Developing Aerosolized TKM-EBOLA as Airborne Transmission of Ebola Likely

Knowing how a virus is spread, also from a cell biology point-of-view, is critical to curtailing its spread and devising effective treatment strategies.   

According to the World Health Organization (WHO), the first symptoms of an Ebola infection are ‘the sudden onset of fever fatigue, muscle pain, headache and sore throat’ (emphasis mine). Then also consider the following:

1)      Ebola once killed a number of monkeys are apparently spreading through the ventilation system in Reston, VA; 

2)      A nurse became infected in a reference hospital for infectious diseases in Spain despite the protective clothing she was wearing and her limited contacts with the infected patients she was looking after (taking temperatures twice);

3)      A single pregnant woman in Liberia infected atleast 10 people helping her as she came down with Ebola;

4)      Ebola virus can infect numerous cell types in the body (frequently cited are the liver, endothelial cells, and phagocytic cells) and is found in high amounts inthe respiratory tract in infected pigs with the virus spreading readily to cohabiting pigs in the colony;

If you still believe in the narrative, even propagated byotherwise fairly reliable sources such as the CDC, that Ebola is only transmitted by direct contact with body fluids, then you should start considering airborne transmission as a main route the infection is spread.

After all, since when are cough droplets not a bodily fluid?

If airborne is indeed an important route of transmission, this would not only raise concerns that just like in avian flu, a few mutations in the virus adapting it to better latch on to the human respiratory tract could further catalyze the spread of the virus, but would also mean that treating it at the respiratory stage could both prevent the virus from fully entering the body as well as limit its spread from person-to-person.

Enter TKM-EBOLA

An RNAi viral knockdown approach in the respiratory epithelium should obviously be able to achieve that goal.  All that would be required is to take the same RNAi triggers now part of the intravenous TKM-EBOLA formulation and incorporate it in something amenable for respiratory delivery.

Back in 2011, Tekmira revealed that it was developing aerosolized liposomal nanoparticles (LNPs) to deliver RNAi triggers to the respiratory epithelium.  A key challenge was to find formulations that not only could successfully transfect respiratory epithelial cells, but also withstand the shear forces involved in nebulizing them.  Initial structural and tissue culture RNAi knockdown results showed that this can be achieved.

The development was seemingly halted at the rodent preclinical stage as the company had to save financial resources as it was fighting off Alnylam in a trade secret case.  After coming out on top of the litigation in November 2012, the company was then able to once again expand the development of its LNP-based nucleic acid delivery technology, in addition to churning out clinical development candidates (e.g. the important HBV candidate to be revealed next week).

 

Given that the company established a separate biodefense unit headed by the ‘LNP-brain’ of the company, now Chief-Technology-Officer Ian MacLachlan, I would not be surprised if LNP nebulization was part of that effort with the next goal of showing efficacy in monkeys.

Such reformulation of TKM-EBOLA is just another example of the versatility of RNA Therapeutics, just as is the ability to rapidly adjust and optimize the medicine as the virus evolves (note: this is e.g. not possible with antibodies).  It also adds to the importance of scaling up the supply of the RNAi trigger now should airborne be recognized as a major route of transmission.  

Long-term, such developments would obviously benefit the development of LNP-delivered RNA Therapeutics for the lung epithelium in general, including mRNA delivery (e.g. for Cystic Fibrosis) and a universal RNAi agent against flu.   

Ebola Emergency Tests Oligo Manufacturing Readiness

With officials scrambling to put in place measures to contain the further spread of Ebola, it is highly likely that RNAi Therapeutic TKM-EBOLA will be on their shopping list.  This, however, requires the ability to manufacture the oligonucleotide-based medicine in quantities sufficient to treat at least 10 thousand or so either infected or potentially infected persons.  In the absence of commercial Oligonucleotide Therapeutics success stories this could prove to be a challenge, although in this case, I believe it's doable.

Manufacturing, an advantage of TKM-EBOLA over PMOs and antibodies

When the US Department of Defense selected TKM-EBOLA as its preferred Ebola development project a few years ago, manufacturing, and not just efficacy and safety should have been part of the equation.  The reason is that e.g. currently about 0.3mg/kg*70kg/day*7 days= i.e. approx. 140mg of TKM-EBOLA RNA oligonucleotide is required per treatment course.  Since its simple chemistry (a couple of spiked-in standardd 2’-O-methyls in an otherwise unmodified RNA) makes it one of the cheapest RNA oligonucleotides conceivable, let’s ballpark its manufacturing cost at $300 per treatment course at some of the largest possible manufacturing scales possible today (kilograms).  Note that the cost of the lipids in TKM-EBOLA is negligible compared to the oligo component.

1.4kg oligo and $3 million for 10,000 treatment courses.

Taking into account that these are the pure manufacturing costs when protocols have been established, and other monies will have to be spent when starting from sequence design---let’s say conservatively $5 million. I believe given the gravity of the current situation, this is a number we can live with (1/200 of investment in the response).

If you do the same Gedankenspiel for Sarepta’s Ebola therapeutic morpholino antisense candidate, you have to multiply the $3M number first by a factor of 30 for the much larger amount of oligonucleotide required and then by another factor of 6 or so for the greatly increased costs of making morpholinos over standard RNAà $500M+.  A non-starter not just for the increased costs, but also because the manufacturing capacities for that amount of oligonucleotides are not readily available today, let alone for the morpholino chemistry where Sarepta has experienced significant delays in obtaining sufficient oligo supplies for a relatively small (~100 patients on drug at 30mg/kg/week for 48 weeks) phase III program in an orphan diseases indication (DMD).

