Tirasemtiv Fails in Phase 3; Side Effects Cited

Cytokinetics halted development of its muscle booster tirasemtiv as a treatment for ALS in November 2017 because the drug, according to a phase 3 clinical trial analysis, did not provide significant benefit to people with the disease. Principal investigator Jeremy Shefner of the Barrow Neurological Institute in Phoenix, Arizona presented the findings in December 2017 at the International Symposium on ALS/MND in Boston, Massachusetts.

“Tirasemtiv did not significantly affect the change from baseline in slow vital capacity at 24 weeks,” the primary endpoint, “or achieve any of its secondary endpoints,” Shefner concluded.

But there may still be a future in ALS for a drug that is more tolerable with the same mechanism of action according to Shefner. Cytokinetics’ CK-2127107 (CK-107), which is being developed in partnership with Astellas Pharma in Tokyo, Japan, also aims to keep muscles stronger longer by slowing the release of calcium from the troponin complex in fast skeletal muscle, increasing the force of contraction. But unlike tirasemtiv, CK-107 doesn’t cross the blood-brain barrier according to Cytokinetics, potentially avoiding many of these side effects (see August 2017 news).

At the International Symposium on ALS/MND, experts weighed in on this approach and its potential for people with ALS going forward.

Gathering Strength

 In 2012, researchers at Cytokinetics proposed that the fast skeletal muscle troponin activator (FSTA) tirasemtiv may be of benefit to people with ALS by increasing muscle strength and improving muscle performance (Russell et al., 2012). The team reported results of the phase 2b clinical trial, known as BENEFIT-ALS, in 2014. While it did not meet its primary endpoint of reducing functional decline (ALSFRS-R) in people with ALS, the rate of loss of their slow vital capacity (SVC) slowed by two-thirds versus placebo, “a potentially very significant clinical effect,” Shefner said.

Finding strength? Researchers at Cytokinetics in San Francisco, California are developing potential therapies for ALS known as fast skeletal muscle troponin activators (FSTAs), hoping to improve the performance of muscles in people with the disease. [Image: Muscle Contraction, OpenStax under a CC BY 4.0 license.]

The results suggested that tirasemtiv may be of benefit to people with ALS by helping them breathe better. Tolerability, however, especially from dizziness, was an issue, leading to a high dropout rate (Shefner et al., 2016). Nearly three times as many participants taking tirasemtiv dropped out compared to those taking placebo. 711 people with ALS participated in the 12-week study.

Hoping to overcome these challenges in the phase 3 clinical trial, investigators extended the run-in open-label period to 2 weeks prior to randomization to screen out those who could not tolerate tirasemtiv and allow others more time to acclimate to the drug. Dosing was also more flexible, with a maximum target dose of 250, 375 or 500 mg/day, allowing the amount of tirasemtiv to be adjusted at any time during the study.

The phase 3 randomized, double-blind, placebo-controlled clinical trial, known as VITALITY-ALS, launched in September 2015. The primary outcome measure was change in SVC at 24 weeks. Secondary endpoints, measured at 48 weeks, included muscle strength, breathing ability (respiratory subscores, ALSFRS-R), and function (ALSFRS-R). 743 people with ALS participated in the 54-week study.

Tolerability of tirasemtiv remained a key obstacle. One out of four participants taking tirasemtiv dropped out of the study by the end of the 2-week open-label period. Of the 566 who were then randomized, 34.2% of those receiving tirasemtiv stopped treatment before week 24, versus 12.2% of those receiving placebo. The most common side effects included dizziness, nausea, fatigue, trouble sleeping and weight loss.

Most participants taking tirasemtiv who dropped out discontinued the study relatively early and tended to be those on the highest dose, Shefner noted. Those who remained on tirasemtiv for at least eight weeks tolerated the drug reasonably well for the rest of the study.

Treatment with tirasemtiv resulted in no significant benefit. SVC in those taking tirasemtiv declined by 13.4% (-15.3%,-11.6%), while in those taking placebo it declined by 14.4% (-16.8%,-11.9%). The difference in the loss of SVC was just 0.92% (-2.13%, 3.96%).

The decline in SVC in the placebo group was less than in most placebo groups noted Shefner. “They did better than expected.” (See Andrews et al., 2017.)

No significant differences between participants taking tirasemtiv and placebo in any of the secondary outcomes were detected, including breathing ability (ALSFRS-R respiratory subscore), muscle strength, function (ALSFRS-R score), and survival time.

“Overall, this is a negative study,” Shefner concluded. “VITALITY-ALS didn’t meet its primary or secondary endpoints, in large part because of poor tolerability.”

