What the thrombocytopenia findings mean for Ionis Pharmaceuticals

Yesterday, Ionis Pharmaceuticals disclosed that severe reductions in platelets had been observed in phase III clinical trials of both IONS-TTRRx for the treatment of TTR amyloidosis and IONS-ApoCIIIRx for conditions related to highly elevated triglycerides.  Severe platelet reductions are dangerous since it can lead to occult, uncontrolled bleeding and poor blood clotting following injury.

Since the conference call was a PR disaster as the CEO of Ionis has major issues with speaking his scientific mind, and since competitor Alnylam has seemingly become the original source and interpreter of the Ionis thrombocytopenia issues (one wonders how they come into possession of these Ionis trade secrets...), I thought it may be useful to briefly come out of blogging hibernation and lay out my thoughts about what these events mean for the technology and the company.

Thrombocytopenia likely limited to systemically administered, unconjugated PS-oligos >200mg per injection

As a hematological abnormality that has historically been observed with phosphorothioate (a ‘sticky’ chemistry) oligonucleotides when given at high doses (>200mg/injection)  I’ve always considered it likely that such thrombocytopenia will be associated with measures of plasma exposure of the oligonucleotides.  Notable examples for thrombocytopenia with phosphorothioate oligos include the DMD exon skipper drisapersen by Biomarin/Prosensa (6mg per kg per week, i.e. around 300mg/week for 50kg boy) and telomerase inhibitor imetelstat by Geron (~10mg per kg per week, i.e. around 700mg/week for average adult).  Actually, isn’t it ironic, or maybe even curious that imetelstat is being developed for conditions where elevated thrombocytes is the problem (see related blog entry)???

Consistent with this notion, there was a study by Flierl et al. in 2015 that looked at the mechanism of platelet activation which may lead to platelet consumption and explain lowered thrombocyte counts.  Without going into the details of the mechanistic aspects of the study, the authors find a strong correlation with peak plasma exposure (c max) of the oligonucleotides and platelet activation.   

So why hasn’t Ionis seen severe cases of thrombocytopenia in the past (excluding use of PS-oligos in cancer patients which frequently suffer from potentially confounding bone marrow suppressions from other drugs)?  The most probable explanation is a) these events are quite rare events and b) that their experience with PS-ASOs at 300mg/week and above has been limited.  At 300mg and especially 400mg per week, safety has always looked a bit dicey such that the 300mg per week dose e.g. for TTRRx was only adopted after 200mg per week was not competitive with the knockdown results produced by ALN-TTR02 from Alnylam. 

Similarly, the initial studies with ApoCIIIRx did not include the 300mg per week dose and was adopted in favor of the very impressive triglyceride reductions seen at doses higher than 200mg.  Usually the dose escalation of the prototypical Ionis phase I studies involved 50, 100, 200, then 400mg per week with 400mg per week never being chosen for the phase II and/or pivotal studies.

What I find highly interesting is that the pharmacokinetics data from the healthy volunteer study of ApoCIIIRx reported by Graham and colleagues in 2013 (see only Table IV) reported a non-linear, 4.5x increase in cmax when doubling the dose from 200mg to 400mg per week.  This could mean that at doses of 200mg per week and higher, the risk of severe thrombocytopenia is dramatically elevated by going past the threshold where platelets become critically activated (à clotting cascade).  

If the cmax theory holds true, then the following should be the impact of the new findings on the Ionis platform.  The summary takes into account the clinical observations by Ionis that the platelet reductions are reversible upon stopping dosing and can be prevented and also treated by steroid use (just as ALN-TTR02 involves steroid use):

1)      Unconjugated, systemically administered antisense at 300mg per week and above (incl. phase III assets TTRRx and ApoCIIIRx): need for tight platelet monitoring.  May involve temporary halt of studies to amend protocols.  Commercially, need for tight platelet monitoring could be a problem for less severe diseases due to convenience and competitive issues.  

Note that for all the liver-targeted programs, backup GalNAc-conjugated versions are in development which should not suffer from thrombocytopenia (see below).  However, systemic programs targeting other tissues such as DMPKRx for myotonic dystrophy will have to be under continued scrutiny depending on the dose.

2)      Unconjugated, systemically administered antisense at 200mg and below per week and below: little impact.  Start collecting data more systematically to learn more about platelet interactions, otherwise no big impact.