When we move to Tekmira’s antibody competition, in particular ZMapp, the situation is not all that different from Sarepta’s with the slight advantage that ZMapp could somewhat tap into the established know-how of monoclonal antibody production.  But in the end, we’d be talking about years of process development and scale-up compared to a few months TKM-EBOLA.

Wake-up call for oligonucleotide manufacturing

Although TKM-EBOLA should be within current oligonucleotide manufacturing capacities, the Ebola situation should get oligonucleotide manufacturers wondering whether they are ready for the upcoming surge in Oligonucleotide Therapeutics approvals and sales.  Following years of disappointment about the lack of big manufacturing requests, CMOs have been loath to build the plants that can churn out hundreds of kilos or even tons of oligonucleotides.

Consequently, I attribute the decisions of first ISIS and Sanofi/Genzyme, then Alnylam (for GalNAc conjugates), and more recently also Sarepta, to shift oligonucleotide manufacturing in-house, to this lack of outside manufacturing capacity.  While having manufacturing in-house may sound attractive for a number of reasons, spreading manufacturing risk across multiple vendors is an accepted risk reduction strategy in this and other industries. 

I am therefore hopeful that the ongoing Ebola outbreak will end up increasing oligonucleotide therapeutics manufacturing capacities to rule out a situation that manufacturing constraints could limit commercialization of agents like ISIS-ApoCIIIRx or the HBV agents with potentially very large patient populations. 

TKM-EBOLA Making RNAi History

Today, Tekmira disclosed that an acceptable regulatory pathway has been found with US and Canadian regulators to use its RNAi Therapeutic against Ebola infection, TKM-EBOLA, in the current outbreak.  In fact, the company added that 'TKM-Ebola, has been administered to patients on an emergency basis and the repeat infusions have been well-tolerated'.

While not going into specifics, it is more or less a confirmation that Dr Sacra who was said to have received multiple courses of a treatment was indeed treated with TKM-EBOLA (he seems to have pulled through).  Further substantiating that suspicion was a comment by a relative that subsequent administrations of the experimental drug were better tolerated:

'He also tolerated the research drug well – better than he had the previous doses he was given.”'

This is consistent with infusion reactions of many intravenously administered drugs being a particular problem during the first administration only.

Then there was another report that a number of suspected, early cases had been evacuated from Western Africa to the US with the intention of giving them experimental treatments.  This, in fact, would be the ideal setting for using TKM-EBOLA, or for that matter most other experimental treatments against Ebola.  It should be remembered that while in the preclinical monkey studies, the efficacy of TKM-EBOLA started to wane if treatment was delayed for more than 3 days following infection of the animal, this experimental setting is more akin to a needle stick accident in the lab given the large amount of virus involved in the innoculum.

By contrast, in the current outbreak in Western Africa, not every contact obviously leads to a successful transmission of the virus, a reflection of the fact that the starting viral population will be much less compared to the experimental setting.  This means that it would take the virus more than 3 days to overwhelm the capacity of TKM-EBOLA and the immune system to stall the infection in its tracks.  Hopefully, Tekmira is conducting analogous innoculum-window-of-opportunity studies in monkeys to get a better sense of how much treatment can be delayed when infectious doses are quite low.

With this in mind, I am more or less convinced that RNAi Therapeutics is saving patient lives for the first time.  I personally would risk an anaphylactic shock in a closely supervised clinical setting any day over the prospect of not getting specific treatment when infected with Ebola. #RNAiHistory

FDA Greenlights Use of TKM-EBOLA in Current Outbreak

Canadian drug developer Tekmira just disclosed that the FDA verbally notified them that it would partially lift the clinical hold it had placed on TKM-EBOLA a month ago.  The clinical hold had been instituted as the result of cytokine elevations that had been observed in a healthy volunteer study of the drug.

By partially lifting the clinical hold, the FDA ‘blesses’ the use of TKM-EBOLA in actually infected patients whose odds otherwise would be to die from the infection.  Since the FDA only has authority over health matters in the US, this is strictly only of relevance for the use in people infected with Ebola either brought back from Africa for treatment just as the two US aid workers, or in case the virus started to crop up in the US. 

I am, however, inclined to interpret the news that the FDA is encouraging Tekmira to consider the use of TKM-EBOLA in Western Africa at the epicenter of the epidemic.   You could imagine that if anything went wrong with the use of TKM-EBOLA, it might have had adverse consequences for the future clinical development of the drug candidate in the US.

Overall, I am pleased with this development as the clinical hold in light of the current health emergency was just unbearable. How to handle the practicalities of using TKM-EBOLA in the field, including who will bear the costs, we will have to see.  Remember, financially, it is Tekmira's HBV candidate that has priority over TKM-EBOLA and so I expect TKM-EBOLA to be part of a broader effort funded by the public health bodies.

What TKM-Ebola Could Achieve in the Current Outbreak

(please read financial conflict at the end)

We are in the midst of the largest recorded outbreak of Ebola hemorrhagic fever virus ever and there is little evidence that its spread is being contained.   Here, I will make the case how TKM-Ebola, the most advanced Ebola therapeutic in clinical development, could help in avoiding ever more damage from the deadly virus.

How TKM-Ebola could help

1.       Give suspected cases an incentive to go to the treatment centers.

2.       Provide medical personnel with a stand-by and therefore help in their recruitment.

The continued spread of Ebola can be partly attributed to a breakdown in confidence in the authorities and fear by medical personnel. 

