Tuesday, March 24, 2015

Isis Pharmaceuticals and Roche/Santaris About to Settle Patent Dispute

According to court documents dated March 20, 2015, it looks like Isis and Roche, the new owner of the original defendant Santaris, are about to settle the RNaseH antisense patent infringement suit brought by Isis.  A settlement would have important implications for the future of Antisense Therapeutics. 

To wit, in 2011 Isis sued Santaris for infringing its RNaseH gapmer patents by Santaris signing on Big Pharma partners regarding RNaseH Therapeutics development.  Isis viewed this as a form of monetizing their IP and consequently sued.  If decided in Isis’ favor, the case would have been a notable departure from the long-held practice of shielding preclinical business and drug development under the safe harbor of the Research Exemption

As such, the case could have had a chilling effect on particularly small innovative biotech companies seeking to improve upon existing technologies, but by this using aspects of those technologies.  Big Pharma, after all, do not rely on partnerships to finance technology development and can thus go on using and improving the IP of other companies in their own labs impugned.
   
Although one could have thus taken the view that losing the case would have been in Roche’s interest in a perverted sort of way, it could also have more immediately jeopardized the value of their acquisition of Santaris (USD 250M) in addition to payable damages.  For example, Roche might have been ordered to cease any RNaseH work in the US which may be impractical for a global research organization like Roche.

Since I cannot imagine that Isis would tolerate Roche to challenge their control over RNaseH antisense gene knockdown and compete for pretty much the same targets, I expect the settlement to take the form of a significant broadening of the companies’ existing relationship around Huntington’s Disease in the form of additional target picks in exchange for a sizeable upfront fee. 


Unlike Isis’ more recent Big Pharma deals with J&J, GSK, BiogenIdec, and AstraZeneca, however, I expect this to involve less early development work by Isis as some of this would be the obvious job of the former Santaris crew.

Sunday, March 22, 2015

Follow-Up to Simplified GalNAc-RNAi Trigger Discussion

Just days after the Matsuda et al. publication on simplified, non-triantennary GalNAc-RNAi triggers (the subject of the previous blog entry), another related paper from Alnylam came out (Rajeev et al. 2015). 

The Rajeev et al. publication further supports that monomeric GalNAc designs as pioneered by Arrowhead Research for the use in RNAi Therapeutics and others (e.g. Matulic-Adamic et al., 2002) before for non-RNAi Oligo Therapeutics applications allow for effective ASGPR receptor recognition and subsequent gene silencing.  

The main difference to the Matsuda paper was that instead of GalNAc-modified nucleotide monomers, non-nucleosidic GalNAc monomers were employed (note: the Matulic-Adamic et al. also explored both nucleoside- and non-nucleoside-based monomeric clustering GalNAc strategies). They, however, were also appended to the 3’ end of the passenger strand as part of the phosphoramidite-based RNA synthesis.

The use of non-nucleosidic phosphoramidite monomers further simplifies the chemistry demands and thus cost of goods of GalNAc-siRNAs.

Ironically, not only does this paper also fail to cite the seminal Arrowhead and Matulic-Adamic research, this significant effort to get away from the apparently costly triantennary design is also at odds with Alnylam’s claims in July 2014 that a patent covering bi- and triantennary conjugates designs ‘broadly cover[ed] conjugate-based delivery of RNA Therapeutics’.

Obviously, if non-bi- and triantennary designs work, then one cannot consider the issued patent to broadly cover conjugate-RNAi triggers.


It will now be interesting to see how broad the claims will be that the patent offices will grant related to the simplified designs.  The re-writing of history effort obviously is not aimed at impressing investors or enabling the field, but part of a GalNAc IP landgrab effort, ideally resulting in the issuance of claims covering any monomeric GalNAc designs.

The one thing that I would like to give Alnylam credit for is that they will put significant resources behind the technologies they consider promising- whether they invented, own, or have a license to them or not- and thus advance RNAi Therapeutics as a field.


