Ebola, Advantage Tekmira

These are critical weeks for Tekmira.  Not only is Tekmira fighting to get back control over its LNP delivery technology, the full-fledged termination of the Ebola biodefense program following the Stop-Work Order would have given the company serious headaches.  As much of the current cash-flow derives from the $140M biodefense contract from the Department of Defense (DoD), the company may have been forced to decide between laying off or furloughing staff until the decision in re Alnylam would provide more funding clarity (November-December 2012).

Luckily, with the DoD deciding to continue Tekmira’s Ebola program, the advantage is again with Tekmira.  My main concern with a negative biodefense decision was that it might have particularly affected the long-term ability of the company to continue to innovate on its LNP technology.  The benefits of the biodefense contract were particularly visible in manufacturing (such as scale-up and lyophilization), thereby allowing the company to build on a key competitive strength.

Of course, it is fair to say that I feel vindicated by the simultaneous decision by the DoD to discontinue Sarepta’s competing Ebola development program: Tekmira’s RNAi Therapeutics approach, now in phase I studies, had the stronger scientific data compared to Sarepta’s antisense approach which had once enjoyed a multi-year head-start (here my 2010 comparison of the two programs).  

Liposomally formulated RNAi Therapeutics also has the advantage of facilitating multi-targeting.  This opens up the prospect for targeting multiple viral, but also host factors, some of which may actually be shared by a number of hemorrhagic fever viruses (HFV). I start getting the impression that setting the stage for the development of such broad-acting HFV therapeutics appears to be an increasingly important aspect of Tekmira’s Ebola program.

I should add that Sarepta will continue to be funded under an analogous $140M contract for Marburg (also a HFV).  Here, the company seemed to have achieved important post-infectionmilestones.  Tekmira does not compete here.  Continuing to fund both an RNAi Therapeutics and an antisense program may also be a strategic risk-mitigating decision by the DoD in case one approach encounters terminal platform issues.

Nevertheless, comments by David Hough from the DoD indicate that the decision was mostly based on the scientific merits:

"Our job is to ensure we're making the most out of every dollar we spend," he noted. "We evaluated each contractor's efforts independently.  The evaluation was conducted using all current data and in accordance with the criteria set forth in the awarded contracts and as stated in the initial solicitation.  This was certainly a tough decision but the final decision was made to move forward on continuing the development of the drug candidate that represents the best value to the Government based on what we know today."

SNALP Delivery Keeps On Giving: Tekmira Receives OK for Ebola Clinical Studies

On Monday, Tekmira announced that it has received the Green Light from the FDA to go ahead with clinical studies of its SNALP-enabled biodefense candidate for the treatment of Ebola infection. Tekmira is developing TKM-EBOLA under a $140M contract from the US Department of Defense following spectacular results in non-human primates reported last year in The Lancet. Depending on whether you want to count in the stalled TKM-ApoB program or not, this marks the 5^th or 6^th SNALP-enabled candidate in clinical development, illustrating the strength of this systemic RNAi trigger delivery platform: TKM-ApoB, ALN-VSP02, TKM-PLK1, ALN-TTR01, ALN-PCS02, and TKM-EBOLA.

In other words, 6 of the last 7 systemic RNAi INDs or IND equivalents were for SNALP-enabled product candidates (period: 2008-2011). This plus the unparalleled, strong pre-clinical track record of this platform demonstrating efficient knockdown in the liver, solid tumors, and viral infections not only in rodents, but also a number of non-human primate models supports the notion that Tekmira’s SNALP is the industry’s most advanced and valuable RNAi delivery platform. There are thankfully other promising RNAi delivery technologies lining up behind SNALP, but this is not Lake Wobegon where everybody can be above average

Next Steps for TKM-EBOLA

Since TKM-EBOLA, as a treatment for a disease in which controlled human studies are ethically or practically impossible, is being developed under the Animal Rule, this phase I study will not only have to demonstrate adequate safety, but more importantly yield pharmacokinetic and potentially biomarker data that replicates what is seen in the successful treatment of the pre-clinical animal models of the infection. At the same time, it may be worth trying to test the limits of how long treatment can be delayed after symptom onset in the animal models as a common criticism of these studies is that in the real world it may take some time before Ebola victims are identified and treated. In The Lancet studies, rhesus monkeys received first treatments already 30 minutes after exposure to the virus which may model a needle stick scenario in an Ebola research laboratory, but not exposure of the civilian population e.g. in a subway system. Similarly, achieving similar pre-clinical efficacies with 1mg/kg as with the tested 2mg/kg dose in The Lancet studies may bring it more in line with the clinical SNALP safety experience so far. On the manufacturing front, it would be helpful if Tekmira succeeded in providing SNALP in lyophilized form which would increase its utility in the field.