I have been viciously attacking the World Health Organization (WHO) that by downplaying the significance of the outbreak it has been a key factor in re-igniting viral spread.  It is the WHO who have tried to minimize the true numbers of infected, possibly in cahoots with local authorities, and laughed off the suggestion that the virus could get on a plane in arguing against any kind of travel restrictions.  Of course, it recently did and I am still waiting to see top WHO officials send their families on a vacation to Western Africa.  But probably the most outrageous insult was in suggesting that the spread of the virus is explained by ‘funny’ cultural practices in these countries such as kissing the dead during burials.

The WHO, probably in the comfort of their headquarters in Geneva, even attacked on-the-ground Medecins Sans Frontieres as alarmist for calling the outbreak ‘unprecedented’ in late March.

This notion that the virus is very bad in spreading from person-to-person and can only do so with the help of obscure practices is obviously wrong given that more than 100 medical personnel have become infected. While I am still waiting for an explanation by the WHO of how this could happen, I refuse to believe that they kissed the dead in the treatment centers or licked any other of their body fluids for that matter.  Has the WHO (and others) maybe considered the unthinkable, namely that the reason why this is the biggest ever spread of the virus is because the virus has mutated and new routes of infections are possible, such as by aerosol?  The US military will have its reason to believe that this could happen, otherwise why would they be so concerned about it being weaponized and spending hundreds of million dollars on the development and stockpile of an Ebola therapeutic such as TKM-Ebola?

And if people that protect themselves with space-suits get infected, how would you feel as a suspected case of Ebola? 

I know I would do anything NOT to go to these treatment centers, because what is obviously for the good of the overall population would only exponentially increase my risk of contracting the infection in case I was one of those wrongly suspected to have Ebola.

In my opinion, providing individual isolation wards with the best medical equipment possible, a dignified environment, and a drug as an option for the patient could make the difference in whether suspected cases will turn themselves in or not.  The argument that ‘this is Africa’ and you cannot expect good medical care there should not count in this day and age when equipment can easily be shipped between continents.  It’s probably far cheaper to do it now than further risking for the virus to go global (obviously, the WHO thinks this is impossible).

And for medical personnel, the benefit of making TKM-Ebola available is obvious and most tangible: since the onset of flu-like symptoms in this population is highly likely to be due to Ebola and because they have ready access to the necessary equipment such as infusion apparatus, they could be treated immediately with the agent.  Treating as soon as possible is thought to be critical for TKM-Ebola to be efficacious.

What is TKM-Ebola?

TKM-Ebola is an intravenously infused RNAi Therapeutic that has been demonstrated to save the lives of monkeys infected with an otherwise fatal dose of Ebola.  It is being developed under the ‘Animal Rule’ in efforts funded by the US government which is afraid that this virus could be weaponized and used as a bioterror agent.  The ‘Animal Rule’ is a development pathway instituted by the US FDA for diseases such as Ebola for which it would either be impractical or unethical to conduct efficacy studies in humans. 

Because natural outbreaks are unpredictable and experimentally infecting volunteers with the virus out of the question, these monkey studies are as good as it gets regarding drug efficacy (so much for the mantra that there are ‘no drugs for Ebola’).

An important second element of the Animal Rule is that human volunteer studies demonstrate acceptable safety at the doses corresponding to the efficacious dose in monkeys.  For this reason, pivotal phase I safety studies have begun this year in healthy volunteers (so much for the notion that licensed Ebola drugs are far off- ‘phase I’ is misleading).

Clinical Hold

Unfortunately, in the midst of the outbreak, the FDA instituted a Clinical Hold on the TKM-Ebola safety study because a case of dangerously high cytokine elevations was observed at the highest dose planned in this dose-escalating/dose-finding study (0.5mg/kg).  I agree that this is to be considered a serious adverse event in a volunteer that is not infected with the virus.

The reason for the cytokine stimulation is likely due to TLR-mediated, lipid-amplified innate immune stimulation, a known risk of liposomal RNAi delivery, especially at doses of 0.5mg/kg and higher.  It is also the reason why all other active development candidates by Tekmira and their licensee Alnylam are conducted in the presence of transient immune suppression with steroids and the like which in many cases is acceptable given the severe diseases these treatments go after.

As indicated, the adverse event at 0.5mg/kg should by no means spell the end of TKM-Ebola.  Firstly, the company argues that the pharmacologic corresponding dose to those curing the monkeys is lower than 0.5mg/kg.  Secondly, a side effect that is not tolerable in healthy volunteers (usually ~20-year old male students) could be well tolerated in subjects with a 70-90% likelihood of dying from a disease in a matter of days.  It is ethically more troubling to involve healthy volunteers in such drug development just as aggressive experimental cancer drugs are hardly ever tested in healthy volunteers.  Lastly, there may be ways to avoid the side effect altogether, such as by using transient immune suppression.  However, I do not know whether transient immune suppression is possible for Ebola, but I expect Tekmira will have the answer for this from their large-scale animal experience.

Next steps

For TKM-Ebola to have the best impact on the current epidemic, the first step would be to start manufacturing it at scales sufficient to treat at least ~1000-5000 patients.  This takes time and given the uncertainty around the future course of the epidemic, the investment needs to be made now instead of waiting until it is too late for a treatment center-focused approached involving an intravenously infused agent.

The next step depends on the feasibility of steroid pre-treatment during an Ebola infection.

In case that it is known that steroid pre-treatment was of little concern (e.g. based on infected monkey studies), start treating rather aggressively (e.g. start at doses of 0.25mg/kg).  In case it was not, go about more slowly by starting at sub-therapeutic doses as low as 0.025mg/kg and treat the initial experience like a dose-escalation study in actually infected patients.  Of course, everybody would need to provide informed consent.  In general, any semblance that the use of TKM-Ebola was imposed by the Western world and the local population used as guinea pigs is to be avoided which is probably a key reason why Tekmira to my mind has been almost in hiding during this whole episode almost to the point that they (and the FDA) are glad about the Clinical Hold.  