Tuesday, March 17, 2015

Alnylam’s Scientifically Dishonest GalNAc Claims

Arrowhead Research, as the successor of Mirus Bio, can regard itself as the father of GalNAc-conjugated RNAi delivery.  Accordingly, in 2007, Rozema and colleagues published a seminal paper in which a multivalent polymer-conjugated GalNAc construct was utilized for the hepatocyte-specific delivery of RNAi gene silencing.

In 2015, Alnylam likes to be recognized as the inventor of GalNAc-oligonucleotide Therapeutics, with competitors like Isis Pharmaceuticals and Solstice Biologics playing the roles of copy-cats, and Arrowhead Research failing to get much mention at all.

This, however, is as noted in the introduction far from the truth, and a recent paper on ‘sequentially assembled’ GalNAc-RNAi triggers by Alnylam (Matsuda and colleagues, 2015) is yet another example for how they would like to re-write history to suit their (IP) goals.  History repeating itself you might think after all we’ve been through with SNALP LNP.

Matsuda re-discovering Rozema

Alnylam likes to laugh off Arrowhead’s GalNAc approach by claiming that you need a magic triantennary GalNAc ligand design with highly specific geometry to achieve tight ASGPR target receptor binding and subsequent cellular internalization.  By contrast, Arrowhead Research would be only using monovalent GalNAc which are known, in isolation, to be much poorer ASGPR binders.

The existence of the triantennary design obviously has not evaded Arrowhead Research.  Nevertheless, they have opted for monovalent GalNAcs most likely for their chemical simplicity and therefore reduced cost of goods.

The apparently high cost of triantennary GalNAc synthesis was acknowledged in the Matsuda paper and was said to be the motivation for testing RNAi triggers in which instead of a single triantennary ligand, monovalent GalNAcs were distributed along the RNAi triggers.

Short story short, having GalNAcs conjugated on 3 sequential nucleotides or every other nucleotide did not impact potency much compared to the triantennary 'parent' design.  In other words, the benefit from multivalent binding can be achieved by bringing monovalent GalNAcs together in space.

This, of course, is the same principle behind the Arrowhead approach, where GalNAcs are added to the free amines along a polymer/peptide (an RNAi trigger is just another polymer).  In the case of the melittin-like peptide, I have highlighted the basic amino acids to which GalNAcs are expected to be conjugated:

NH-LIGAILKVLATGLPTLISWIKNKRKQ-COOH

As you can see, towards the C-terminus (right hand side) of the peptide, there is a cluster of 4 positively charged amino acids that is expected to generate a multivalent ASGPR binder (note that 3 and 4 GalNAcs have similar binding affinities).

Shockingly, while masquerading as the inventors of GalNAc Oligonucleotide Therapeutics with statements like these…

The triantennary GalNAc ligand was subsequently used for hepatocyte-specific delivery of antisense oligonucleotides and short interfering ribonucleic neutrals (siRNNs) in mice, and anti-microRNA therapeutics in humans, confirming the value of the parent trivalent design.’

…they failed to even cite the Rozema paper and went on to say that now (i.e. for the first time) they were going to test the hypothesis that sequential monovalent GalNAcs could do the same job.  This obviously is a clear case of willful scientific dishonesty in their campaign to re-write GalNAc history.

Silence Therapeutics not even a pimple

While the Matsuda paper is geared towards claiming the sequential GalNAc assembly idea and is an affront to Arrowhead Research, it is also a reminder that Silence Therapeutics has been similarly treated with disregard in Alnylam’s ‘invention’ of ‘enhanced’ GalNAc-siRNAs. 

This is because (like Arrowhead Research actually), Alnylam, at least in essentially all RNAi trigger examples in the Matsuda paper, uses the AtuRNAi trigger design, US patents of which claim 2’-O-methylation every other base with a staggered pattern as it regards the annealed guide and passenger strands.




