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).
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?
ReplyDeleteYour 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.
ReplyDeleteDirk, your insight is appreciated. Have you put a toe or 2 back into TKMR or still all in ARWR? just asking. Thanks friend.
ReplyDeleteNo, still about 90% into ARWR! Keep a 2-year perspective on ARWR for now and you will probably do well.
ReplyDeleteAdded 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.
"accumulating some Marina Biotech on a lottery ticket for a successful turnaround as investors embrace RNAi Rx again"
ReplyDeleteWith due respect Dirk, did seeing Benitec's 100% + jump in just 8 weeks influence your Marina punt?
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.
ReplyDeleteBut don't get me wrong, Marina is far, far...far from being another Arrowhead.
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."
ReplyDeleteWould you please explain your thinking behind that last sentence.
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.
ReplyDelete