Phase 3 Trial Results of Tirasemtiv Show Potential of Similar Therapies for ALS, Researchers Say

Phase 3 Trial Results of Tirasemtiv Show Potential of Similar Therapies for ALS, Researchers Say

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 Cytokineticsreldesemtiv, 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.

Patricia holds a Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She has also served as a PhD student research assistant at the Department of Microbiology & Immunology, Columbia University, New York.
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Patricia holds a Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She has also served as a PhD student research assistant at the Department of Microbiology & Immunology, Columbia University, New York.
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6 comments

  1. MARYSE GAUTHIERDIGIROLAMO says:

    Hi,my husband been diagnostic april 2016 ALS but sadly he past away in Oct 26 2018
    he was on trial Tirasemtiv without Riluzole for the first two years
    no symptoms and took Riluzole too only the last 5 months of his life
    As his doctor said in his case tirasemtiv help him to live longer
    PleaseContinue the research to help other people in this terrible sickness

  2. Kenneth Mitchell says:

    I was on the reldesemtiv trial. My liver function enzymes and renal function markers were effected. I had lower GI symptoms. I noticed no improvement in speech and swallowing.

  3. Brian says:

    9.7% vs 14.2% decline in the 500mg group seems like a significant difference;32%. What is the cut off for deeming results Statistically significant? Didn’t Radicava get FDA approval with a similar differential?

  4. Mind of a Person with a will to survive
    Rising up back from a fall
    Did the tests, took my chances
    Went the distance, now I am mad
    Just a person with a will to survive
    Some many times someone dies without a cure
    You trade in your dreams for this dreaded disease
    Don’t lose your grip on hope and faith
    You must fight to stay alive
    Its the beast of ALS
    Its the thrill and disappointments in clinical trials
    People being denied and dying while in trials
    Rising up as warriors to challenge our enemy
    No one can tell how to survive
    ALS beast stalks its prey
    It shows no mercy
    ALS is watching us all
    With the eye of a dark monster
    Face to face, we conquer our fears
    Hanging tough, staying faithful
    ALS stacks the odds til we take to FDA
    To Protest long trials with skill of a survivor
    No More Excuses – Too Many Lost too soon

    youtube.com/c/ALSNEWSNOW Mike Henson June 12 and June 13 ALSA PROTEST

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