Adriano Chiò of the University of Torino, Italy, agreed. “The drug has probably failed because of the side effects, but the mechanism seems to be a good one, and is something that should be followed.”

FSTA: The Next Generation

Cytokinetics is doing just that. Their next-generation FSTA, CK-107, is being tested at the phase 2 stage in people with ALS to determine if the drug can help muscles stay stronger longer, including those needed for breathing. The primary outcome measure is once again change in SVC.

The choice of the primary endpoint seems reasonable, said Chiò. The effect of tirasemtiv did seem to be dose-dependent, albeit not one that reached significance. And, SVC, according to Chiò, captures changes that are difficult to measure including function and quality of life.

The outcome measure is emerging as a potential alternative to track disease progression in ALS and is being increasingly used as an endpoint in clinical trials (see December 2017 news; Andrews et al., 2017).

Shefner agreed. “Even though in this trial there was not a significant effect on SVC, it was the measure that showed the biggest effect,” said Shefner. “If the drug is potent enough, and the side effects are low enough, I would expect to see other functional effects as well.”

Jonathan Glass of Emory University School of Medicine in Georgia, however, thinks it is too early to say whether this strategy could be of benefit to people with ALS. This trial “teaches us that we have to be very honest” about the interpretation of results from Phase 2 trials in which there appears to be some signs of benefit despite an overall negative outcome, he said. “Unfortunately we are too optimistic.”

Keep Out. Researchers at Cytokinetics, in collaboration with Astellas Pharma, are now developing a new muscle booster, CK-107, that is unable to cross the blood-brain barrier in hopes to improve tolerability. [Courtesy of Kim et al., 2008, Nature Reviews Microbiology.]

But researchers at Cytokinetics nevertheless remain hopeful that this muscle-boosting approach may be of benefit and therefore, drugs like tirasemtiv that may be better tolerated should still be pursued. “We believe the tolerability profile of tirasemtiv interferes with the demonstration of therapeutic activity,” said Daniel Wolff, Chief Medical Officer of Cytokinetics, during a conference call in early December.

Shefner agreed. “The adverse effects are almost all central nervous system events,” said Shefner, “and so we don’t expect to see those effects [with CK-107].” In addition, he noted, the drug is more potent than tirasemtiv and results in a larger increase in muscle performance, according to results in healthy volunteers (Andrews et al., 2017).

CK-107 is also being tested in Phase 2 clinical trials as a treatment for other disorders including spinal muscular atrophy.

“We are profoundly disappointed in the outcome,” said Shefner. “But there was a clear biological signal, and that still gives us hope for the next study.”


Russell AJ, Hartman JJ, Hinken AC, Muci AR, Kawas R, Driscoll L, Godinez G, Lee KH, Marquez D, Browne WF 4th, Chen MM, Clarke D, Collibee SE, Garard M, Hansen R, Jia Z, Lu PP, Rodriguez H, Saikali KG, Schaletzky J, Vijayakumar V, Albertus DL, Claflin DR, Morgans DJ, Morgan BP, Malik FI. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med. 2012 Feb 19;18(3):452-5. [PubMed].

Hansen R, Saikali KG, Chou W, Russell AJ, Chen MM, Vijayakumar V, Stoltz RR, Baudry S, Enoka RM, Morgans DJ, Wolff AA, Malik FI. Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve. 2014 Dec;50(6):925-31. [PubMed].

Shefner JM, Wolff AA, Meng L, Bian A, Lee J, Barragan D, Andrews JA; ; ON BEHALF OF THE BENEFIT-ALS STUDY GROUP. A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jul-Aug;17(5-6):426-35. [PubMed].

Andrews JA, Miller TM, Vijayakumar V, Stoltz R, James JK, Meng L, Wolff AA, Malik FI. CK-2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve. 2017 Nov 18. [PubMed].

Andrews JA, Meng L, Kulke SF, Rudnicki SA, Wolff AA, Bozik ME, Malik FI, Shefner JM. Association Between Decline in Slow Vital Capacity and Respiratory Insufficiency, Use of Assisted Ventilation, Tracheostomy, or Death in Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2018 Jan 1;75(1):58-64. [PubMed].

Further Reading

Hwang PM, Sykes BD. Targeting the sarcomere to correct muscle function. Nat Rev Drug Discov. 2015 May;14(5):313-28. [PubMed].

CK-107 clinical trial clinical trial design disease-als disease-sma muscle muscle strength SVC tirasemtiv topic-clinical topic-randd
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