Reldesemtiv for amyotrophic lateral sclerosis

Last updated Nov. 6, 2023, by Inês Martins, PhD
Fact-checked by Patrícia Silva, PhD

What is reldesemtiv for ALS?

Reldesemtiv is an investigational oral treatment that has been tested in clinical trials for treating amyotrophic lateral sclerosis (ALS).

The therapy, developed by Cytokinetics, was granted orphan drug status in the U.S. and European Union, which were expected to accelerate its development and review for ALS.

The company decided to discontinue the clinical development of reldesemtiv, however, after interim data from a Phase 3 trial failed to demonstrate an improvement in clinical outcomes over a placebo.

Therapy snapshot

How does reldesemtiv work in ALS?

In ALS, the progressive loss of motor neurons — nerve cells that coordinate voluntary movement — causes muscle weakness and fatigue. This can result in problems with movement and breathing, and various other ALS symptoms.

Reldesemtiv is a second-generation fast skeletal muscle troponin activator developed to improve muscle function and delay muscle fatigue by amplifying responses to weak nerve impulses.

Skeletal muscles are those that are attached to bones that enable voluntary movement. They are complex structures made up of multiple muscle fibers, each containing long filaments of proteins called sarcomeres responsible for muscle contraction.

Sarcomeres are activated by calcium. Usually, the release of calcium is triggered by signals from the nervous system, which result in muscle contraction. Due to the loss of motor neurons, however, nerve signals are reduced in ALS, which limits the release of calcium and muscle function.

Reldesemtiv is intended to boost the activation of a calcium-sensitive sarcomere protein called troponin that plays an essential role in the contraction of fast skeletal muscle fibers. It was expected to increase muscle contraction despite reduced nerve signaling.

How was reldesemtiv administered in ALS?

Reldesemtiv is an oral medication available in the form of oral tablets. In ALS clinical trials, participants received the therapy twice a day at daily doses that ranged from 150 mg to 600 mg.

Reldesemtiv in ALS clinical trials

The safety and tolerability of redelsemtiv were first determined in three Phase 1 trials that tested it in 110 healthy volunteers. Across the trials, the treatment was deemed safe and well tolerated, and significantly increased the force of muscle contraction at doses ranging from 30 mg to 4,000 mg.

Based on those findings, Cytokinetics launched a Phase 2 clinical trial to test it in people with ALS.

FORTITUDE-ALS Phase 2 trial

The Phase 2b trial FORTITUTE-ALS (NCT03160898) enrolled 458 adult patients, diagnosed up to two years earlier, at dozens of sites in North America, Australia, and Europe.

Participants were randomly assigned to receive one or three doses of reldesemtiv (150 mg, 300 mg, or 450 mg), or a placebo, twice daily for 12 weeks. Across the groups, the tablets were taken every 12 hours and within two hours after a meal. Participants could continue on their standard ALS medications.

The trial’s main goal was to determine whether reldesemtiv could slow the decline in lung function, as assessed with changes in the percent predicted slow vital capacity, a measure of how much air a person can exhale from a full breath.

The trial failed to meet its primary goal. While all the doses of reldesemtiv resulted in slower declines in lung function over the 12 weeks, the differences failed to reach statistical significance.

Secondary measures of changes in the ability to perform daily functions, determined with the ALS Functional Rating Scale-Revised (ALSFRS-R), and muscle strength led to similar findings.

Nonetheless, a post hoc analysis, that is, one conducted after the trial was complete and all the data had been gathered, showed reldesemtiv significantly slowed functional decline on the ALSFRS-R scale in a group of patients with moderate to fast progressing ALS.

Similarly, a different analysis found that patients with a shorter disease duration — whose symptoms had started less that two years before enrollment — also saw significantly smaller declines in ALSFRS-R scores with reldesemtiv compared with a placebo.

COURAGE-ALS Phase 3 trial

Cytokinetics then launched the COURAGE-ALS Phase 3 trial (NCT04944784) to evaluate reldesemtiv in ALS patients with moderate to fast disease progression whose symptoms had begun within the past two years.

The trial enrolled about 460 participants who were randomly assigned to either 300 mg reldesemtiv twice a day or a placebo for 24 weeks (about six months). After that, all were to receive the twice-daily therapy for another 24 weeks. During the trial, patients could continue to receive Rilutek (riluzole) or Radicava (edaravone) as their standard ALS therapies.

After completing 48 weeks in COURAGE-ALS, the patients were invited to join an open-label extension called COURAGE OLE (NCT05442775) wherein all would continue to receive reldesemtiv for another 48 weeks.

The trial’s main goal was to determine changes in ALSFRS-R scores over the first six months. Secondary measures included changes in lung function, muscle strength, and quality of life, as well as a combined measure of changes in functional status, time to respiratory problems, and death.

However, an interim analysis, conducted after more than 200 patients completed 24 weeks of treatment, showed reldesemtiv wasn’t showing signs of benefits in any of these measures compared with a placebo — meaning it was unlikely to achieve its primary and secondary goals.

Based on the findings, the company decided to discontinue both COURAGE-ALS and its open-label extension, and to stop reldesemtiv’s clinical development program.

Common side effects of reldesemtiv

Safety data from reldesemtiv is only available from a Phase 2 clinical trial, wherein it was deemed well tolerated. The most common side effects reported in people who received reldesemtiv included:

• fatigue
• nausea
• constipation
• increases in cystatin C, suggestive of kidney problems
• increases in liver enzymes, indicative of liver damage.

ALS 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.