Tuesday, February 25, 2014

Tekmira Setting New Standards in mRNA Therapeutics…and They Have Only Started

Tekmira today presented impressive data on pre-clinical messenger RNA (mRNA) delivery to the liver and solid cancers (PR here, slide deck here).   The data presented at the AsiaTides in Tokyo greatly exceeded those reported in the literature, including a 4 log increase in potency of liver gene expression compared to the seminal paper by Kariko et al.paper (2008)

Importantly, the formulation process and chemistry were optimized for mRNA delivery thus generating electron-dense ~80nm particles and easily surpassing >90% encapsulation efficiencies that are thought to be required to pass regulatory CMC muster.

Tumors giving liver run for its money

What had caught my eye when Tekmira presented firstmRNA delivery data at the Tuebingen mRNA conference in October 2013 and which was further substantiated in the present presentation, in terms of absolute gene expression, their mRNA delivery seems to perform as well if not better in liver cancer and non-liver cancer models compared to in normal hepatocytes.  This could be due to a less RNA degradative environment in tumors versus the liver of which an important function is detoxification.  This is supported by the fact that the duration of mRNA expression in tumors greatly exceeded that in the liver (a gene with a short protein half-life was used).

This made me think of the recent oncology spin-out (Onkaido)by mRNA Therapeutics company Moderna, the darling of mRNA Therapeutics which has raised around half a billion dollars in partnership money (AstraZeneca, Alexion, DoD) and fund raisings over the last 18 months alone.  The spin-out and internal focus on genetically defined orphan diseases may mean that Moderna would like somebody else to fund Onkaido, for example as part of a joint venture.  Remember, for most Big Pharma companies, RNA Therapeutics are first and foremost interesting for oncology as it allows them to go after the targets that their scientists have been dreaming about for so long yet were not able to drug.

Given that most of the de-risking in oncology drug development occurs late in clinical development, it is debatable whether Tekmira, already with a lead candidate in oncology (TKM-PLK1) should focus their in-house mRNA development attention towards oncology initially and whether this might not be better done as part of a spin-out/joint venture (Onkaido and/or Big Pharma).

For the liver, mRNA expression was detected in essentially every hepatocyte.  This supports the use of SNALP-mRNAs not only for the use of the liver as a factory for protein production, but also for diseases with defects in single genes expressed in the liver, including those genes that act only in the cell that they were expressed in (cell autonomous).  Compared to oncology, such indications would also allow for earlier clinical de-risking and together with orphan status mean that they better match the profile of a (still) sub $500M market cap company.

More upside

Given that Tekmira has only been working on mRNA Therapeutics for a year plus (1-year stability data were presented) and since simple off-the-shelf mRNA chemistry was used, one can only dream which diseases could be addressed and where the company could go with this, including developing their own mRNA Therapeutics instead of viewing it as a simple monetization opportunity. 

Tekmira mRNA developments that I am looking out for include advances in mRNA delivery to the lung epithelium.  Tekmira has been, and according to the presentation is still actively working on inhaled LNPs, and it would be logical if they adapted that effort towards mRNA delivery.  Expressing CFTR in lung epithelia for the treatment of cystic fibrosis (CF) would be an obvious target here that could rally a lot of support from various stakeholders (important for companies like Tekmira).  Gene therapy involving the inhalation/instillation of DNA to the lung has failed, in large part due to the difficulty of getting the DNA from the cytoplasm across the nuclear membrane into the nucleus.  Just like in RNAi, mRNAs only need to get into the cytoplasm, a much simpler task.  Moreover, in CF you should not need to get the mRNA into every cell.

A final opportunity for Tekmira is the co-formulation of mRNAs and siRNAs into a single LNP.  Imagine an oncology drug targeting both cancer drivers such as PLK1 and overexpressing tumor suppressors.


Disclosure: long TKMR.


Anonymous said...

RGLS to present at Cowens next week.
Mr.X originated out of Cowens. Given the strong showing of mRNA at TIDES, I am left wondering if it is not TKMR/ARWR/MRNA/BLT or anybody else we should be watching but instead all eyes should be focused on RGLS for confirmation of a scientific breakthrough. Not ALNY or ISIS.
Perhaps this is why Mr. X took the job at BIIB.
Any chance of hearing your TIDES presentation Dirk?

Dirk Haussecker said...

I just provided an assessment of the current state of the Business of RNA(i) Therapeutics somewhat more tailored to the company representatives listening and less with investors in mind.

However, the great thing about presenting and blogging is that it brings up questions about what I might be missing. Always happy to reassess my views in light of new data.

About Mr. X....it never works that way. If there is a relationship, it's often just the opposite.

Anonymous said...

Does anyone know what the TOX data looks like for PLK1 siRNA therapy?

I was under the impression that PLK1 is required for any dividing cell, so I thought TOX may be a problem.

Anonymous said...

I can well imagine Mirna wanting to get a piece of TKMR in order to have influence at BoD level while representing PFE interests.

Your disdain for PFE participation in this space is well noted, but you must also know PFE cannot be ignored as we enter a new construct for commerce in medicine.

Therefore, the TKMR cap. raise may well be a placement to Mirna. Terms of which include a licence for FTO and future options.

I for one will be disappointed if it is a placement to money men along the lines of ARWR's.

Anonymous said...

Dirk, after your tongue in cheek PFE-$100b-TKMR deal comment the other day and now seeing the actual, I am puzzled why TKMR has not named the buyer.

Is this PFE wishing to remain anonymous still? Or is there just no legal onus on either party to divulge such info?

Anonymous said...

Benitec plans to establish a small laboratory in California, headed by Dr Suhy, which will allow us to:
? Quickly design, test and validate therapeutics in-house – that development is currently outsourced
? Update and extend our technologies with relevant advancements in RNAi and gene therapy
? Provide further opportunities for partnering programs with large pharma

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