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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Portola, part 1: the new drug application for betrixaban

Two readers emailed in to point out that I misinterpreted the meaning of the net clinical benefit figure. As much as I hate being wrong, I hate misleading people even more  – so I’ve pulled the piece until I get a chance to take another look at the data.

A word of thanks for the readers who wrote in with their disagreements.


pSivida’s drug Durasert might be rejected by the FDA

pSivida [$PSDV on the NASDAQ] is conducting Phase 3 trials on a drug called Durasert. PSDV hopes that Durasert will prevent the recurrence of a disease called uveitis, which is inflammation of one of the parts of the eye. Although preliminary data from Durasert’s phase 3 trials suggests that it is effective at preventing the recurrence of uveitis, I think it’s possible that the FDA will reject the New Drug Application that PSDV sends in. The drug and delivery method that Durasert is based on has consistently been shown to increase the risk of cataracts.

Worrisome Safety Data

Whenever we talk about medications in the eyeball (which I’ve found myself doing a lot more than I expected when I started this site), there’s usually one overriding safety concern: intra-ocular pressure (IOP). Intra-ocular pressure is the pressure in the eyeball, and many medications increase it. Part of what made the Eyegate Pharmaceuticals trials so exciting is that their drug might actually decrease IOP, but pSivida isn’t so lucky. Their drug increases IOP significantly, although after an initial spike, IOP appears to be fairly stable – check out the following graph.

Phase 3 Durasert trial safety data
Durasert increases intra-ocular pressure, but pressure stabilizes after an initial spike

However, even if IOP isn’t a huge safety concern for Durasert, there’s something more ominous. At the beginning of the Phase 3 trial, 51% of the eyes had already had cataract surgery. Even so, by ~1 year into the study, 45% of the eyes treated with Durasert had to have cataract surgery, while about 10% of the control eyes had to have cataract surgery. Given that the phase 3 Durasert trials are supposed to go for about 3 years, I think it’s safe to assume that the majority of patients will have needed cataract surgery by the end of the study.

Phase 3 Durasert trials show cataract growth
50% of participants already had cataracts removed, but 45% have new cataracts

The cataract issue has been a recurring problem with PSDV’s drugs.

Cataract Issues in Previous Drugs from pSivida

Durasert is a slightly weakened dose of PSDV’s drug Iluvien (Durasert has 0.18g of the active compound, “fluocinolone acetonide,” while Iluvien has 0.19g). Iluvien was rejected three times by the FDA before finally receiving approval. Each time, the rejection came down to the same issue – taking Iluvien gave the patients increased risk of developing cataracts, with little improvement over the standard of care.

Retisert, yet another formulation of fluocinolone acetonide by PSDV, had the same issue – a study pitting Retisert against a different treatment found that 100% of the Retisert-treated eyes had cataract progression (versus 50% for the other treatment) and that eyes treated with Retisert were at 4.7 times more risk of cataract progression.


Durasert has absolutely shown efficacy, but I think that PSDV will struggle with the cataract issue.

Data from Phase 3 Durasert study
Durasert handily beats the placebo in preventing Uveitis recurrence. The question is: is it worth it?

Now, in fairness I should mention that cataract removal is a fairly easy procedure. Still, though, given how much Iluvien struggled, I am not confident in PSDV’s ability to get a Phase 3 pass on the first go-round.

Prediction: Phase 3 Pass on primary efficacy endpoints – but NDA rejection by the FDA

Durasert is effective, but gives patients cataracts. I can’t say whether the trade-off is worth it, but I can tell you that this company isn’t worth investing in.

Chimerix’ drug brincidofovir should be viewed with skepticism


Chimerix [$CMRX] is testing the drug brincidofovir on patients who have received allogenic hemopoeitic cell transplants (HCT). In English, “allogenic hemopoeitic cell transplants” means “bone marrow cell transplants from another person.” Specifically, CMRX is testing their drug on HCT patients who have adenovirus infections.

The adenovirus is the virus that causes the common cold, but in patients with HCT, the adenovirus can be incredibly deadly. Patients who have received cell transplants are almost invariably on drugs to suppress their immune system so that their bodies accept the transplant. What’s worse, just like there’s no treatment for the common cold, there’s no real treatment for adenovirus infections, especially for patients with HCT. Chimerix is hoping to change that with their new drug.

The Problems

With all that in mind, brincidofovir seems to be a promising drug candidate — at least on the surface. I have a lot of issues with the research they’ve done so far. For me, the quality of the research tends to be the number one determining factor when investing in a biotech. It’s more than just a data thing, it’s an integrity thing.