On the other hand, the fact that the rhesus model seems to closely replicate, if not represent a particularly severe form of the human disease, and the absence of a (experimental) therapy for Ebola that has shown comparable promise, should position TKM-EBOLA well for stockpiling despite any lingering real-world concerns. From an Army point-of-view, as long as it has been shown to be safe and well tolerated in humans, having the most promising treatment as a stand-by for a virus as deadly as Ebola is better than nothing at all, a consideration that may result in stockpiling even before, or in the absence of FDA licensure.

In that regard, TKM-EBOLA will be mainly competing with AVI Biopharma’s morpholino antisense candidate AVI-6002 which is being developed under an essentially identical contract with the DoD. A Nature Medicine paper published last year reported that this candidate was successful in rescuing ~60% of infected rhesus macaques, although this represents a roughly 3-fold increase in risk of dying compared to the highly comparable SNALP studies in The Lancet. Nevertheless, AVI Biopharma still enjoys a slight time advantage as it has already begun phase I safety studies earlier this year. A late-October 2011 update by AVI stated that treatment in the first 5 of 6 dose-escalating cohorts was well tolerated and that the Data Safety Monitoring Board recommended further escalation to the last 9mg/kg cohort. Nevertheless, once years behind the AVI program, Tekmira has done well catching up with the competition.

Importance beyond TKM-EBOLA

Besides representing an invaluable strategic asset for Tekmira (it is earning the company significant hard cash now and revenues from stockpiling may come well ahead of the customary 5-10 years it usually takes a normal drug to navigate the FDA approval maze), the approval of the IND further demonstrates that SNALP is indeed the productive delivery platform that also I have long had hopes for it to be, with applications not only for knockdown in the liver and solid cancers, but also phagocytic cells (an important target cell population for the Ebola indication). It is also a stamp of approval by various regulatory agencies around the world that SNALP (including reliable manufacturing) is fit for clinical development. An IND for ALN-TTR02 and phase I results for ALN-PCS02 are next.

Comment on Roche Partnership with PTC

Roche disclosed today that it has signed a collaboration with PTC Therapeutics for the treatment of Spinal Muscular Atrophy, including a $30M upfront fee for pre-clinical assets. This follows a similar deal by AstraZeneca and PTC in oncology earlier this year. PTC develops a platform for the modulation of post-transcriptional processes using orally available small molecules.

What is disappointing to me is that these are examples of Big Pharma companies with an interest in RNA Therapeutics (note that AstraZeneca has a relationship with Silence Therapeutics for which a go/no-go is imminent), but which feel more comfortable risking their money on a technology based on phenotypic tissue culture screens with considerable uncertainty as to clinical relevance and the safety risks inherent in modulating very general gene regulatory mechanisms, instead of using the much more straight-forward oligonucleotide approaches. The reason? Oral bioavailability and coziness with small molecule chemistry. The fate of these collaborations will be an important test case of whether putting patient convenience and other marketing considerations ahead of what is the scientifically best approach will bring Big Pharma the desired outcome. Of note, only a few months ago, Genzyme handed back PTC a candidate for the treatment of Duchenne Muscular Dystrophy and Cystic Fibrosis after spending more than $100M on it.

My view: Technical success trumps patient convenience when it comes to diseases as severe as SMA, DMD, or cancer.

Interested in the Chinese market for RNAi Therapeutics, but language barriers exist? Get expert help from somebody that understands RNAi.

A comparison of Tekmira’s and AVI Biopharma’s Candidates for the Treatment of Ebola Virus

I was quite amused today, while driving a car on Borneo, the local radio report the headline ‘US scientists said that they are ready to start clinical trials for Ebola’. It was yet another reminder that oligonucleotide therapeutics, including RNAi is firmly emerging from the research stage, entering the medical arena and gaining more widespread attention.

