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.

As Ebola Spreads Fear in Western Africa, Pressure Mounts to Deploy RNAi Antiviral

A day or so following reassurances by the Guinean authorities that the Ebola virus outbreak had been contained and was under control, news is making the rounds of confirmed lethal cases in Conakry, the 2 million capital city of the country, and in neighboring countries in Western Africa.  With the death toll rising, the disease spreading internationally, and the virus paralyzing affected areas, pressure is mounting to call in an RNAi Therapeutic which has proven to be effective in the most stringent efficacy models possible.  66 are thought to have died from the disease by now, at least 4 of which are healthcare workers.

The therapeutic, developed by Tekmira Pharmaceuticals and funded by a $140M contract from the US Department of Defense, has shown 100% post-exposure survival in monkeys infected with the otherwise highly (90%) lethal Zaire strain of the virus.  This is the same virus ravaging through Western Africa right now.  Because of this, the Ebola therapeutic which targets two viral sequences simultaneously and which entered phase I in-man studies earlier this year, there is a very high likelihood that TKM-Ebola will be applicable in this situation.

Only days ago, TKM-Ebola was bestowed fast-track status by the FDA.

Under normal circumstances, licensure of TKM-Ebola would follow the Animal Rule.  According to the Animal Rule, treatments for diseases for which it is either impractical or unethical to conduct efficacy studies, can be approved by the US FDA if sufficient efficacy can be demonstrated in stringent animal models (monkeys here) and human safety at corresponding dose levels.  Ebola obviously is a candidate for the Animal Rule since experimental infections of humans cannot be done ethically and natural outbreaks are so rare and unpredictable.

Following the demonstrations of animal efficacy, the ongoing single- and multi-dose ascending phase I in-man study for which the single-dose phase appears to have already concluded is designed to confirm such safety.  To make sure that the findings are robust, this is typically followed by larger animal efficacy and human safety studies.  At this point (~2016/7), the FDA would make its decision regarding licensure which would lead to stockpiling orders from the US government for preparedness against bioterrorist attacks.

Arguments for deployment of TKM-Ebola in Western Africa

Although TKM-Ebola has not completed the formal requirements under the Animal Rule, it is fair to assume that TKM-Ebola, the most advanced Ebola anti-viral in development, will do more good than harm in a disease without alternatives besides supportive care.  With a lethality of 80-90%, I would certainly take my chances.

A deployment would serve at least two purposes.  Firstly, it would give us a chance to confirm the effectiveness of the RNAi Therapeutic in actual humans.  In addition to the scientific value, if I were the US government, I would be eager to take advantage of the unique opportunity at testing efficacy before spending billions on an agent for which there is only theoretical human efficacy.

Secondly, having TKM-Ebola as a standby in hospitals would help restore some calm and confidence, especially among the healthcare workers which need to contain the outbreak.  It is also most likely that from a logistics point-of-view, this is the population where TKM-Ebola would be most effective as it is here where the disease can be detected and drug administered early enough for the treatment to be effective (within 2 to 3 days following exposure).

In order for TKM-Ebola to have maximal impact, manufacturing would have to be scaled up (I estimate ~2 months for the production of large lots) and the logistics around diagnostics and treatment administration put in place.  Nobody knows whether the current outbreak will spread further, but it is better to be prepared in case it does.  As the suspected Canadian case this week illustrated, Ebola is now just a plane ride away from us. 

Watch out for the April 1 presentation by Dr. Ian MacLachlan from Tekmira on the latest data for TKM-Ebola which will be in front of a sell-out crowd at the FILO 2014 conference in Galveston, Texas.