Monday, October 28, 2013

Tekmira Grabs Leadership Position in Messenger RNA Therapeutics

Messenger RNA Therapeutics is the latest addition to the RNA Therapeutics tool box.  A simple concept, it has only been recently revived outside the therapeutic vaccine realm when it was shown (e.g. Kariko et al. 2012 and Kormann et al. 2011) that certain nucleic acid modifications can minimize, if not abolish innate immune responses triggered by these long RNAs.

Of course, in addition to representing an increased innate immune challenge compared to RNAi Therapeutics, like RNAi Therapeutics, the key technical challenge for mRNA Therapeutics is the effective delivery into the cytoplasm of target cells.  When AstraZeneca paid Moderna Therapeutics $240M in upfront alone earlier this year for a limited technology license, I half rolled my eyes telling myself ‘not again’.  

The ‘not again’ refers to Big Pharma getting distracted by supposedly gate-keeping IP claims regarding the RNA inducer all the while ignoring the critical importance of delivery.  As we know, this mis-attribution of value has caused much trouble in the history of RNAi Therapeutics.

Enter Tekmira

I further believed that the SNALP LNP technology by Tekmira is most readily adapted for mRNA delivery among the RNAi delivery technologies.  So it was pleasing when Tekmira disclosed last week at the 1st International mRNA Health Conference in Tuebingen, Germany, that they indeed have been pursuing mRNA delivery and presented first data indicating that they are most advanced in this effort.

As it is difficult to compare the amounts of proteins expressed with the different technologies due to the unique half-life of each mRNA and protein, the leadership hypothesis is partly based on an assumption, namely that there is a close relationship between SNALP LNP delivery of siRNA and mRNA.  More importantly, however, due to their ample experience of commercially translating SNALP LNP delivery for RNAi Therapeutics with over half a dozen SNALP-enabled candidates that have entered clinical development and with the demonstration of scale-up, they should have a first-mover advantage.

Liver and solid cancers

In particular, Tekmira presented data on mRNA delivery in mice for the liver and solid cancers.  The liver is of interest both as a target organ itself and also as a factory for the production of proteins secreted into the circulation.  The data showed that robust levels of the luciferase marker protein could be made in the liver.  However, the data also reminded me of one (certainly not insurmountable) challenge with mRNA Therapeutics: the relatively short period of time (<24 a="" as="" been="" boundary="" data="" designed="" expression.="" expression="" gene="" half="" has="" have="" hours="" however="" indicate="" life="" lower="" luciferase="" nbsp="" of="" ote="" p="" platform.="" protein="" reporter="" robust="" short="" so="" specifically="" that="" the="" to="">

In that light, the tumor expression data were particularly intriguing.  Not only were the tumor peak expression levels comparable to the liver, but they also were maintained over a longer period of time (~2 days) and generally declined more gradually.  Since the same mRNA was delivered, this observation would be consistent with delivery to the tumor over time, as one would expect if the EPR effect plays an important role here.  The data also support a depot effect following extravasation meaning that intratumoral SNALP-mRNAs can be stable so that they can be taken up in a delayed fashion and yet be functional.  Such observations incidentally should also prove quite useful for the development of RNAi delivery for solid tumors and I look forward to more such cross-fertilizations between siRNA and mRNA delivery.   

Tekmira the logical partner for AstraZeneca

The new disclosures would seem to warrant AstraZeneca partner with Tekmira on mRNA delivery.  After all, having spent $240M for IP puts them under pressure to do something with their rights.  As I do not think much of Moderna’s own LNP delivery efforts (order my latest OTS 2013 Report to see why), AstraZeneca would be well advised to look outside of that partnership for delivery solutions.

It also so happens that AstraZeneca’s IP rights relate to protein expression for metabolic disorders (--> liver as a critical metabolic organ) and cancers, precisely the two areas where Tekmira’s technology should be most useful initially.    

And who knows, maybe Big Pharma is not always that dense as it sometimes seems and all this had been in the making months ago and the CEO of Tekmira is about to make good on his partnership ‘promise’ (in that case, sincere apologies to AstraZeneca).


Anonymous said...

I know it's early, but would you consider the mRNA approach the leading platform for RNA-based gene upregulation? What do think about RaNA's platform that targets lncRNA and does it without a delivery vehicle?

Dirk Haussecker said...

Your questions are appropriate, but cannot be answered in a sentence or two. Lots of aspects to weigh, so it will largely depend on the application.

Anonymous said...

Dirk, your insight is appreciated. Have you put a toe or 2 back into TKMR or still all in ARWR? just asking. Thanks friend.

Dirk Haussecker said...

No, still about 90% into ARWR! Keep a 2-year perspective on ARWR for now and you will probably do well.

Added a few RGLS for a trade on AASLD and Kidney Week, plus accumulating some Marina Biotech on a lottery ticket for a successful turnaround as investors embrace RNAi Rx again.

Anonymous said...

"accumulating some Marina Biotech on a lottery ticket for a successful turnaround as investors embrace RNAi Rx again"

With due respect Dirk, did seeing Benitec's 100% + jump in just 8 weeks influence your Marina punt?

Dirk Haussecker said...

Not directly, but looking at the RNAi environment in general. Note that MRNA is worth $5M only currently and with the right strategy it could multiply. I even believe they will have a lab before Benitec will ever have one. Of course, the investment is based on the hypothesis that Michael French will respect current shareholders when it comes to refinancing the company and setting up that lab. If they can revive the FAP trial, they'll even have an active clinical program plus a few that utilize Marina tech and are in the hands of partners.

But don't get me wrong, Marina is far, far...far from being another Arrowhead.

tettrazini said...

Dirk, sometime ago (12/13/2012)you wrote, "Although GalNAc-siRNAs and DPCs are currently clearly competing, there is also scope for them to synergize, especially in the area of oligonucleotide chemistry. Curiously, Alnylam did seek access to DPCs earlier this year, supposedly for its evaluation in one of its 5x15TM programs. Learning about DPC siRNA chemistry may be of at least equal, if not considerably more value to Alnylam."

Would you please explain your thinking behind that last sentence.

Dirk Haussecker said...

Tet, it's not much. Just meant to say that there was value of just learning about DPCs and then apply the lessons to GalNAcs without taking an outright license pick from Arrowhead.

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