3)      GalNAc-conjugated antisense: no impact. Essentially all the Ionis pipeline, including ApoCIIIRx, has been re-engineered for some time now to be GalNAc-conjugates.  This is because of their 10-100 fold increased potency over the unconjugated versions thus decreasing the doses to well below those expected to cause severe thrombocytopenia.  Even at the same doses, plasma exposures will be much reduced due to the rapid clearance into the hepatic compartment as demonstrated by Shemesh et al in one of the most recent publications by Ionis.  No thrombocytopenia events to my knowledge were seen with RG-101 (for HCV) by Ionis' 'satellite company' Regulus Therapeutics, where a up to 8 mg/kg of GalNAc-conjugated phosphorothioate oligonucleotide has been administered.

4)      CNS programs: no impact. Peak plasma exposures are insignificant for intathecally administered oligonucleotides as used in Ionis’ CNS franchise, a franchise which includes exciting drug candidates such as phase III asset nusinersen for the treatment of spinal muscular atrophy (SMA) and candidates for other severe neurodegenerative diseases.

In summary, the only programs which could be significantly impacted by the thrombocytopenia findings are the programs that target tissues outside the liver and which involve systemic administration.  The liver franchise remains intact especially with the new GalNAc versions although there could be some minor delays and increased competitive impact in those diseases that Alnylam is free to go after according to the Ionis-Alnylam IP agreements.  The important CNS franchise remains fully intact. 

Disclosure: long Ionis and doubled down yesterday.

Why Marina Biotech Deserves a Chance

Oligonucleotide Therapeutics is hot.  Outside of immune-oncology which is breaking new ground in cancer, Oligonucleotide Therapeutics is where the real innovation in drug development happens today. In fact, Oligonucleotide Therapeutics already has become the third major drug discovery engine and I posit that at the development stage it has already surpassed monoclonal antibodies.

   

This is also reflected by the valuations of the two best known proponents in the field, Alnylam and ISIS Pharmaceuticals which are both worth around $8 billion, a valuation that given its purchasing power that comes along with it positions them to become major pharmaceutical companies.

It is then long after the behemoths and mid-tier companies like Arrowhead Research and Regulus Therapeutics which struggle for similar recognition with market caps in the 0.5 to 1 billion dollar range, that Marina Biotech comes in with an anemic, fully diluted market cap of ~30M.

Vicious circle

A 300x valuation difference to the leaders will put off most investors from conducting more in-depth research.  Surely, a $30M valuation shows that its technology does not work.

  

This detrimental circular logic extends into business development where Marina Biotech has essentially given away valuable pieces of its technology stable for pennies.  Licenses to CRN technology to Novartis for a mere $1M or UNA technology to Arcturus for a few hundred thousand dollars are sad examples of this.

Of course, at the time the deal were done, Marina Biotech was in dire straits financially and this was exploited in cold blood by its partners.

OK, that’s business, nothing personal, and good on Novartis and Arcturus for their bargains.

Overall, Marina Biotech is probably one of the two most prolific deal makers in the industry along with ISIS Pharmaceuticals, reflecting its broad assets in Oligonucleotide Therapeutics.

UNA-CRN Antisense Oligos, it’s as simple as that

This, however, is also a distraction for management and I am afraid that the CEO, Michael French, keeps looking under the wrong lamp posts for capital.

In his opinion, Marina Biotech should be the one-shot shop for Big Pharma looking for solutions against certain disease targets where the best mechanism of action is not apparent. 

Myotonic dystrophy type I, a muscle wasting disease caused by a toxic nuclear RNA, is probably a good example of this, and this is also Marina’s lead development project if we ignore for a moment its legacy program in familial adenomatous polyposis (FAP) now in phase I clinical development.

I, however, struggle to come up with many more examples of this, and if I were a Big Pharma, I would just evaluate the different strategies in-house and, if necessary, then gain access to that one most promising mechanism of action.

This blogger, on the other hand, believes that the public markets should be Mr French’s audience.  Times have changed and the public markets have become a much more attractive source of capital for supporting platform companies like Marina Biotech. Big Pharma, on the other, likes to talk about innovation, but ends up acquiring only specific development candidates close to the finish line.  And if it engages in innovation, it usually fails as a result of their organizational rigidity and leaders better suited to run fast-food companies than technology companies.

Imagine how the simple message that Marina Biotech has a chemistry strategy that can do what ISIS Pharmaceuticals has achieved would resonate with investors?  

I am referring here to the potential of combining UNA with CRN (similar to 2.5 cET by ISIS Pharm or LNA by Santaris/Roche) chemistry which just as proposed for usiRNAi triggers  could evade some fundamental IP in the field by virtue of UNAs not being your typical modified base, an idea that has gained wide support in RNAi Therapeutics (à Tekmira, Arrowhead Research, Arcturus).

