Rare Disease Report

Will Tirasemtiv be Effective in ALS? A Conversation with Fady Malik of Cytokinetics

NOVEMBER 06, 2017
Jim Radke, PhD
On December 8 at the 28th International Symposium on ALS/MND in Boston, Cytokinetics will present the results of its phase 3 clinical trial testing the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis (ALS). The results will determine whether the drug will be ready for submission to the US Food and Drug Administration (FDA).

Tirasemtiv is a fast skeletal muscle troponin activator; a novel approach to improve muscle function in people who are progressively losing it. Results from previous phase 2 studies were mixed, but the company is hopeful that by focusing on the most appropriate outcome measure (respiratory function), the drug will exhibit its clinical value to ALS patients.

ALS is a degenerative neuromuscular disease in which motor neurons that control muscle activity progressively die. As the disease progresses, ALS patients lose the ability to walk, talk, and eat, among many other activities. The average life expectancy of an ALS patient is 3-5 years after being diagnosed. Death is typically the result of respiratory failure.
Recently, Rare Disease Report spoke with Fady Malik, M.D., Ph.D., head of research and development at Cytokinetics, about tirasemtiv and the phase 3 clinical trial.

Rare Disease Report: What is the mechanism of action in and target of tirasemtiv?

Dr. Malik: In ALS, the amount of nerve input into the muscle is declining over time, and that's a consequence of nerve fibers dying; nobody really understands why that occurs in this disease. We’ve developed a drug that targets the calcium sensor in muscle.

When a nerve activates a muscle, it causes calcium to be released from the inside the muscle, and that calcium is a signal to the sarcomere, which is really the motor or the engine in the muscle. That calcium is a signal for the engine to turn on and the muscles contract. Now, the sensor of that calcium signal is the protein called troponin and our potential therapy binds to troponin and makes it more sensitive to calcium. Our drug makes the engine more sensitive to the signal coming in and amplifies the effect of the nerves. So, a troponin activator ,which is what tirasemtiv is, then amplifies the nerve input that's coming in and causes the muscle to produce a greater effect.

RDR: Why is respiratory function the primary outcome measure in the phase 3 trial?

Dr. Malik: The most important of our skeletal muscles is the muscle that allows us to breathe – the diaphragm. And the nerve that goes to the diaphragm is the phrenic nerve. We're measuring breathing function by asking patients how much air can they breathe in and breathe out in a single breath. That's called vital capacity and it's called vital capacity because it is vital to the patient to be able to breathe adequately and to avoid needing mechanical support.

What we found in our earlier phase 2b trial with several hundred patients is that the decline in breathing function was slowed by tirasemtiv.

RDR: Can you summarize the earlier studies that led to the current phase 3 study?

Dr. Malik: The excitement around this phase 3 trial is that it builds on what we learned in our phase 1 and 2 programs.

The first step with this molecule was showing in healthy volunteers that the output of the nerve was amplified by the muscles and the muscle produced more force.

Then moving into ALS patients, we did a number of studies to understand how tirasemtiv behaved in patients with ALS. In the first study we asked the simple question ‘after taking this drug do you feel better, worse, or the same?’  Patients could tell you very clearly whether they could do more or less and then we also asked their physicians the same question. And there seemed to be an effect. Patients could tell that their function improved. We then moved into a longer and larger study to look at the effect over 12 weeks, in the phase 2 BENEFIT ALS study. And it was there that we saw for the first time that tirasemtiv preserved the function of a muscle, the diaphragm in this case, because we were measuring breathing function in that study.

Now, the primary endpoint of that s handwriting, swallowing, breathing, walking and so on. Even a single point on a 40-point scale has a large impact or loss of function for the patient. The trial failed on that endpoint but what we saw was a significant effect in the secondary endpoint, which was vital capacity. So, at the end of 12 weeks patients had their breathing function only declined by about a third compared to the placebo group. And that was consistent across all of the subgroups of patients we looked at. This was a very robust clinical effect.

So now we are testing that robust effect seen in the phase 2b study, in a phase 3 trial. And we also wanted to extend that finding. That is, can we show that tirasemtiv works longer than 12 weeks? In the phase 3 trial, we're measuring the endpoint at 24 weeks and we have also left the patients on drug for up to a year.

It's a very exciting moment for us and we hope the data will show a very robust and clinically meaningful effect for patients with ALS.

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