiv showed promise in early clinical trials in both conditions, a Phase 3 study in people with ALS — which had hoped to show the treatment would improve functionality and muscle strength — was terminated early after analyses indicated that the experimental treatment was not providing any functional benefit for patients. 

Following these results, development was discontinued for both conditions.

How does reldesemtiv work?

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. As a muscle-directed therapy, reldesemtiv does not target SMA’s underlying cause — reduced production of the SMN protein — and is therefore intended to complement disease-modifying therapies (DMTs), which work by raising SMN levels.

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. The therapy has also been shown to further improve muscle function when added to SMN-targeting treatments such as Spinraza (nusinersen) in mouse models.

How was reldesemtiv administered?

In a clinical trial that tested the therapy in SMA, reldesemtiv was administered as an oral suspension at doses of 150 or 450 mg twice daily.

Reldesemtiv in 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 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. The patients included in the study varied in their mobility status: some could walk independently (ambulatory), while others were unable to walk without assistance (nonambulatory).

None of the patients, recruited at sites across North America, had previously received Biogen’s Spinraza, the only available DMT for SMA at the time. They were randomly assigned to receive one of two doses of an oral suspension 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 the clinical trial that tested the therapy in people with SMA, the most commonly reported side effects of reldesemtiv included:

• headache
• nausea
• fatigue
• constipation.

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