It should also be noted that only Marina Biotech has the ability to combine both UNAs and CRNs. Despite their licenses, neither Arcturus nor Novartis can do that.

What I also like about the UNA-CRN antisense focus is that such a simple molecule is ideal for a small company like Marina Biotech which does not have much research to speak of.  The antisense concept is so simple that even a blogger would be able to translate it into the clinic from the comfort of his home.

Marina Biotech, of course, is no ISIS Pharmaceuticals, and I should state that my ‘never-touch portfolio’ which I established last summer almost exclusively consists of ISIS Pharmaceuticals which, at the time, accounted for more than half of my stock holding.

Marina’s Outlook

Depending on risk tolerance (an investment in Marina Biotech is still a survival play), however, Marina Biotech has its rightful place in the investment space which explains this blog entry in the first place.  If Michael French could only get himself to commit to a simple CRN-UNA ASO strategy and show some data from its Myotonic Dystrophy program, Marina’s severe undervaluation relative to peers would instantly become obvious.

It’s OK, however, to analyze clinical data from its FAP program as long as it does not cannibalize investments in the ASO platform.  It may also be an excuse to enter the GI ASO space which, following a $700M+ license from Nogra Pharma to Celgene, has come into high demand among Big Pharma.  Although I do not think GI-ASO is technically a robust opportunity as the liver and CNS, if Big Pharma likes to part with $$$, why not cater to them?

Following the filing of an S-1 securities registration statement and in light of Marina’s financial position (cash runway until mid-2015), it is obvious that Marina Biotech will raise capital in the near future.  It will be telling on what terms this will be done and who will participate.  While you will read in most biotech investment textbooks not to invest in those times, remember that in 2013 somewhat similar circumstances set up Arrowhead Research for a more than 10x return in less than a year.

ISIS Demonstrates Wider Utility of RNaseH ASOs for Nuclear Targets

While research astounds us on a daily basis with unexpected discoveries, sometimes it is what we don’t know and haven’t bothered to ask is what is astounding.  One example of the latter in the field of Oligonucleotide Therapeutics is the poor understanding of which tissues and cell types and therefore disease indications are most appropriate for a particular (delivery) approach based on the ability to engage targets there.   

Antisense Therapeutics, over 30 years in the making, has been the biggest violator of this principle.  Smug in the belief that delivery is not necessary, the approach has been to just apply the oligonucleotide and then pray that it will go to the right place and work its magic, especially in cancers.  Only after decades, the field through much clinical trial and error has come to the realization that the liver and kidney may be pharmacologically favored target organs.

In a long overdue tour-de-force, Hung and colleagues from ISIS Pharmaceuticals recently published in the journal Nucleic Acid Therapeutics a detailed investigation of the global biodistribution and RNaseH knockdown efficacy of phosphorotioate antisense chemistries (PS-ASO) following systemic application: Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. This parallels a similar study for the direct application of this chemistry to the CNS presented at this year's OTS meeting which has yielded the surprising insight of the broad CNS distribution of PS-ASOs following focal administration. 

As a result of the latest research, a roadmap of target organs was created.  Importantly, through the application of newer RNA immunohistochemistry methods rather than the old harvesting and mashing up organs, the study looked at the specific cell types within an organ that were amenable to RNaseH knockdown.  This is important in at least two ways.  Firstly, it allows us to reject a potential target in organs where bulk knockdowns have shown a rather deep knockdown, but where the detailed organ analysis shows that the particular cell type in which one desired the knockdown does not show such a knockdown (e.g. kidney).  Secondly, it allows one to reconsider targets and cell types within organs for which bulk knockdowns have not been observed (e.g. the small intestines).

Another valuable piece of insight of the study was that it compared the old, second-generation 2’ MOE chemistry with the higher affinity locked nucleic acid chemistry version pioneered by Santaris (in this case the cET ISIS knock-off version of LNAs).  In addition to increasing the knockdown potency in traditional tissues such as liver, kidney, and adipose tissue, the chemistry allows for appreciable knockdowns in some less traditional tissues such as muscles.  Unfortunately, the direct comparison between 2’ MOE and LNAs was only performed in mice and at the very high 50mg/kg dose.  In the non-human primate study, also at a very high (35mg/kg) dose, no such direct comparison was  performed and from this, it seems that the new organs enabled by the higher-affinity chemistries were limited to the muscle and lung.

