Cytokinetics, the maker of Tirasemtiv, announced that it has opened enrollment for its Phase III clinical trial, VITALITY-ALS, of their lead candidate ALS therapeutic using a novel endpoint, slow vital capacity (SVC). Earlier studies of Tirasemtiv suggested that a subgroup of people with ALS may have shown improvement in this specific measure of lung function. Since this is a Phase 3 study, it is at the “pivotal” phase of clinical development. Traditionally, after a compound reaches its endpoints in a Phase III clinical trial, a company will pursue approval from the FDA to market the compound as an effective treatment

What is Tirasemtiv?

Tirasemtiv (aka CK-2017357 or CK-357) is a chemical compound developed to enhance the signals between motor neurons and neuromuscular junctions (NMJ). As ALS progresses, the connection between motor neurons and NMJs deteriorates, causing a decrease of energy passing from one to the other to signal movement until the connection is eventually lost. As these connections go away in ALS, the muscle atrophies. The drug promises to make the most of weakening neuromuscular junctions by helping fast twitch fibers in skeletal muscles hold on to calcium, enabling more powerful contractions. These so-called fast skeletal muscles are needed in part, to maintain a healthy breathing rate. The compound has been formulated as a pill and is intended to be swallowed, not crushed.

What has occurred in the clinic previously?

Tirasemtiv was first introduced by Cytokinetics in 2008 and has been in several clinical research programs since, including a Phase II study which read out results in 2014. The Phase II study, called BENEFIT-ALS, enrolled 711 people at 75 different sites across 8 countries. In total, 473 PALS completed the Phase 2b study. The results of that study were complex, but in general, those who were on active compound did statistically significantly better according to a number of measures of breathing function and muscle strength when compared to those on placebo. Some adverse events such as nausea and weight loss were reported from those on the maximum dose of the drug.  However, researchers believe that the outcomes in the previous study provided evidence that tirasemtiv may have a “clinically meaningful impact” on PALS and are hoping to repeat and expand on those findings in the Phase 3 VITALITY-ALS clinical trial.

How is this trial designed and different?

A total of 445 PALS will be enrolled in this new study across 75 different sites in both North America and Europe. At the time of the publication of this article, there were 5 sites listed actively enrolling PALS into the trial, including 4 in the USA and 1 in Canada. As the other sites are announced and open, they will be added to the clinical trial listing on our website here. It is important to note that enrollment in this trial is limited to only PALS within 24 months of their disease onset.  Since the drug company is attempting to measure impact on breathing function with tirasemtiv alone, PALS who are using any form of breathing aide, such as a C-PAP, diaphragm pacer or ventilator will be excluded from the study.  Similarly, with little known longer effects, PALS who have previously participated in a stem cell treatment trial will not be invited to participate in VITALITY-ALS.

All PALS will be placed on the low-dose of the compound (250mg) for a two week lead in period and then be assigned to one of four arms: 250mg/day, 375mg/day, 500mg/day or placebo. Cytokinetics has designed the study to determine what effect the compound has on their primary endpoint, slow vital capacity (SVC), after 24 weeks of dosing, and they will determine efficacy on secondary endpoints (ALSFRS-R and muscles tests providing a “muscle mega score”) after the trial is completed after 48 weeks. This innovative clinical trial design will be hotly followed in ALS throughout this year and next.  Results from this study should be expected in early 2017.

Bottom Line:

The ALS Therapy Development Institute believes this an important clinical trial in ALS. Since this is a Phase 3 study, it is at the “pivotal” phase of clinical development. Should VITALITY-ALS reach its endpoints, it is common for the company to pursue approval from the FDA to begin to market the compound as an effective treatment. In addition to being at what is typically the final phase of clinical research, this study represents an important advancement in ALS research with the use of slow vital capacity as the primary endpoint. Most clinical trials in ALS have relied on the ALS Functional Rating Score (Revised) as the primary endpoint and the approval here by the FDA to use SVC instead marks a serious change in not just clinical trial philosophy but also clinical trial practice in ALS. 

Until this trial is completed, it is not known whether or not Tirasemtiv is an effective treatment for ALS. As with all in the ALS research community, the ALS Therapy Development Institute will eagerly watch this trial and anticipate its results.

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