As you may also have heard by now, 3 months after the impressive publication in The Lancet by Tekmira and collaborators that liposomal siRNA essentially cured non-human primates from otherwise lethal infections of Ebola virus, morpholino antisense company AVI Biopharmaceuticals followed up with results from their own Ebola non-human primate treatment studies in the equally prestigious journal Nature Medicine (Warren et al.: Advanced antisense therapies for postexposure protection against filovirus infections). Since both companies were recently awarded highly lucrative government contracts from the US Department of Defense to further develop these two oligonucleotide therapeutic candidates for the treatment of Ebola and therefore have to be considered competitors for further contracts, I will briefly compare and contrast the results from the two studies.

One remarkable benefit of having both lines of research enjoy funding from the DoD is that they have been highly standardized which makes them very comparable to the extent that even the animal laboratory was shared, I believe. So no excuses with 'in our hands' or the likes. In each case the goal was to evaluate the RNAi or antisense in a post-infection model whereby the oligo Rx was first given once 30-60min following intramuscular injection of rhesus macaques with 1,000 plaque forming units of the Zaire strain of Ebola, an amount many orders of magnitudes higher than needed to kill such an animal if left untreated.

Just as a reminder, in this treatment regimen, Tekmira’s intravenously administered SNALP-RNAi when given 3 times every other day or daily for 6 days following viral exposure rescued 2 of 3 and 4 of 4 animals, respectively.

In the AVI study, morpholino antisense molecules which have been slightly altered compared to previous studies to be positively charged to facilitate enhanced cellular uptake and improved target RNA binding, were also given daily, although in this case the follow-up administration period lasted for 10-14 days and the dosage was 40mg/kg compared to 2mg/kg siRNA. In addition to intravenous administration which the investigators refer to as the preferred route of administration for needle stick scenarios and the like, some studies involved simultaneous intraperitoneal and subcutaneous administrations.

Route of administration, however, did not seem to make much of a difference since in both cases around 60% of the monkeys were rescued from near-certain death: 5 of 8 in the subQ+i.p. regimen, and 3 of 5 in the intravenous regimen.

Put differently, the risk of dying from Ebola infection was 14% in the Tekmira study (1 out of 7 animals; 0 of 4 with the optimized protocol) compared to 39% in the AVI studies. Although the numbers are still small, this indicates an almost 3-fold risk reduction with SNALP-RNAi compared to morpholino antisense.

So while Tekmira’s SNALP-RNAi may in fact now lead the race towards a drug that can treat Ebola virus infection, it is far from over. AVI is apparently ready to move into safety studies with human (healthy) volunteers. In addition to such clinical studies, both companies and their collaborators will have to test in further non-human primate studies how long they can delay treatment after the initial infection, as ‘in the field’, as opposed to laboratory accidents and first responder situations, treatment will only begin after first symptoms emerge.

However, with the current efficacy of TKM-Ebola and what appears to be an already extensive pre-clinical safety database, if the initial human studies are uneventful, the case could be made that a first-generation Ebola standby for needle pricks and first responders in local outbreaks may be quite close indeed. In fact, researchers exposed to these viruses should be pushing for it, and the fact that the current SNALP-RNAi has to be administered intravenously should not be a problem for such purposes.

AVI’s antisense morpholino though may have some advantages over the SNALP-RNAi for wider outbreaks in that it may be administered subQ, although a pure subQ protocol has not been tested yet in the post-infection model and I am not clear about the practicalities of administering 40mg/kg x70kg= 2.8 grams (!) of oligonucleotides subQ. With the more potent, second generation SNALP-RNAi formulations ('LNP' is the official designation now), subQ administration of liposomal siRNAs should become more practical and I would not be surprised if some of the future Ebola contract funds were to be spent on further developing subcutaneous LNP administration.

While it was not obvious from the paper in The Lancet, reading the latest paper, it is quite clear that the 2 companies and probably even different groups within the Army that work on Ebola Rx are strongly competing with each other. It reminds me of the strategy of principal investigators of some ‘post-doc labs’ where at least 2 different post-docs are being competitively put on the same project. This way, the principal investigator increases his chances of timely success. Not being a military man myself, it would also make sense from a military point of view to even have 2 alternative Ebola Rx stockpiles, just in case one turns out to be more desirable than the other in a real emergency.

In the end, while the value of biodefense agents is often difficult to determine, the DoD Ebola program brings two significant benefits. One is that the program allows the involved companies plenty of room to develop their underlying platform technologies such as facilitating the scale-up of their manufacturing processes. The other is the images evoked by viruses such as Ebola and the attention it directs towards this rapidly growing area of oligonucleotide therapeutics. Even a remote island like Borneo is an escape from it no more.