Why Marina Biotech could be the 2014 high-flyer

Regular readers will notice that I have shifted some of my investment attention to Marina Biotech.  The main reason for this is that this company which is considered by many to be dead, actually owns the rights to a high-affinity ASO chemistry (CRN) of a potency that is equivalent to Santaris’ LNAs and probably superior to ISIS’ cET while the market cap of Marina is just one-thousandth that of ISIS Pharmaceuticals.  Even when one considers that the in vivo safety (especially) and potency evaluations lag behind the others due to the budget constraints of Marina Bio, I believe it is a risk worth taking given the enormous valuation gap and the fact that CRN PS-ASO biodistributions and activities can be assumed to be similar to the competing chemistries.

What is more, Marina Bio is pursuing a program in type I myotonic dystrophy which represents the sweet spot of indications uniquely facilitated by these chemistries: muscle as a new druggable target organ and still shielded from superior RNAi competition; a rare, severe orphan disease; and a toxic nuclear RNA.

Largely depending on the recapitalization strategy (partnering first before capital raise or vice versa), this program together with SMARTICLE RNAi delivery and access to usiRNAi triggers, has made me accumulate 1.5% of the company with the intention of increasing my position.  Of course, financial success can only happen if other investors share my view that we should therefore give Marina Bio another chance.  As always, invest at your own risk and according to your unique financial circumstances.

A shameful title

If you re-read the title of the paper and even the entire publication, you may be forgiven for going away with the impression that it is open season for RNaseH knockdown in muscles and other tissues and organs.  This is far from the truth as the ‘exemplary’ target chosen in the study was the nuclear non-coding RNA MALAT.   This is because a high-profile Nature publication by ISIS Pharmaceuticals itself (Wheeler et al. 2012) has shown that whereas largely cytoplasmic m-e-s-s-e-n-g-e-r RNAs (i.e. RNAs encoding for proteins as even a decent high-school kid will know) expressed in muscles were entirely recalcitrant to RNase H knockdown, the mutated nuclear retained DMPK underlying myotonic dystrophy was susceptible to such action.  Curiously, while Wheeler et al. was cited in the Hung paper, the authors failed to point out this important and very obvious caveat.

This can be no innocuous omission as ISIS Pharmaceuticals in one of their patent applications has expressed the striking difference between mRNA and nuclear RNA druggability by PS-ASOs as follows (highlights are mine):

Reduction of Nuclear-Retained RNA

Data provided herein demonstrates that sensitivity to cleavage by ASOs is dramatically increased for a nuclear-retained RNA making it possible to reduce nuclear-retained targets in tissue that has low uptake of oligonucleotide by a pharmacologically relevant amount. For example, out of the more than 4,000 transcripts that Isis has targeted by antisense, MALAT1, a non-coding, nuclear-retained RNA, is demonstrated to be one of the most sensitive targets for antisense oligonucleotide/RNase H inhibition. The data demonstrate a great number of oligonucleotides targeting over the majority of the transcript that inhibit by more than 50% in vitro. The data also demonstrates very low IC50 values in multiple cell types. Half-life studies have also shown that the MALAT1 is stable over a period of at least 10 hours. Subcutaneous administration of oligonucleotide targeting MALAT1 at doses commensurate with other oligonucleotide drugs (e.g., liver targeting drugs) achieved pharmacologically relevant reduction of MALAT1 in skeletal and cardiac muscle. Dosing at 50 mg/kg biweekly for 3.5 weeks achieved a 89% and 85% reduction in gastrocnemius and quadriceps, respectively, and 54% reduction in heart (as compared to 95% reduction in liver). Pharmacologically relevant reduction of MALAT1 has also been achieved in tumor xenograft models.

As a member of the Oligonucleotide Therapeutics Society, it greatly saddens me that the related journal is letting ISIS Pharmaceuticals get away with the highly misleading, and simply wrong title.  There is no arguing around it.  Followers of the competitive oligonucleotide therapeutics investment arena know that the game here is to make RNaseH antisense appear much more widely applicable than it actually is.  What is more, it was at the 2011 OTS meeting in Boston where the ISIS CEO Stan Crooke in his keynote made the ignonimous statement that ‘mipomersen has no side effects’.  

I strongly suggest to the society and the journal Nucleic Acid Therapeutics which are supposed to foster the development of the technology broadly to keep a watchful eye on the growing corporate influence, especially by 'generous sponsors' ISIS and Alnylam Pharmaceuticals.