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.

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