Tekmira Sets New Standard in Ebola, Widening Reach of SNALP Delivery

When a small biotech company from Canada trading at less than 1CAD announces plans to list on the Nasdaq, one ought to pay attention, especially when this company is well known for its fiscal conservatism. The recent publication (Geisbert et al.: Postexposure protection of non-human primates...) on the treatment of Ebola infection by Tekmira and collaborators at Boston University and the US Army Medical Research Institute of Infectious Diseases (USAMRIID) in the prestigious journal The Lancet indeed supports that their optimism of good news to come out over the next couple of months is well-founded.

By demonstrating the complete protection of non-human primates, aka monkeys, from an otherwise lethal dose of Ebola virus using the company’s SNALP delivery technology, this paper sets a new standard in the development of anti-hemorrhagic fever virus treatments. More than the potential direct financial value of such a drug in the form of further biodefense funding for the benefit of SNALP technology development and long-term prospects of stockpiling contracts, the real significance of this publication is that it confirms SNALP, developed and owned by Tekmira, to be the industry-leading systemic RNAi delivery technology where successful non-human primate data have become routine, and furthermore extends the reach of this technology from targeting genes in the liver and solid cancers (already a plethora of applications here) to infectious and likely inflammatory diseases, too. Given that Big Pharma is well aware of the potentially revolutionary nature of RNAi Therapeutics and Tekmira’s current key enabling position in the space, it should only be a question of time that a bidding war for Tekmira will commence, if it has not already.

Ebola presents a biosecurity threat due to its deadly nature and the concern that it may be weaponized while no drugs can successfully treat it. Oligonucleotide-based approaches look most promising in the race to develop drugs against Ebola and other hemorrhagic fever viruses. AVI Biopharma in particular has staked a good part of that company’s future on winning biodefense stockpiling contracts from the US government, and as a result their antisense morpholino protein translation inhibitors have historically led the development. Such therapeutics aim to slow down the spread of the virus enough to give the immune system a chance to catch up and clear the virus.

In 2006, AVI and their collaborators around Dr. Bavari from USAMRIID reported results on a combo of morpholino antisense molecules against 3 Ebola genes (L polymerase, VP24 and VP35- targeting 3 different genes to address potential mutational drug resistance) in mice, guinea pigs, and non-human primates (rhesus macaques; Warfield et al.: Gene-specific countermeasures against Ebola virus...). In each case, 1,000 plaque forming units (pfu) of Ebola virus were administered, doses more than sufficient to essentially kill all the animals. In mice, somewhere between 50-500 microgram of drug (about 2-20mg/kg) administered either a little bit before or after the viral infection was enough to effectively protect the animals. In guinea pigs, 10mg of each oligo (~30mg/kg) also protected the animals well. Interestingly, even more protection was observed when the oligos were administered relatively late (up to 4 days) after viral infection compared to administration before viral challenge. While the pharmacologic explanation remains to be worked out, the ability to protect from Ebola relatively late after the infectious event is an important property of an Ebola antiviral.

While mice and guinea pig data are a routine component in the development of Ebola antivirals, success in these models by no means predicts success in primates, including humans, where the rhesus macaque model has become the gold standard. For this reason, 1,000 pfu of the Ebola virus Zaire were injected intramuscularly accompanied by a complex schedule of essentially daily drug injections (12.5mg to 200mg per dose) starting at day 2 before up to 9 days after viral challenge.

Initially, only a single antisense oligo against VP35 was tested which showed most efficacy in rodents. This proved to be ineffective with all 4 animals dying within 7 and 8 days post-infection. However, using the triple combo, 2 out of the 4 drug-treated animals survived the virus with one succumbing to a bacterial infection (= 50% or 75% survival depending on how you look at it). The most common side-effects were thrombocytopenia and an increase in liver enzymes, both of which are consistent with Ebola infection.

Until the Tekmira study, this has been the most advanced published study of an Ebola antiviral drug. One draw-back of the non-human primate studies, however, is that the treatment schedule does not allow for predicting how the triple morpholino combo will perform when given only after the viral challenge. Moreover, protection was not complete.

In unpublished follow-ups, AVI Biopharma and USAMRIID reported apparent advances in the potency of the morpholino chemistry (PMO vs PMO+). When rhesus macaques were treated with the new chemistry for up to 15 days, 75% of animals survived (I assume an n=4) ‘when the treatment period ended’. Clearly, more details are required to ascertain that this represented an improvement over the 2006 study, including survival data beyond the 15 day treatment period.