To support the accelerated development of Ebola therapeutics and vaccines, including TKM-EBOLA you can add your signature to the following change.org initiative: http://www.change.org/en-GB/petitions/food-and-drug-adminstration-fast-track-drug-and-vaccine-research-for-ebola-hemorrhagic-fever

Disclosure: Tekmira constitutes a meaningful part of my investment portfolio and I have to credit the WHO for greatly increasing its value.

Implications of Ebola data for Tekmira HBV Program

Like it or not, it is the HBV program that is driving the interest in Tekmira, at least in the near-term.  Therefore, the 15% sell-off in the stock yesterday following the Clinical Hold imposed by the FDA can be interpreted to be due to the uncertainty of what it means for the HBV program.

It is my working hypothesis that for the treatment of HBV via the immune reactivation pathway, the use of even transient immune suppression is to be avoided.  On the other hand, the recent Ebola clinical results by Tekmira suggest that transient immune suppression may also be desirable for 3^rd gen SNALP delivery.  As TKM-HBV is expected to utilize '3^rd gen' SNALP delivery, too, the Ebola results with immune activation seem like a bad omen.

While this cannot be ignored, there are a few reasons to believe that this might be too simplistic.

1.       Difference in dose

Although there was an apparent tendency for immune stimulation throughout the dose escalation with TKM-EBOLA, it was only at the high dose of 0.5mg/kg where a dose-limiting toxicity was observed. And according the yesterday's press release on the Clinical Hold, it is in particular cytokine elevations that were observed at 'higher doses' that are the issue.  

 Since unlike Ebola, HBV only replicates in hepatocytes, and because SNALP potency is highest in hepatocytes, the efficacious dose for HBV may be well below 0.5mg/kg with 3^rd gen formulations.  Of note, even 2nd gen SNALPs are highly effective at 0.3mg/kg based on the Tekmira-enabled ALN-TTR02 candidate now in phase III.

2.       Different sequence, different immune stimulation

It is known (e.g. Judge et al. 2005: Sequence-dependent immune stimulation of the mammalian innate immune response by synthetic siRNAs) that immune stimulation by RNAi, especially when liposomally formulated, is highly dependent on the actual sequence and modification pattern of the RNAi trigger.  Since TKM-EBOLA and TKM-HBV are different in that regard, it is well possible that while one 3^rd gen formulation is immunostimulatory, the other is not.

3.       Immunostimulatory by design/by screen

Scientifically, I was most disappointed by the Ebola immune stimulations as Tekmira made a big deal in the wake of similar observation in 2010 with TKM-ApoB that with improved, more predictive immune stimulation assays, they would now be able to screen out the immunostimulatory formulations.  In a black-and-white world you would conclude ‘obviously not!’.

In a world of shades of grey, I can imagine that TKM-EBOLA might have happened to slip through this part of the screening process.  The reason is that since Ebola infects a number of cell types besides hepatocytes (endothelial cells, phagocytes etc), the impressive efficacy of TKM-EBOLA always stood out as something quite unusual.  So while containing the spread of the virus by hitting it particularly hard in the liver might be part of the mechanism, I am quite receptive to the notion that the scientists did not mind all that much some immune stimulation when the RNAi formulation had so much efficacy.

With HBV, however, the company might be much more careful in screening out immunostimulatory potential.

I can now hear Sarepta investors yell ‘it’s an artefact’, but I would caution them that Sarepta and the morpholino field at large is proposing morpholinos with cationic appendices for infectious diseases while these are not really considered for genetic diseases.  What I don’t understand is that why a modification that is supposed to be helpful in e.g. suppressing viral gene expression should not likewise be useful for suppressing human gene expression.  So maybe the value of these modifications is in tickling the immune system?

4.       Not all 3^rd gen are created equal

In response to a questioner in the Q1 financial conference call, the CEO of Tekmira said that the definitions of the various SNALP generations is not as clean as you would like from a chemical point-of-view.  Instead, the definition largely is a reflection of the potency improvements of the formulations.  Therefore, since TKM-EBOLA has a different set of target cells than TKM-HBV, it is well possible, even expected, that the formulations will also differ in their lipid compositions.  Since lipids are an amplifier of the liposomal-RNAi immune response, differences therein could have big implications as to the immune stimulation of the various formulations.

Disclosure: I am long Tekmira and only partially heeded my own advice of stepping out of the TKM-Ebola ‘Haertetest’ (trial provided not much upside to investors).  On the other hand, Tekmira has upside potential from a number of non-Ebola programs especially HBV and mRNA delivery.  As the worst case scenario, an outright termination of TKM-EBOLA, is a real risk, it becomes more and more difficult to get the timing right ahead of the upcoming TKM-HBV data.  If, however, you don’t mind volatility and are a long-term investor, it’s another matter.  However, at least for me, Tekmira is not the stock any more to maintain a 100% position in.

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.

With Success, Pure-Play RNAi Therapeutics No More

As RNAi Therapeutics are charging forward towards first marketing approvals, it is time to consider how this will change the face of some of the pure-play companies involved.  Alnylam is set to become the dominant player in TTR amyloidosis, Arrowhead Research and Tekmira are vying to become just that in Hepatitis B, and Tekmira is increasingly isolating their biodefense division involving the formation of a filovirus alliance with non-RNAi modalities (prophylactic and therapeutic vaccines) as revealed yesterday.

