Eight weeks of treatment with investigational add-on oral therapy reldesemtiv safely improved motor and respiratory strength in adolescents and adults with spinal muscular atrophy (SMA), according to final data from a Phase 2, hypothesis-generating clinical trial.
These findings support further clinical testing of reldesemtiv, designed to aid skeletal muscle function, to confirm its therapeutic potential in these patients, the researchers noted.
The results, “Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study,” were published in the journal Neurotherapeutics.
Developed by Cytokinetics and Astellas, reldesemtiv is an orally available selective fast skeletal muscle troponin activator designed to improve muscle contraction by slowing the rate of calcium release from regulatory proteins (troponins) in skeletal muscle fibers.
By acting on the troponin complex, reldesemtiv is thought to increase in the capacity of skeletal muscles to contract, despite lesser nerve stimuli due the SMA-associated progressive loss of motor neurons. Motor neurons are the specialized nerve cells that control muscle movement.
Reldesemtiv does not target the underlying cause of SMA — a lack of SMN, a key protein for motor neuron and muscle health — and is therefore meant to complement SMA’s disease-modifying therapies (DMTs).
The therapy received orphan drug designation in both the U.S. and Europe as a potential SMA treatment. This status is meant to accelerate reldesemtiv’s development and review, as well as to provide long marketing exclusivity periods upon approval.
The Phase 2 placebo-controlled and hypothesis-generating trial (NCT02644668) evaluated the therapy’s safety and effectiveness in 70 adolescents and adults, ages 12 to 72, with SMA types 2 and 3, who had not been previously treated with Spinraza (nusinersen), the only DMT approved for SMA at the time.
Participants, recruited at sites across the U.S. and Canada, had a mean age of 29.4 years, with 20 (28.6%) of them being adolescents. Most were male (58.6%) and white (90%), and had type 3 SMA (91.4%); less than half (44.3%) retained the ability to walk.
Patients were grouped according to whether or not they could walk, and randomly assigned to an oral liquid of either 150 mg of reldesemtiv (24 patients), 450 mg of reldesemtiv (20 patients), or a placebo (26 patients), taken twice daily for eight weeks.
The trial’s main goal was to assess the therapy’s effects on eight validated outcome measures — assessing muscle strength, motor and respiratory function, and functional mobility. Secondary goals included its pharmacokinetics (the therapy’s movement into, through, and out of the body) and safety measures.
More than 92% of patients in the reldesemtiv and placebo groups completed the study.
Results showed that changes in outcomes measures from the study’s start to week eight “were not significantly different from placebo in either reldesemtiv dose group with the exception of the 6MWT [6-minute walk distance test] and MEP [maximum expiratory pressure],” the researchers wrote.
Of note, 6MWT measures the distance a patient can walk in six minutes, while MEP reflects expiratory (respiratory) muscle strength.
A dose-dependent effect was observed in 6MWT scores, with both reldesemtiv groups showing an increase during the study relative to the placebo group. This improvement was more pronounced in the high-dose group.
Better 6MWT scores were significantly different from placebo in the high-dose group at week 4 (a difference of 35.6 meters) and at four weeks after the last dose (30.8 meters). Improvements in 6MWT were also more frequent among reldesemtiv-treated patients than among those given a placebo.
Both reldesemtiv groups showed significantly greater improvements in expiratory muscle strength at the end of treatment compared with the placebo group.
In addition, older age appeared to be associated with greater increases in 6MWT, while lower MEP at study’s start was linked to greater MEP improvements. Highest peak blood levels of reldesemtiv also associated with statistically significant and clinically meaningful changes in both 6MWT and MEP.
Similar rates of adverse events were observed in reldesemtiv and placebo groups, with most being mild or moderate in severity. The most frequently reported side effects included headache (19.2% in the placebo group and 25% in the combined reldesemtiv groups), nausea (19.2% and 11.4%), and fatigue (15.4% and 9.1%).
Four serious adverse events were reported (two in each reldesemtiv dose group), but they were easily resolved and deemed unrelated to the therapy, the researchers wrote. Adverse events led to treatment discontinuation in two patients in the placebo group and one being given reldesemtiv at high dose, 450 mg.
“In this hypothesis-generating study, 6MWD and MEP improved versus placebo in patients with SMA receiving reldesemtiv, consistent with increased skeletal muscle force production by reldesemtiv,” the researchers wrote.
These positive findings, “in association with tolerability of the doses employed in this trial, support further clinical development of reldesemtiv for the potential treatment of patients with SMA,” they added.
Researchers anticipate that future reldesemtiv trials will likely involve longer treatment, higher doses, and a greater number of patients, including those who are currently using or were previously treated with a disease-relevant DMT.
Besides SMA, reldesemtiv is also being evaluated as a potential treatment for amyotrophic lateral sclerosis.
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