Monday, November 10, 2014

Co-delivering Antisense and RNAi for Cancer

The upcoming phase I top-line data for ISIS-STAT3Rx in liver cancer (HCC) to be presented at the upcoming EORTC-NCI-AACR triple meeting in Barcelona (Nov 18-21) will be an important test of the potential utility of RNAseH antisense oligonucleotides (ASOs) incorporating high-affinity chemistry in oncology.  

Based on the body language by ISIS Pharmaceuticals* and last week's $7.5M milestone payment from partner AstraZeneca for progress on ISIS-STAT3Rx (aka AZD9150) , I am tempted to speculate on more than just ‘encouraging’ results.  On the other hand, Regulus Therapeutics partner Sanofi at the Canton Nucleic Acid Forum (CNAF) also last week, noted the need for formulating antisense oligonucleotides to get their anti-miR21 oncology candidate into liver cancer tissue. It is likely that they will be using liposomes for that (--> Tekmira?).

* I was surprised that at the CNAF in Guangzhou, China, Brett Monia from ISIS mentioned STAT3Rx and cancer right after gene silencing in the liver as the next interesting application for ASOs- that is ahead of even the exciting CNS opportunity.

The discrepancy in body language may be explained by just cultural differences (conservative, blasé Big Pharma versus risk-taking, enthusiastic biotech); it may also be a reflection of different requirements for effective tissue concentrations with RNaseH versus anti-microRNA modalities or different target requirements.  Whatever the reason, the Sanofi comments clearly support the notion that getting naked, even phosphorothioated oligonucleotides into cancer tissues is not as robust as with other tissues such as the liver and kidney.

I am therefore pleased that it is a Big Pharma, the last place where I had expected that from, that is connecting the dots and is considering delivery formulations, even the supposedly ‘toxic’ LNPs.  The concept is that the nanoparticle would facilitate a higher tumor concentration of the oligonucleotide, and once in the tumor interstitial space, cellular delivery may be facilitated via two routes.  Firstly, it may be traditional liposome-dependent cell uptake and cytosolic release.  Alternatively, those LNPs that get stuck in the interstitial space would spill the phosphorothioate oligo which may then diffuse further and get into the target cell by self-delivery. 

The same concept, of course, applies not only to phosphorothioate ASOs, but also to self-delivering RNAi triggers (+/- conjugation).

But why stop there? I propose that for cancer delivery, one should strongly consider and co-formulate RNAi triggers and ASOs into a shared nanoparticle.  They could target either the same gene, or they could target different genes thus taking into account the desire for a multi-pronged attack on cancer   (-> resistance).  In that scenario you would benefit from the superior gene silencing efficacy of RNAi triggers in those cells that they were able to reach, but then extent your reach with the help of the more agile, penetrative single-stranded antisense molecules. 

As such, PS-ASOs have an advantage in addressing intra-tumor heterogeneity of the EPR effect which is a well-recognized problem of nanoparticle delivery for cancer.

Another benefit of combining RNAi triggers with RNaseH ASOs is that you could achieve additive gene silencing activity when going after a shared target.  For example, if the RNaseH ASO and the RNAi trigger had both say a 70% knockdown activity on their own in the nucleus and cytoplasm, respectively, the combined activity would likely be ~90% which genetically could make a huge difference.

There is also a potency benefit, although more minor, when going after different targets because at least in RNAi, the best you can hope for when combining RNAi triggers against different targets is that they do not interfere/compete with each other.

With solid cancer data from both Tekmira (RNAi) and ISIS/AZ out over the coming weeks, we will soon get a sense of whether the field has moved forward in oncology and what the next steps ought to be.


musial said...

With ISIS raising capital today again contradicting now twice previous management statements, it speaks to the limited partnership interest in unpartnered drugs

Anonymous said...

There hasn't been a new drug partnership since (I believe) the BIIB deal. You recall that was a weirdly friendly partnership. ISIS gets paid even if the target is addressed by a BIIB small molecule. There is some kind of BIIB management team in-house with ISIS, working with ISIS's top operational officers. That is really more of a partnership than a simple licensing deal. It looks to me like BIIB is doing a very slow and very formal, old-fashioned courtship. I think ISIS is playing a little coy. She's got a great dowry and other suitors. I think ISIS is keeping herself pure by not doing any more “partnering”. A powerful partner most certainly does not want a bunch of secondary hanger-ons after the wedding. I think Stan is getting a bit older and slowing down, as is natural. I think he'd sell at something over $100 pps. If we can get to $70-$80 then BIIB could offer $120, with maybe part stock, part cash. I think from any suitor's viewpoint, it is very important that ISIS not partner any more drugs. I think from BIIB's particular standpoint it is important to them to have the wedding before SMN is approved. It's one thing to be the guy who licensed from his future wife, the cure to the number one genetic neurological killer of infants, it's another thing to the THE company that delivered the cure. I think BIIB has enough of an ego to want to be THE company. This will be an historic event in man's “evolution” and understanding and manipulation of the genome. Sure there was Viteravine and Mipo, but SMN is the one that will be written up in the history books. The story will last for thousands of years. I think the top guys at BIIB don't want to be a footnote or secondary reference, ten thousand years from now. I think the top guys at BIIB want their specific names in the main text of the “official” historical record of the evolution of man's understanding and manipulation of the human genome, even 10,000 years from Xanadu did.

Anonymous said...

BIIB may be courting ISIS, but I hope the answer is thanks, but no thanks. ISIS should be valued like Regeneron, or rather, more than Regeneron. Stan is rich already and what kind of legacy would that be -- to be a footnote to BIIB. $125 per share is too cheap a price to pay in order to erase real the story of 25 years of struggle, and swimming against the current, to realize fundamental change to medical discovery and patient treatment. Why should BIIB get to take credit for that? I would vote against it. But I don't think Dr. Crooke will go for that deal in the first place, and why should he?

Anonymous said...

No way an offer for ISIS would approach REGN's market cap. The later has material growing revenue, ISIS does not and it's all on the come

Some day maybe but ISIS has to get past its past of over promising and under delivering

Anonymous said...

Just returned from the CNS Anticancer Drug Discovery & Development Conference in Miami. Dr Amy Heimberger of MD Anderson presented pre-clinical data on the delivery of mircoRNA-124 to immune cells that modulated the glimoa immune microenvironment via STAT3. Her data showed improved outcomes in mouse model GBM.

The delivery was accomplished using Arcturus LUNAR technology. So in less than two months Arcturus has shown successful pre-clinical data for LUNAR in siRNA, messengerRNA, and now microRNA. Impressive.

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