In light of these results, the SNALP-RNAi study sets a new standard for the efficacy of a prospective Ebola drug. This claim is supported by the fact that the model used in the Tekmira study was essentially identical to the one in the AVI study: rhesus macaques infected with 1,000 pfu of EBOV Zaire and treated with triple oligo combos against the L polymerase, VP24, and VP35 genes (note that any combination of siRNAs can be formulated in one step into SNALPs meaning that it is entirely amenable to rapid response applications). However, in this case the drug (2mg/kg siRNA) was given only after viral challenge, albeit starting already at 30 minutes after the challenge, either daily for 7 days or every other day for 6 days. Moreover, in the daily treatment regimen which is most similar to AVI’s study, all 4 animals receiving the SNALP-siRNA cleared the virus and survived while 2 out of the 3 animals in the alternate-day group survived.

Importantly, this was achieved in the absence of immune stimulation by the SNALP, which was very effectively abrogated by the 2’-o-methylation of the siRNAs. This is notable, because while the 2006 paper on SNALP-siRNA for Ebola in guinea pigs by the same group showed promising efficacy (>60% protection), it was clear that immunostimulation caused by the unmodified siRNAs and amplified by the SNALP was certainly a safety issue then (Geisbert et al.: Postexposure protection of guinea pigs...). Overall, the treatment regimen, 2mg/kg siRNA in SNALP every day for 7 days represents a very stringent test of the safety of SNALP and was very well tolerated, with minor increases in liver enzymes most likely attributable to the viral infection and not the SNALP-siRNA treatment.

It should also be noted that this study employed 1^st generation SNALPs which means that the 10 to 100-fold more potent 2^nd generation SNALPs as recently reported in Nature Biotech should widen the therapeutic window even more and is important when thinking about safety studies in human volunteers. It is clear, however, that while this study is an eye-opening proof-of-concept of SNALP-RNAi for the treatment of acute viral infections (at least those affecting SNALP-relevant cell types, phagocytic and hepatocytes in this case), any further development (objectives: pharmacology, biomarkers, testing SNALP RNAi at later time-points) towards biodefense stockpiling SNALP-RNAi for Ebola and/or an FDA-approved treatment for accidental needle sticks and sporadic Ebola outbreaks will depend on support by public funding agencies. It is difficult to imagine that this study can be ignored by the US government. The series of head-turning, top-quality SNALP papers in journals like Nature Biotech, Nature, Journal of Clinical Investigations, and The Lancet certainly won’t be ignored by Big Pharma.

Merging Antisense with RNAi Therapeutics to Create Fitter Companies

Yesterday’s long awaited data presentation on phase III results from ISIS Pharmaceutical’s lead antisense gene knockdown program was met by disappointment in the investor community: ISIS down over 15% on the day. While the exciting news is that the drug, mipomersen, looks like it is very close for approval for the severe, but very rare condition of homozygous familial hypercholesterolemia (hoFH) and importantly also possibly other forms of highly elevated LDL-cholesterol, part of the disappointment may be related to the long-term outlook on antisense for gene/mRNA knockdown: a 27% reduction in ApoB levels following 6 months of 200mg weekly injections with a safety profile (a number of cases of elevated liver enzymes, injection side reactions) that may be adequate for the severe cases of hypercholesterolemia, but not necessarily for less severe diseases. And this is for an organ, the liver, which has one of the best pharmacologies for antisense. Also, while a 27% knockdown may be therapeutic for a few targets, especially in metabolic disease, for most other targets it is insufficient.

Lack of high-quality gene knockdown opportunities would lead to an inefficient use of its capital that includes an enviable $600M+ cash pile and an equally remarkable cash-flow from their ‘satellite businesses’. Maybe partly because of this realization, but also of course because it believes that its IP is transferable to all areas it considers antisense, ISIS is not standing still and continues to innovate in areas such as RNAi Therapeutics and the promising gain-of-function antisense technologies of splice modulation and microRNA inhibition.

On the other side of the fence, RNAi Therapeutics is also facing a challenging investment environment. Capital is particularly difficult to raise for early-stage platform technologies. While some companies such as Alnylam, Tekmira, Sirna Therapeutics (historical example), and mdRNA are making good strides in establishing broad RNAi drug development platforms, this alone does not make up for lack of steady newsflow from mid- to late-stage clinical results that can support rich valuations in biotech. This is also not helped by some obvious mis-steps within the industry itself with the main sins being spending money on lawsuits and prematurely entering programs into the clinic, ironically not least in an attempt to keep investor interest levels high.