Under normal circumstances, getting drugs approved that revolutionize the treatment of particular diseases provides great incentives to protect the resultant franchises.  Witness BiogenIdec .  BiogenIdec started out as a molecular biology pioneer and serendipitously established itself as the major player in multiple sclerosis, and is now considering all therapeutic modalities, including RNA Therapeutics, to build on that strength and further expand into neurology.  

Although it breaks my scientific heart, I do not expect that to be any different for RNAi Therapeutics companies.  HBV is a great example since an immune de-repressing RNAi Therapeutic alone is unlikely to facilitate the 100% cure rates now seen with combinatorial HCV treatments.  Instead, the addition of a direct immune-activating agent such as a TLR agonist should enhance cure rates and shorten treatment durations.  For an acute fatal infection such as Ebola, you also do not want to limit yourself to one treatment, but recruit multiple mechanisms to save an infected person, or start vaccinating populations around areas of viral outbreaks.

To extract maximal value from such disease indications, it is often best to combine the various options under one roof.  It may be partly this fear of moving away from your roots that is responsible for ISIS Pharmaceuticals giving up marketing rights early on for a few cents on the dollar worth (SMN, myotonic dystrophy, TTR).

Having said that, just like BiogenIdec with recombinant proteins and monoclonal antibodies, most of these RNAi Therapeutics companies will continue to focus their internal R&D efforts on RNAi Therapeutics.  In special cases such as Ebola and other biodefense opportunities, a spin-out may create most shareholder value without damaging the platform technology value of the parent company.

Nothing of what I just said is revolutionary.  It is, however, worth keeping in mind as the first major RNA(i) Therapeutics wave will make landfall in 2-3 years. 

The Ebola Clinical Trial a Real ‘Haertetest’ for SNALP LNP Delivery

In German, a Haertetest is a test that challenges the performance of something under the most exacting conditions.  

It is therefore an apt description for the Ebola clinical trial now underway which is testing the safety and tolerability of SNALP LNP delivery following multiple consecutive daily administrations.  This compares to once-weekly and once-a-monthly regimens tested so far.  If SNALP LNP comes out positive from this, it would provide great comfort around the safety and tolerability of the industry’s most potent delivery technology for gene knockdown in the liver, in addition to paving the way towards more biodefense applications.

Teething problems with 1^st gen SNALP LNP

In January 2010, Tekmira reported clinical results from the phase I study of TKM-ApoB, the first clinical candidate employing SNALP LNP technology.  This trial was terminated prematurely due to immune stimulations observed at 0.6mg/kg, a dose at which only minimal target knockdown was observed at that.

This event triggered a healthy amount of soul searching and meant that subsequent SNALP LNP trials had to employ transient immune suppression.  A number of important practical lessons were learned from this.  

Firstly, it showed that the preclinical immune stimulation tests had been inadequate and this prompted the development and adoption of a more predictive test to better screen out candidates that are immunostimulatory before they enter humans.  Secondly, the phase I results were consistent with the notion that the DLinDMA lipid itself (and not just the RNAi trigger), the basis for the 1^st gen SNALP formulations, was immunostimulatory and that new lipids were needed.  And lastly, it highlighted the need to develop more potent SNALP formulations, including new lipids.

Research rises to the challenge

Three years following these events, all three challenges have been successfully addressed.  Today, the potency of SNALP LNP has increased ~30 fold from 1^st gen to 3^rd gen formulations (based on measuring gene knockdown in the liver), with the 2^nd gen MC3-based SNALP generation already with a confirmed 10-fold improvement in clinical potency based on phase I and II results of ALN-TTR02.

Tekmira not shy to ask the tough questions

Despite the progress, detractors of the technology like to point out that (transient) immune suppressions has still been employed in subsequent clinical trials.  With the recent initiation of the phase I study of TKM-Ebola by Tekmira, this has changed however.  Not only that, transient immune suppression has been dropped even as administration intensity is ratcheted up to 5-7 daily administrations. This compares to once-a-month and once-a-week dosing schedules anticipated for SNALP LNP applications involving gene knockdown in the liver and solid cancers, respectively.

The reason why TKM-Ebola necessitates daily administrations is due to the rapid progression of the otherwise fatal Ebola virus.  Therefore, in order to get it approved under the Animal Rule, Tekmira needs to demonstrate the safety and tolerability of SNALP LNP in human volunteers under conditions where they are able to rescue monkeys from succumbing to otherwise fatal infections.  

Moreover, while 0.2mg/kg already provided good protection in the monkey studies (2/3 survival), it was the 0.5mg/kg dose that complete protections were achieved.  0.5mg/kg also happens to be the ‘magic’ dose for SNALP LNPs following which idiosyncratic immune stimulations and other side effects may be expected.

The reason why I am pretty sure that TKM-EBOLA, despite the daily administrations and up to 0.5mg/kg dose, should not involve immune suppression is because it would be incompatible in a viral infection.  There is also no evidence that such pre-treatments are planned in the clinicaltrials.gov entry nor when Tekmira reported the monkey results.  The same considerations apply to the HBV candidate by Tekmira for which an IND is expected by year-end.

Should Tekmira come out of this trial unscathed, it would further de-risk the entire SNALP LNP platform and solidify its position as the most potent oligonucleotide therapeutics technology for gene knockdown in the liver, for hemorrhagic fever applications, and possibly oncology.

Where some see risk, others see opportunity.    

