People with amyotrophic lateral sclerosis (ALS) who tolerated higher doses of tirasemtiv showed a trend toward slower decline in breathing muscle activity, although the difference was not statistically significant between those treated with the investigational therapy and those on a placebo, a Phase 3 clinical trial shows.
These results may have been hampered by the fact that the investigational therapy at higher doses was not always well-tolerated by the participants, according to the researchers.
Although Cytokinetics suspended the development of tirasemtiv in late 2017 when this trial failed its primary and secondary objectives, the results still support the potential of a new generation of fast skeletal muscle troponin activators, such as Cytokinetics‘ reldesemtiv, now in development, they conclude.
Tirasemtiv, which was also being developed by Cytokinetics, was designed to activate a protein called troponin that is found in voluntary muscles. To contract, muscles receive calcium ions from nerve cells that bind to troponin. By making muscle cells more sensitive to calcium, tirasemtiv was intended to improve muscle strength in patients with ALS.
Trial findings were recently published in the study, “A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis,” in the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.
In the Phase 2b BENEFIT-ALS trial (NCT01709149), tirasemtiv, at a dose of 250 milligrams twice a day for 12 weeks, significantly slowed the decline of muscle strength and of slow vital capacity, a breathing test that reflects the strength of skeletal muscles used for breathing.
In the Phase 3 VITALITY-ALS trial (NCT02496767), researchers evaluated tirasemtiv treatment for an extended period of 48 weeks. The primary objective was change in percent predicted slow vital capacity from the start of the study to 24 weeks.
Before they were randomized to receive either tirasemtiv or a placebo, patients participated in a two-week open-label phase in which they received 125 milligrams of tirasemtiv twice a day. After successful completion of the open-label phase, patients were then randomized to receive either placebo or one of three daily doses of tirasemtiv (250 mg, 375 mg, or 500 mg) for 48 weeks.
Of 744 patients, 565 tolerated open-label tirasemtiv and proceeded to the randomized treatment — 188 received placebo and 377 had at least one dose of tirasemtiv. Most of the patients (74.5%) were taking Rilutek (riluzole), the first treatment approved by the U.S. Food and Drug Administration for ALS, at the start of the trial.
In total, 248 patients (65.8%) completed 24 weeks of treatment with tirasemtiv and 204 patients (54.1%) 48 weeks. In the placebo group, 165 patients (87.8%) completed 24 weeks of treatment, and 130 (70.2%) the 48 weeks.
After 24 weeks, 97 patients (77%) received 250 mg/day, followed by 60 (47.6%) and 39 patients (31.2%) in the 375 mg/day and 500 mg/day dose, respectively. This showed that treatment discontinuity increased with higher target doses.
Adverse effects including dizziness, fatigue, and nausea were the most common reason for discontinuing treatment and were more frequent in the tirasemtiv group.
Researchers found no significant differences in the decline of slow vital capacity between the placebo and tirasemtiv-treated groups — 14.4% versus 13.4%, respectively. Neither were any differences seen for additional trial goals, including respiratory subscales of the ALS Functional Rating Scale-Revised (ALSFRS-R) or the time to assisted ventilation.
They then analyzed the results by looking at patients who tolerated tirasemtiv at their randomized dose. This showed that patients who tolerated the highest daily dose of tirasemtiv (500 mg) showed a decline in slow vital capacity of 9.7%, while in the placebo group, it dropped by 14.2%. Although not statistically significant, this represents a 32% slower decline in slow vital capacity for patients treated with 500 mg daily of tirasemtiv.
“Although this phase III study failed to show a meaningful effect of tirasemtiv on slow vital capacity, subanalyses suggest that tirasemtiv had a biological effect on slow vital capacity such that fast skeletal muscle troponin activation remains worthy of further study,” the researchers wrote.
In fact, recent data from a Phase 2 trial has suggested that investigational reldesemtiv, Cytokinetics’ other fast skeletal muscle troponin activator still in development, reduces lung function decline and overall disease progression in ALS patients, without significant adverse events.