By merging with antisense, both the pipeline maturity profile could be enhanced and resources spent more efficiently by avoiding the temptation of entering programs into the clinic prematurely and otherwise weeding out programs that serve to artificially fill pipelines. The latter point, of course, would also apply to the antisense company, and the antisense company would further benefit from gaining access to the most potent and therapeutically promising gene knockdown technology known, RNAi Therapeutics. As the intricate relationship between Alnylam and ISIS Pharmaceuticals or the acquisition of Coley as a launch pad for Pfizer’s RNAi Therapeutics ambitions demonstrate, the scientific barriers for such mergers should be relatively minor. One risk, however, that cannot be ignored, particularly for those companies that have been built for sale, is that by combining various drug development platforms, the new entity may become a less attractive candidate for a Big Pharma acquisition. When it comes to mere survival, however, a combination should be the lesser evil.

I will now briefly discuss three fantasy combinations, at least one of which I would speculate to see within the next year.

1) Alnylam Pharmaceuticals and ISIS Pharmaceuticals (probably not within the next year). Without a doubt the most influential and potent leaders in RNAi Therapeutics and antisense, respectively. Already highly entangled through their IP cross-licensing agreements and microRNA therapeutics spin-off Regulus, a combination would create an almost cash flow-positive dream team with over $1B in cash, blocking IP, unmatched expertise in nucleic acid chemistry, clinical pharmacology, and RNAi Therapeutics. First revenues from the sales of mipomersen and continued IP licensing revenues would support a solid pipeline consisting of mipomersen label extensions, RNAi Therapeutics opportunities for liver and solid cancers, full ownership of the miR-122 program for the treatment of HCV, and transitioning antisense towards splice modulation, microRNA inhibition (with Regulus), and possibly other gain-of-function antisense applications. As part of the re-organization, some programs could easily be sacrificed without punishment by the markets. John Maraganore would be the CEO of the combined company, allowing Stanley Crooke to follow his passion in the science of oligonucleotide therapeutics.

2) mdRNA and AVI Biopharma (how soon?). The transition of antisense for gene knockdown to gain-of-function applications is most noticeable in the case of AVI Biopharma. After many years of attempting gene knockdown with their steric-block morpholinos, the company finds success in applying its technology for the modulation of gene splicing. It is considered the closest competitor to Prosensa’s Duchenne Muscular Dystrophy exon skipping program which has only recently entered an attractive $25M upfront plus multimillion bio$$$ milestone and royalty deal with GSK after a series of high-profile publications on DMD-related exon skipping. The partnership potential of AVI’s DMD program then as well as its recent capital raising should provide the needed capital cushion for the combined company to invest in RNAi Therapeutics for gene knockdown and some new splice modulation opportunities. mdRNA, of course, is scheduled to run out of cash early next year and it would be a miracle if the two companies had not contemplated such a merger, particularly after AVI Biopharma moved in as mdRNA’s neighbor not too long along up from Oregon. With AVI’s cash reserve, the combined company may then find it easier to attract platform partners for mdRNA’s technology further bolstering the financials.

3) Silence Therapeutics and Archemix (not really an antisense company, but close enough). It is almost two months now that Silence announced to be in reverse merger talks. Since then, however, not a word except for so-so news on the results of opposition proceedings at the EPO related to their core patent. What Silence needs is cash (who doesn’t?), and what it can offer is a phase I cancer program, RNAi Therapeutics drug development expertise, and an siRNA structure that is not without use, although facing very serious patent challenges. What Archemix needs with its growing pipeline is access to public markets as evidenced by a previously failed reverse takeover attempt with cash-rich NitroMed, as does by the way Quark Pharmaceuticals which should also be counted as a possible Silence Therapeutics merger candidate. The fact that Silence Therapeutics has some aptamer in its blood line and the increased investment by Archemix into aptamer-mediated delivery of RNAi (Dicerna) and microRNA (miRagen) Therapeutics should help a combined company find a common language. Until any such deal is announced, however, Archemix would have to be prepared though that yet another potential partner will walk away from it last minute as Silence Therapeutics should also be receptive to other offers.

Which one is the most likely combination? Add your vote on the right.