Friday, July 4, 2014

Tekmira Ebola Candidate Halted as Disease Spreads in Western Africa

There could not have been a worse timing for the Clinical Halt imposed on Tekmira’s RNAi candidate for the treatment of Ebola viral infection, TKM-EBOLA.  Just as the disease is reaching epidemic proportions in Western Africa (>500 dead), the world’s leading drug candidate for this infection with validation in the most stringent monkey models got stopped in its tracks following concerns by the US FDA regarding its immunostimulatory potential that was evidenced in the single-ascending dose part of the study (discussed here).

Efficacy in monkeys is the best you can hope for in the absence of an actual outbreak such as the current one, so I was hopeful that TKM-EBOLA could become part of the solution, especially by providing an incentive for patients to identify themselves and come to the treatment centers.  It is the prospect of dying surrounded by people in space suits instead of loved ones, and even worse the prospect of being infected by Ebola in the first place from fellow ‘inmates’ if you have been misdiagnosed that keeps people away from the hospitals.  This appears to have been key to the continued spread in addition to cultural practices such as kissing the dead as the WHO likes to emphasize (in my opinion, the condescending attitude by the behind-the-curve, out-of-touch WHO has been the 3rd key factor).

I suggest to mobilize the financial resources to fly in the latest medical equipment and offer patients to be treated with something that might help them survive.

Instead, immune-related side effects such as flu-like symptoms in healthy volunteers made the FDA ask Tekmira to provide additional data and explanations to justify proceeding to the multi-dose ascending part of the study conducted under the Animal Rule regulatory pathway.

In a way, this development might be considered support for those that have said that it is too early to treat patients with TKM-EBOLA, or any other experimental treatment for that matter.  On the other hand, you could also argue that this only shows that it is unethical to test it in human volunteers where the tolerance for side effects is much less than in somebody with a ~70% risk of dying from an infection otherwise.  Just look at the cancer drug development field, and at least in RNAi Therapeutics, I have never seen them tested in healthy volunteers even in phase I, but straight in cancer patients that have little to lose.

In fact, the immune stimulation could be the price to pay for a cure as it might be part of the mechanism of action of TKM-EBOLA either by shutting down viral protein translation and/or by interfering with the virally-induced cytokine storm itself.  These scientific issues, also as it relates to Tekmira’s platform in general, will be discussed in a follow-up post.

Test of Tekmira's credibility

I would like to close with some remarks on the credibility of Tekmira’s management.  

Management did in fact disclose the risk that there might be delays with the phase I study following results from the single-dose part of the study when it said there would be FDA review ahead of the multi-dose part of the study: 'Interim safety data submitted to the FDA for review May 7, 2014.'

Although this could be read as part of the normal regulatory process, the fact that they disclosed it made me believe that this was a real possibility.  The positive spin on the data obviously falls under the Safe Harbor of ‘forward-looking statements’ and no foul play here.  In fact, many biotechs would not even have disclosed the FDA review. 

On the other hand, many investors went along with the positive sentiments by management and will feel disappointed now.  In order to redeem themselves to this constituency, management will now have to prove that they were already prepared for this event and that they can speedily answer the questions and provide the requested data so that the trial may resume asap and that TKM-EBOLA may be offered to those in Western Africa now that it can be considered that the drug has been fully vetted for safety.


Anonymous said...

As always much appreciated that you continue to educate.. keep up the great work dirk.

Anonymous said...

A little while ago the CEO of BLT made a presentation to AZ selling their wares. In it, it was stated their ddRNAi technology was being used by Tekmira along with several others.
Now TKMR's Ebola program gets halted.
Not a good look for TKMR. Or BLT. Or any of the other companies named in the AZ presentation. And kind of rings the death knell for ddRNAi as a platform technology.
Wouldn't be surprised if the Calimmune trial meets the dame fate. Or the BLT HCV trial.
Which makes the recent TV appearance of the BLT CEO and his claims all the more bewildering.

Anonymous said...

Where does that leave ssRNAi? Maybe it really is "da bomb"
Dirk, I know you've spoken highly of ssRNAi previously, and of ISIS. Now you're saying TKMR is a no go except if you're long.
Does that mean ISIS is a buy in your opinion? Or ALNY because they're about to deal with ISIS and you're on their payroll.

Anonymous said...

Don't be so quick to write off BLT. They're in trials now and will be able to put Dirk's "no lab" issues to bed once n for all very soon.

I think previous poster is wrong about ISIS developing ssRNAi. That's what RGLS was set up for.

Wouldn't be surprised if BLT buys them out same way they did

Anonymous said...

Is RGLS the proprietary holder of ssRNAI? Sounds like that's what previous poster is saying.

Dirk, I'm sure you've said ssRNAi is proprietary to RGLS. Is this true?

If anyone will know it will be you.

Anonymous said...

Pardon me, but wasn't the study done in healthy patients? Therefore, there was no "virally induced" cytokine storm, but is due to the presence ofxenobiotic material. Then again, whether cytokine stimulation will have any good/bad effects remain to be seen. This was discussed in the 2010 article. And isn't the MOA of rnai fairly well understood? Does the immune system play a role? In rnai therapy? How much?

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