It therefore looks more and more like Alnylam will have to approach Silence Therapeutics for a license sometime before enhanced GalNAc-siRNAs hit the market (at least 2 by 2020 according to Alnylam’s 2020 guidance), if not ALN-TTRsc already (~2017-8).  If Alnylam will have to approach Arrowhead Research for a license regarding GalNAcs, I do not know, but given Alnylam’s noise, worth paying attention to the intricacies of the various IP estates. 

Thursday, March 5, 2015

Arrowhead Acquires 30 Alnylam Exclusive, Priority Target Picks and Plus More from Novartis

Arrowhead Research keeps mopping up the billions of Big Pharma dollars spent on RNAi Therapeutics R&D and IP.  After acquiring the Roche assets for dimes on the dollar in 2011, heralding Arrowhead Research becoming a real biotech company, it is now Novartis’ turn to give their RNAi assets to dedicated RNAi hands.

What Arrowhead bought

For $10M and $25M in cash and stock, respectively (representing a dilution of ~5%), Arrowhead research acquired

1)      new Novartis RNAi trigger chemistry that the company claims to fall outside competing RNAi trigger IP (thus avoiding milstone and royalty obligations);

2)      intriguing new RNAi trigger chemistry that supposedly enhances RISC RNAi effector loading of RNAi triggers in the cytoplasm and which  could enhance the potency and duration of gene silencing; and

3)      the RNAi-related IP rights that Novartis acquired from Alnylam in 2005, most notably the 30 target picks.

Arrowhead in the house

10 years ago, Novartis made headlines by getting access to 30 exclusive target picks under Alnylam RNAi trigger IP.  For the privilege of picking targets not only ahead of Alnylam, but also excluding Alnylam from these targets, Novartis paid $10M in cash and made a $58M equity investment at a 16% premium to the ALNY trading price back then (so say $20M overall), plus the usual biotech milestone (up to $700M) and royalty obligations.

At the time, Alnylam was criticized for selling much of the farm.  This is because 30 target picks might have been too much given the state of RNAi delivery technology at the time.  Archrival Sirna Therapeutics gloated that it would never enter into such broad sweeping deals and consequently started to win business from other Big Pharma names, culminating in the $1B acquisition by Merck in 2006.

Novartis had time until October 2010 to officially nominate its target picks. At the time, SNALP LNP delivery to the liver was the only game in town for clinically relevant RNAi delivery.  Therefore, if Novartis had any brains, it would have spent some of the picks on the juiciest liver targets in addition to their oncology dreams.  

Usually, I don’t give much credit to the critical thinking ability of Big Pharma, but given that a number of Novartis RNAi folks came from Sirna Therapeutics and had worked on liver targets such asHBV early on, it is a good assumption that, yes, a few targets are aimed at the liver.

Note also that Alnylam never entered the HCV drug development race, instead pointing to their unwillingness to compete with its microRNA joint venture Regulus Therapeutics for the target.  I never bought that argument and instead suspected that Novartis was on HCV.

This, of course, adds an interesting facet to the somewhat uneasy relationship between Arrowhead Research and Alnylam and how today's deal impacts Alnylam’s 3 STAr franchises, namely viral hepatitis, cardiometabolic, and orphan diseases.

Value of Novartis RNAi assets in the eye of the beholder

I fully expect the usual suspects to spin today’s news as Arrowhead Research (once again!!) acquiring assets that a Big Pharma had put on hold (in the case of Novartis in early 2014) and nobody else allegedly wanted.  This may be partly true given that Novartis did not appear to be successful at developing strong RNAi delivery technologies.  So the Novartis RNAi assets in isolation may not have been worth that much.

Arrowhead, however, is in a different position given that its DPC delivery technology is being validated in the clinic.  I expect the ARC-AAT results towards the end of the year to remove any doubt about that.  Moreover, Arrowhead is on track to commit its subQ DPC version into clinical development, instantly increasing the value of any cardiometabolic targets that Novartis may have picked.