With that said, here are the issues I have with CMRX:

The current trial of brincidofovir doesn’t have any sort of placebo control, and I haven’t found a good explanation why that might be. Previous trials were controlled, and for what’s ostensibly a Phase 3 trial I don’t see what the rationale for not controlling the data could be.

Second, the researchers compared the survival rates from their trials to historical survival rates for HCT patients with adenovirus infections and found no difference. CMRX mentioned that they think this is because they deliberately tested high-risk patients. This might be true, but it’s impossible to tell. Along the same lines, in the Phase 2 study (which was placebo-controlled) there was no difference in the primary endpoints between patients treated with placebo and patients treated with brincidofovir.

These adenovirus trials are not the first time brincidofovir has been tested. The last set of trials were on a different virus in the same clinical population. As you can probably guess, those trials were unsuccessful.  In addition, in some of the previous research I looked through, I saw methods that I really didn’t like. Chimerix did some things that I would generally consider “sketchy:”

If patients discontinued the study drug to start treatment for CMV infection or for other reasons, but the plasma CMV DNA level was 200 copies per milliliter or less and CMV disease was not confirmed, treatment with CMX001 was considered to be successful.

-Phase 2 Trial of brincidofovir

To provide some context, brincidofovir was supposed to prevent patients from getting a disease called CMV. What the researchers are saying here is that if people dropped out of the study to treat CMV, they were counted as “success” cases. In a lot of CMRX’s trials so far, we’ve seen what looks like a really potent effect on keeping virus counts down — but the patients are dying anyway. After seeing this kind of crap, I was a lot less surprised.

The Good

Chimerix has plenty of cash on hand – at the current burn rate, they can go about 3 more years before they run into trouble. That should be enough to either get them to success or conclusively determine that brincidofovir is not a viable drug.

As I mentioned above, CMRX’s drug seems to be doing something. The difference in virus counts for patients treated with brincidofovir is indisputable. The issue, of course, is that CMRX has yet to keep people from dying.


Chimerix plans to release the full set of data from the adenovirus trial in the first half of this year. After the data dump, I think it’s very possible that the drug will continue on to a comparative trial. Not because the results are that promising, but rather because the need for a safe treatment is so dire. And to be frank, I think CMRX is a bit desperate.

This is one of the cases where I would love to be wrong, because the adenovirus is killing a huge number of HCT patients. I would love it if brincidofovir ended up becoming a miracle drug — but I can’t in good conscience recommend investing in it.

Prediction: Phase 3 Failure

There are just too many issues with the data for me to feel good about Brincidofovir or Chimerix. I do not recommend investing. 

Aeterna Zentaris


Aeterna Zentaris [$AEZS] is developing a drug called Zoptrex (zoptarelin doxorubicin). The phase 3 results for Zoptrex should be due by the end of December.

After doing some due diligence, we predict with high confidence that the phase 3 trial will fail to meet primary endpoints. If we are correct, it is likely that the company will not survive.

  • Phase 2 results for Zoptrex in endometrial cancer were weak, even with a softball study
  • Phase 1 data appears to show that Zoptrex might be less effective than the drug it is trying to replace
  • Zoptrex trials were not completed in 3 other types of cancer
  • Aeterna’s 2Q2016 financial statement admitted they do not have enough cash to continue another year of operations

The Drug

Zoptrex’s research history does not look great. Aeterna has two terminated clinical trials for Zoptrex, one for TNBC (a specific type of breast cancer) and one for urothelial (e.g. in the bladder/urethra) cancer. Both of these clinical trials were terminated for not being able to recruit enough participants. Even more importantly, a trial testing Zoptrex on prostate cancer was suspended because they didn’t have enough of the drug.

The clinical trial that has proceeded is for endometrial cancer. Currently, they’re running a phase 3 trial which is comparing Zoptrex (Aeterna’s drug), to the standard treatment, doxorubicin. The primary endpoint is overall survival, which is fairly common. You may have noticed that the standard treatment (doxorubicin) sounds a lot like the clinical name for Zoptrex (zoptarelin doxorubicin). That’s because Zoptrex is essentially the standard treatment paired with a compound that’s supposed to “aim” doxorubicin at the cancer cells more effectively.

Is it going to work?

Well, in the phase 1 trial, Aeterna tried a range of different doses: 10, 20, 40, 80, 160 and 267 mg/m2. The patients only responded to 160 and 267 mg/m2, and Aeterna was forced to continue with an effective dose of 267 mg/m2 for the phase 2 and phase 3 trials. This is bad because with chemotherapies, more is not better. More is worse, actually, because the side effects get worse and worse.

