Reldesemtiv (Formerly CK-2127107)

Reldesemtiv (formerly CK-2127107) is an investigational oral therapy developed by Cytokinetics for spinal muscular atrophy (SMA). A previous collaboration between Cytokinetics and Astellas to advance the development of reldesemtiv ended in late 2021.

The therapy is also being evaluated for amyotrophic lateral sclerosis, another progressive neuromuscular disease.

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 telling the muscles to contract become gradually weaker, reducing muscle force. Muscles contract when motor neuron-derived signals cause calcium to be released inside muscle cells.

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 are those that allow faster voluntary movement of short duration, and which 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 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 types 3 and 4 — reldesemtiv was shown to have a calcium-sensitizing effect and to increase skeletal muscle force in response to nerve stimulation.

As a muscle-directed therapy, reldesemtiv does not target SMA’s underlying cause — low to no levels of SMN, a key protein for motor neuron and muscle health — and is therefore meant to complement disease-modifying therapies (DMTs), which work by raising SMN levels.

A previous preclinical study supported that hypothesis by showing that adding the experimental therapy to SMN-raising therapies resulted in greater muscle function improvements compared with the individual therapies alone in a mouse model of SMA.

Reldesemtiv in clinical trials

The safety, tolerability, pharmacokinetics (the movement of a drug into, through, and out of the body), and pharmacodynamics (the effects of a drug on the body) of single and multiple ascending doses of reldesemtiv, given as an oral liquid, were assessed in five Phase 1 clinical trials involving more than 110 young and elderly volunteers who were healthy and did not have SMA.

Results showed that the therapy was generally well-tolerated at all doses up to 4,000 mg and that it effectively increased muscle response to nerve stimuli in a dose-dependent manner. Also, these effects were found to be superior to those previously reported for tirasemtiv, a first-generation FSTA.

These promising data prompted the launch of a hypothesis-generating Phase 2 trial (NCT02644668) that evaluated the therapy’s safety, pharmacokinetics, 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, had previously received Biogen’s Spinraza (nusinersen), the first approved DMT for SMA and the only 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 that treatment with reldesemtiv significantly improved patients’ aerobic capacity and endurance, as well as their respiratory muscle strength, compared with a placebo. Greater benefits were observed with the therapy’s higher dose and these improvements were sustained for at least one month after the last dose.

No significant changes were observed in other measures of motor skills, lung function, and muscle strength.

Adverse event rates were similar between patients receiving reldesemtiv and those on placebo, with the most frequent being headache, nausea, and fatigue.

Cytokinetics anticipates that future reldesemtiv trials will likely involve higher doses, longer treatment duration, and a greater number of patients, including those who are currently on or previously received a DMT approved for SMA.

Other details

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, as well as to provide long marketing exclusivity periods upon approval.

 

Last updated: Jan. 20, 2022, by Marta Figueiredo PhD

 


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