Tekmira Expands Biodefense Efforts to Cover Both Ebola and Marburg Virus

Following the successes with its Ebola biodefense program, Tekmira has started to present increasingly promising data for treating a related filovirus, the Marburg virus.  With 100% survival rates in non-human primate models and new RNAi triggers that should cover a broad spectrum of strains and possibly related viruses, the company is well positioned to also take away the Marburg indication from competitor Sarepta which in turn has become preoccupied with its exon-skipping drug candidate for DMD.  

For the Ebola program alone, the $100M market cap company estimates that the successful development of a drug under the so called Animal Rule could result in stockpiling orders from the US government worth about $100M annually.

From guinea pigs...

In a publication last month, Tekmira and their collaborators from the UTMB in Galveston, Texas, reported the successful treatment of guinea pigs infected with a number of different strains of the Marburg virus.  Because the development of treatments for rapidly mutating viruses and viruses with a multitude of divergent strains is hampered by sequence diversity, a broader strain coverage was achieved, like in Tekmira’s Ebola approach or in Arrowhead’s chronic HepB strategy (ARC520), through the concurrent use of two siRNAs in a single formulation.

Given that rodents have limited predictiveness for anti-filoviral efficacy in Man and given that the formulation was apparently a 1^st generation D-LinDMA-based SNALP, I was not all that excited about the publication due to the apparent early stage of development.

...to non-human primates

In a positive surprise therefore, the Chief Scientific Officer of the company, Ian MacLachlan, presented gold standard non-human primate data of SNALP RNAi Therapeutics for Marburg virus at the ongoing OligoDIA regulator-industry conference.  Accordingly, Tekmira’s newer LNP formulations (‘SNALP-G’) were shown to fully protect monkeys from death due to Marburg infection when given at 0.5mg/kg (=the magic safety threshold for SNALP).

As an important comparison, Sarepta last year reported ‘83% to 100%’ protection rates in comparable models when treatment was initiated up to 96 hours after infections with its newer PMOplus morpholino chemistry.   It is therefore of interest to test the impact of further delaying treatment with SNALPs.

As I have been following Tekmira’s biodefense program over the years, one development I noticed, especially in the era of budget cuts, was the apparent push by the Department of Defense for biomergency treatments that can address not just multiple strains of a virus, but multiple viruses all-in-one.  Intriguingly, one of the bullet points in Tekmira’s slide presentation on goals for the Marburg program (slide 36) talks about the ‘Design broad spectrum siRNA to target multiple MARV and Ebola’.  Does this mean that the ultimate prize here are stockpiling contracts for a single drug addressing both Marburg and Ebola?

Having a better ear for and adjusting to the needs of the DoD is also one reason why I believe Tekmira will continue to have the upper hand over competitor Sarepta with its DMD distractions and an investor base that could not care less about the Marburg program.  Although the targets were explicitly not disclosed, I wonder whether there are host factors one could target and which would be beneficial for various viral applications.  This would be an alternative to trying to come up with target sequences that are conserved across the viruses.

Finally, serving as yet another example of illustrating the value of biodefense contracts for platform technology companies, Tekmira disclosed plans that a first clinical trial with a lyophilized SNALP formulation, TKM-EBOLA, is planned for the first quarter of 2014. 

RNAi Therapeutics Ebola Candidate Achieves Critical Milestone

Yesterday at the TIDES meeting, Tekmira reported new efficacy data for its Ebola RNAi Therapeutics development program.  The non-human primate data suggest that the main remaining hurdle before regulatory approval for this biodefense agent (on which any government stockpiling contract would hinge), safety in healthy human volunteer studies, is now more realistic than ever.     

Is second time's the charm?

In 2010, Tekmira and collaborators from the Geisbert lab and the US Army reported in The Lancet of a breakthrough in the post-exposure treatment of Ebola infection.  In the gold-standard rhesus monkey model for Ebola infection, their were able to demonstrate that SNALP-RNAi could effectively rescue Ebola-infected animals from near-certain death. 

The efficacy, however, depended on doses of 2.0mg/kg is likely too high a SNALP dose to be considered safe.  Based on the SNALP human clinical trial experience to date, first dose-limiting toxicities are observed at 1.0mg/kg (note: SNALP potencies are very comparable between humans and monkeys).  Moreover, at doses higher than 0.5mg/kg, sporadic signs of immune stimulations (flu-like symptoms) can be observed.  These caused Alnylam and Tekmira to adopt precautionary transient immune suppressions with corticosteroids in some of their other SNALP-based clinical studies.   

It therefore became important to take advantage of the improvements in SNALP potencies and develop more potent Ebola SNALP-RNAi candidates.  Fortunately, Tekmira was able to get the blessing from the US Department of Defense for this, and announced in April that it would receive up to ~$7M in additional funding on top of the up to $34M initially agreed upon in order to bring such a candidate to the end of phase I clinical studies. 

Importantly, since Ebola efficacy trials cannot be conducted in humans, the regulatory approval of TKM-Ebola will be according to the Animal Rule.  The Animal Rule states that for indications where human efficacy trials are not possible due to ethical considerations, it is sufficient to show efficacy in accepted animal models and then establish drug safety at corresponding doses in healthy human volunteer studies.  

With the new formulation, 12 out of 12 monkeys treated with the magic dose of 0.5mg/kg RNAi stayed alive in a post-exposure treatment setting, compared to only 1 out of 6 treated with placebo.  This means that should the human volunteer trials show good safety at the same 0.5mg/kg dose level, Tekmira will stand a good chance at gaining regulatory approval under the Animal Rule.  Of note, the first Ebola trial were likely conducted in the absence of corticosteroid pre-treatment and it is very likely, also in light of Alnylam's recent announcement of tapering off corticosteroids in the ALN-TTR02 trial, that the future TKM-EBOLA studies will also be conducted without them.

