Cytokinetics ($CYTK)’s Phase 3 Drug Tirasemtiv’s Efficacy is Questionable

Cytokinetics [$CYTK] is putting their drug Tirasemtiv through Phase 3 trials. Tirasemtiv is a drug which hopes to treat ALS (also known as Lou Gehrig’s disease). The cause of ALS is still unknown – although genetics almost certainly play a role – and the majority of patients die of respiratory failure within two to four years. As such, there’s a huge clinical need for effective ALS treatments. Of course, if developing an effective treatment was easy, somebody would already have done it, right?

ALS is a neurological disease in which the parts of the nervous system that talk to the muscles begin to die. In most cases, the disease begins in the limbs, but inexorably spreads across the body – most patients eventually die once the nervous system is no longer able to tell the respiratory muscles to keep breathing. Tirasemtiv helps muscle fibers bind to calcium, which is how muscles receive signals from the body that tell them they should be contracting. CYTK hopes Tirasemtiv will help muscle fibers stay active and keep patients alive for longer.

Unfortunately, I am skeptical about whether CYTK will be able to pull that off.

Tirasemtiv’s Phase 2 Trial

In a phase 2 trial, CYTK tested Tirasemtiv’s ability to keep patients healthy. In a fairly well-controlled study, researchers tracked changes in ALSFRS-R scores (a measure of the severity of ALS) over 12 weeks. Unfortunately, at the end of the 12 weeks, the ALSFRS-R scores of patients on Tirasemtiv were no different than the scores of patients taking placebo.

However, CYTK decided that there was a significant difference in the predicted Slow Ventilation Capacity (more on that in a moment), which is a measure of lung function. Since we know that many patients eventually die of suffocation, CTYK felt that the change in slow ventilation capacity (SVC) function was worth investigating further. Accordingly, the ongoing Phase 3 trial of Tirasemtiv is using SVC as the primary endpoint.

A note for my statistically-minded readers – the measurement of SVC was a pre-specified endpoint in the phase 2 study. For everybody else, this is important because, basically, if you collect a bunch of data and start measuring everything after the fact, you will eventually find something that’s significantly different. Because the researchers at CYTK planned to measure SVC before beginning the study, we can avoid that type of error.

So, things seem okay so far, but I’ve found something that I consider to be important. When you look at all of the patients treated by Tirasemtiv, there’s a significant effect on SVC. However, when you look more closely, it turns out that only the healthiest half of patients saw a significant effect.  

SVC was only significantly effective for a subgroup of patients (taken from CYTK’s corporate presentation)

As you can see in the table above, Tirasemtiv was only effective in patients with a baseline SVC better than the median. However, the baseline SVC was quite high at the beginning of the study – 87.8% of normal. Since the minimum entry criteria was to have a SVC at least 50% of normal, that would mean that patients with SVC between 50 to ~85% (assuming the median and mean are close) saw no benefit from Tirasemtiv.

Median SVC was already quite high (taken from CYTK’s corporate presentation)

So even though the Phase 3 study for Tirasemtiv increased the baseline SVC requirement to 70%, there will still be a significant proportion of study participants for whom the drug doesn’t work.

Finally, we see that in every measure but one, Tirasemtiv did not beat the placebo.

Taken from Shefner et al., 2016


Data from Tirasemtiv’s Phase 3 study is expected in Q4 of 2017. As always, it’s entirely possible that I’m wrong. However, I think I’ve demonstrated fairly convincingly that if Tirasemtiv didn’t work on the primary endpoint, didn’t work on most of the secondary endpoints, and only worked on the healthiest subgroup patients for the secondary endpoint that CYTK is excited about, it’s probably not a safe investment.

Shorting a biotechnology stock is never a good idea. My recommendation is that you simply do not buy shares of $CYTK. If you already have them, the decision, I suppose, is up to you.

Prediction: Phase 3 Failure

Tirasemtiv simply has not demonstrated enough efficacy to make CYTK worth a buy.

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