Here’s the clincher: 267 mg/m2 actually works out to be more doxorubicin than the standard dose of doxorubicin by itself. So much for aiming at the cancer cells more effectively.

This may be beating a dead horse, but in the phase 2 trial for Zoptrex, there were also several points of concern:

  • Only 23% of the patients enrolled in the trial had had prior chemotherapy or hormonal therapy, so we would expect good efficacy from this first-time treatment
  • 50% of the patients in the trial received a different drug (carboplatin/paclitaxel) while undergoing treatment with Zoptrex
  • Only 23% of patients responded to the drug, even though it was the first time they’d had chemotherapy

All of the above is fine for a phase 2 trial, which is typically about safety and demonstrating the beginnings of efficacy. However, with such weak efficacy results in both phase 1 and phase 2, we have serious doubts about the ability of Zoptrex to beat out the standard treatment during the phase 3 trial.


Financially, AEZS is hanging on by its fingertips. In June 2016, the financial statement admitted that they did not have enough cash to continue for another year of operations. This comes after several years of struggling — they have issued several rounds of fundraising, and in late November 2015 AEZS was forced to issue a press release titled “Aeterna affirms fundamental strength of business.” This press release followed on the heels of a 100:1 reverse split, in which outstanding shares were consolidated from some 656 million to 6.6 million. In October of that same year, AEZS closed their office in Quebec City.

In an effort to develop some cash flow, AEZS put together a sales team and developed a program in which they worked as sales consultants for other biopharma companies, but this program has been struggling as well — their sales commissions dropped by almost 50% in the second quarter of the program.

How to trade on this prediction

Finally, the important part! We never recommend shorting a biopharma stock because of a simple equation: the potential upside (if the stock goes to zero) is limited, while the potential downside (if the stock goes to $100, for instance) is unlimited. That’s a bad day.

Instead, if you’re bearish on $AEZS, we recommend that you use an options strategy which will cap your downside. The simplest way to do this would be to buy puts. If we’re wrong at the stock takes off, the worst possible outcome is that your puts become worthless. If you had shorted AEZS, though, you could be on the hook for many times your initial investment.

We can’t say it enough: Never open a position with unlimited downside.

The better bet? Buy some puts with a strike date in late December / early January, after the Phase 3 data is supposed to be released.


It’s never fun to predict that a drug or a company will fail. If Aeterna shuts down, lots of people will lose their jobs, and investors will lose a lot of money. Still, we’re here to make sure that you aren’t one of the people losing money.

Prediction: Phase 3 Failure



Anthera Pharmaceuticals

In June 2012, ANTH announced that their Phase 2B trials of the drug Blisibimod failed to meet the primary endpoints, though it demonstrated a “trend towards significance.”

The pre-specified primary efficacy endpoint, clinical improvement at 24 weeks in the SLE responder index for the pooled blisibimod dose groups, was not met due to a lack of clinical efficacy in the 100mg weekly and 200mg monthly dose groups

Despite the failure, however, they elected to continue with Phase 3 trials, using only severely affected patients.

“The extensive data in the target severe population from our Phase 2 clinical program supports the initiation of a much smaller yet differentiated Phase 3 registration plan with the selected dose of blisibimod in patients with severe systemic lupus erythematosus.  We have prospectively demonstrated for the first time the possibility for a subcutaneously administered BAFF inhibitor to be used in the treatment of a severe lupus population.  The subgroup of severe patients from our Phase 2 study clearly identifies those patients most in need of therapy and most likely to benefit from our potent BAFF inhibitor blisibimod,” said Paul F. Truex, Anthera’s President and Chief Executive Officer. “Feedback from the EMA Scientific Advice process combined with an End of Phase 2 meeting in the third quarter will form the basis of our final phase 3 study designs.”

The data from this Phase 3 trial is due in Q4 of 2016.

I believe that Anthera moved to Phase 3 despite a lack of efficacy because the drug, Blisimibimod, is one of only two in their pipeline and that if the drug fails, the company crumbles with it. In the Phase 2B results, even the targeted subgroup (which they used for the Phase 3 trials) did not see a statistically significant effect from the drug.

To cap it all off, in the last 12 months, insiders have made 1 open market buy and 4 sales.

I do not recommend that you short this stock. Shorting a binary event leaves you open to catastrophic failure. Instead, purchase put options, which not only leverages your investment but also puts a cap on the total amount you can lose.

Prediction: Phase 3 Failure

Disclaimer: I hold puts on ANTH.