Since 0.5mg/kg is right on the border, however, there still remains an element of risk before victory can be declared on the safety front.  It is therefore good to hear that 4 out of 6 monkeys stayed alive at the 0.2mg/kg dose. This should provide a good safety cushion despite the aggressive daily treatments that will be required in this demanding setting.

Critical human safety data, ideally from repeat-dosing studies, should be forthcoming in 2014 as Tekmira has guided that it will commence clinical studies with the new candidate by the end of 2013.

Update 16/5/2013: One issue on the efficacy side of the equation that I forgot to mention in the original post is that the DoD might ask the company to test TKM-EBOLA with longer delays after the infection in monkeys.

SNALP Shows Good Potency with Subcutaneous Dosing

Also at the TIDES meeting, Tekmira presented efficacy data for SNALP when given via the subcutaneous route of administration.  To wit, SNALP has largely been administered intravenously which may not be suitable for a number of indications, especially the lower risk, chronic diseases.  Pfizer once famously criticized the state of RNAi delivery as being limited to intravenous options.

Comments like these (which are very relevant for partnering purposes) and trends in the industry to adopt subQ dosing, most notably Arrowhead’s DPCs and Alnylam’s GalNAc-conjugates, probably motivated Tekmira to explore this route of administration with SNALP further.

 

Based on an early ApoB patent application, Tekmira had clearly had some familiarity with subQ, and I had always wondered why the company did not pursue this further.  It could be that the more potent SNALP chemistries now allow for much more potent and robust subQ RNAi gene knockdown.

The new data show a very impressive 96% knockdown of transthyretin (TTR) with a single subQ administration of 1.0mg/kg SNALP in rodents.  This compares to a much more modest ~55% knockdown with ALN-TTRsc at 1.0mg/kg given on 5 consecutive days, the subQ GalNAc-siRNA candidate by Alnylam which just entered clinical development for the FAC form of transthyretin amyloidosis.

Of course, we need to learn more about the safety of subQ SNALP to know whether it really is a clinically viable strategy and superior to the competition.  GalNAc-siRNAs in particular look quite benign, albeit not very potent.  However, since peak plasma concentrations seem limiting for SNALP in terms of safety (infusion reactions can be managed by slowing the infusion), subQ, due to its slower systemic release might actually turn out to be safer, not just more convenient.  On the other hand, my impression is that subQ SNALP could cause the type of ‘nuisance side effect’ that is frequently seen with phosphorothioate antisense.

The GalNAc comparison is obvious since Alnylam developings both a SNALP- and a GalNAc-based TTR RNAi Therapeutics in parallel.  In terms of competition for potential partnering, however, the DPCs by Arrowhead Research would be the more appropriate and challenging comparison.  I look forward to watching the race unfold as healthy competition is propelling the RNAi Therapeutics field into a highly competitive industry.

Viruses, Beware! This time, RNAi Therapeutics Mean Business

Viral infections have long been thought of as an attractive therapeutic area for RNAi Therapeutics.  Unfortunately, with the exception of Tekmira’s Ebola biodefense effort funded by the US Department of Defense, this area has had trouble taking off: Nucleonic’s ddRNAi-based HBV program should never have gone into the clinic (and as expected was soon terminated thereafter), and there is considerable concern that the main mechanism of action of Alnylam’s ALN-RSV01 for respiratory viral infection is due to innate immune stimulation of the unmodified RNAi trigger, not RNAi-mediated gene knockdown.

As RNAi Therapeutics as a whole has turned the corner in 2012, so has antiviral RNAi Therapeutics. 

This assessment is based on two quality programs that have either made it into the clinic recently, Calimmune’s ddRNAi candidate for HIV (LVsh5/C46), or is close to it (Arrowhead’s DPC-delivered anti-HBV candidate ARC520 for which an IND is planned in Q2 2013).  In addition, there is expectation that Tekmira’s Ebola program will be able to take advantage of the significant improvements in SNALP delivery technology, thereby considerably increasing the odds for an FDA approval under the Animal Rule (note the recentapproval of a second drug under this rule).

Suppressing Immune Suppression

Antiviral RNAi Therapeutics have to overcome the important theoretical limitation that even a potent, e.g. 99% knockdown of a viral transcript or particles may not be sufficient as in theory a single infected cell may fuel viral rebound.  It turns out that rather than blindly aiming at knockdown potency, RNAi Therapeutics are likely to be more successful when targeting an important mechanism employed by virtually all viruses: avoiding detection or removal by the immune system.

In the case of HBV, a disease affecting North of 200 million patients worldwide, the virus produces large amounts of the Hepatitis B Surface antigen (HBsAg).  This is thought to suppress, by acting as a decoy, the development of a productive anti-HBsAg immune reponse.   It is thus widely believed in the industry that reducing HBsAg is required to finally generate a drug that can achieve a functional cure, essentially paralleling the recent developments in HCV.  Interferon-based treatment regimens may actually partially work via this mechanism, but cure rates are rather low and come with considerable side effects in the form of severe flu-like symptoms.  Moreover, protein-targeting anti-HBV agents such as small molecule-based polymerase inhibitors do not seem to reduce HBsAg.  This leaves RNAi Therapeutics as the most promising mechanism of action.

A recent article in PLOS Pathogen suggests that the Ebola virus similarly churns out decoy viral proteins so as to subvert the immune system into making antibody duds that do not effectively remove the real viral particles.  It is therefore intriguing that an Ebola drug candidate by Tekmira should not only aim at providing the immune system with more time, but also that it would facilitate it mount a more effective antibody response.

