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.
Oyasuminasai.
Disclosure: long TKMR.
6 comments:
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?
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.
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.
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.
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?
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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