No Escape

Another attraction of the RNAi Therapeutics approach for viral diseases is the fact that such agents may be more successful in prohibiting the virus to mutate around the drug and thereby escape its actions (viral escape).  Consequently, all antiviral RNAi trigger selection strategies focus on sites that are conserved in the various genotypes and quasispecies.  Even if the virus is successful at mutating around conserved sites, it is then relatively simple to include a second (such as in Tekmira’s Ebola program) or third RNAi trigger targeting a conserved site such that the virus would have to mutate around two sites at the same time- a highly unlikely event.

In addition to these general antiviral mechanisms, RNAi Therapeutics may also work through more virus-specific mechanisms.  Calimmune’s ddRNAi-based HIV candidate LVsh5/C46 for example down-regulates the cellular receptor for viral entry, CCR5, such that HIV particles cannot enter cells and integrate into their genomes in the first place.  As an ddRNAi gene therapy approach, LVsh5/C46 further takes advantage of the fact that you can express a therapeutic protein along with the RNAi trigger, thus uniquely combining mechanisms of actions in a single drug.    

Smooth Sailing Ahead

Of course, it is impossible to tell whether an RNAi Therapeutic will actually overcome a virus in each case and receive regulatory approval.  Nevertheless, I believe that the above candidates for Ebola, HBV, and HIV stand a real chance. 

The Ebola program by Tekmira is arguably the most advanced, and it is difficult for me to see how based on the non-human primate data and the lower dosages required for SNALP delivery, which should widen the therapeutic window, approval can be denied under the Animal Rule.

For the HBV and HIV candidates that are being developed along more conventional regulatory pathways, I  am similarly optimistic that they will generate some excitement in the near-term.  This is because viral load is a powerful biomarker, often also an approvable endpoint, and even early clinical studies should be able to generate such outcome data (if Arrowhead could help it, they should go straight into patients with ARC520). 

After orphan diseases involving the liver and oncology, antiviral applications are therefore poised to become the third major support of the RNAi Therapeutics platform.

Tekmira Regains Control over Leading Delivery Technology

When Tekmira filed its lawsuit against Alnylam in March 2011, it found itself in an impossible position: Alnylam’s apparent mis-use of SNALP-related trade secrets not only diminished their strategic value to Tekmira, including depriving it of potential pharmaceutical partnerships, Tekmira may even not have been able to use the technology it invented.  As a result, it might have been left to die in a little cage with ‘1^st generation’ technology as its technology was making rapid progress.    

Cash and Control

Based on the disclosed terms of last night’s settlement with Alnylam (Tekmira's version here, Alnylam's version here), Tekmira got essentially all that it needed: control over its leading systemic RNAi Therapeutics delivery technology, including the contested MC3 lipids of which the IP was assigned to Tekmira, and a $65-75M payment (~$16-18M of which will go to pay outstanding legal fees).  The payment, of course, will finally allow the otherwise financially conservative company to push forward their development pipeline with interesting therapeutic candidates such as TKM-PLK1.  Notably, as part of the settlement, Tekmira obtained full ownership over this candidate which I believe addresses one of the most exciting RNAi targets in oncology. According to the Q3 financial results, also released today, TKM-PLK1 has been making good progress, including showing signs of drug activity and will advance into phase II studies next year.

Beyond the cash, the new IP licensing arrangement between the companies is at least as valuable.  Importantly, Tekmira has regained exclusive sub-licensing rights to ‘LNP intellectual property’, an incredibly important part of the settlement as before that Alnylam enjoyed such control, mainly via its rights to the Semple-Wheeler IP covering important aspects of ionizable SNALP technology.  This should open the door for Tekmira to enter into the long-expected pharmaceutical partnerships. Novartis and Takeda are here the most obvious near-term candidates for platform-type relationships.

Assuming that the new relationship is not restricted to RNAi Therapeutics, an added bonus is that the settlement could similarly pave the way for relationships in the microRNA Therapeutics space, particularly for the delivery of microRNA mimics.  Only recently, privately-held Mirna Therapeutics made headlines by raising $34.5M to fund the development of a microRNA mimic into the clinic, indicating the significant interest in this area of drug development.

Value of the Trade Secrets

Less clear is the damage to the trade secrets that were at the center of the dispute and on which much of Tekmira’s strategic advantage rested.  Numerous groups and companies have attempted home-brew liposomal RNAi trigger delivery, but only Tekmira’s technology has made it into the clinic.  Especially the ability to formulate and manufacture the particles is what set Tekmira apart from the competition.  In their press release, however, Alnylam stated their intention to use its own LNP manufacturing capabilities.  Apparently, it has already established such GMP manufacturing capability over the last year (in a separate building apparently for added suspense).  Assuming that Tekmira did not assist them in establishing such manufacturing, this indicates that the number of people with critical knowledge to the trade secrets has grown.  This can be particularly a problem in the wake of lay-offs in a place like biotech world capital Cambridge, Mass. 

Still, I assume there to be significant hurdles for other companies to replicate Tekmira’s processes, and with its liposomal experts, Tekmira should continue to lead in advancing SNALP delivery, making it the liposomal delivery partner of choice.

With cash of around $50M (excluding the $10M which are contingent on likely 2013 development milestones for ALN-VSP02 and ALN-TTR02), partnerships likely to come in due to the clarified IP situation, the $141M DoD Ebola biodefense contract (a new more potent and safer formulation will be used) and the income stream from Talon Therapeutics, Tekmira has thus emerged as the vibrant RNAi Therapeutics company it should have become 3 years ago.  Nevertheless, today's terms underline the value of Tekmira and RNAi delivery in general.  Exciting times ahead.