This illustrates that for Arrowhead Research today was about expanding its RNAi trigger IP leverage in addition to increasing its chances of finding the best possible RNAi trigger against a given target from its broad stable of RNAi trigger structures and chemistries (usiRNAs, Dicer-substrates, canonical), and finally adding a unique RNAi pharmacology trick to its toolbox.  All of this to be married with its DPC delivery technology so that the result would be worth far more than the sum of its parts.


Today, we have only glimpsed part of the strategic and technological importance of the deal. Stay tuned as the movie unfolds.  Kudos to Arrowhead Research for making the bold, but mostly right strategic decisions.

Monday, March 2, 2015

RNA Therapeutics Are Back in the Cardiometabolic Game

In the mid- to late 2000s, in the wake of Vioxx, I remember sounding the alarm bell on developing RNAi Therapeutics for cardiometabolic indications.  The FDA would simply refuse to approve cardiometabolic drugs even when strong data on widely accepted biomarkers such as blood glucose in diabetes and LDL-cholesterol levels in cardiovascular disease suggested that they should be efficacious.  Instead, the agency was demanding ridiculously expensive outcome trials for even the most underserved patient population, making cardiometabolic drug development difficult to justify financially.

Regulatory and technology changes

10 years later, the situation has changed dramatically due to a confluence of regulatory and technology changes.  In the regulatory arena, the staged approval process which involves a fast-to-market strategy for high unmet need orphan populations based on surrogate markers followed by the roll-out in larger patient populations, partly supported by the clinical experience gathered from the orphan indications, has been successful at rekindling interest in cardiometabolic drug innovation in general.

In terms of technology, both RNAi and antisense technologies have matured to a point that the risk:reward proposition looks highly promising not only for the most severe patient populations, but suitable for even the more general population.  The Old is exemplified by gen 2.0 RNaseH antisense oligonucleotide mipomersen for which it will be very difficult to break into markets beyond the ultra-orphan homozygous familial hypercholesterolemia one due to its weak drug activity and considerable side effects. 

In RNAi Therapeutics, the Old was represented by the need for intravenous administration with the former gold standard in RNAi delivery, 1st and 2nd generation SNALP liposomal nanoparticles (LNP), and their confounding effect on lipid metabolism (see the need for various normalizations in the phase I results of ALN-PCS02).  

Today, however, we not only have improved SNALP LNPs and 2nd generation RNaseH antisense (2.2), but more importantly GalNAc-targeted RNAi and antisense technologies by Arrowhead Research, ISIS Pharmaceuticals, Regulus Therapeutics, and Alnylam.  Importantly, due to their highly specific targeting of hepatocytes in the liver, the therapeutic window has been widened considerably.  In addition, the surprisingly long duration of target engagement makes monthly, if not quarterly dosing conceivable, therefore not only erasing, but surpassing oral small molecules in terms of patient convenience.  And we have not even considered the superior therapeutic utility that they promise by their ability to go after all conceivable targets- individually or in combination.  This, after all, is what we all should care about most.

The attraction of cardiometabolic applications is also reflected by the recent establishments of related franchises by Alnylam (cardiometabolic STAr) and ISIS Pharmaceuticals (Akcea lipid commercial subsidiary), with development programs targeting ApoCIII (ISIS Pharmaceuticals), PCSK9 (Alnylam/The Medicines Company), Lp little a (ISIS Pharmaceuticals), and ANGPTL3 (ISIS/Alnylam) looking already very favorable.  In addition, ISIS Pharmaceuticals sports a couple of interesting diabetes-focused programs (targets: PTB, GCGR, GCCR) which are showing novel therapeutic/safety profiles that could be suitable for specific sub-populations in the enormous, but equally complex diabetes market (e.g. insuling sensitization, reduction of glucose production).

Competitive outlook
    
As ISIS Pharmaceuticals and Alnylam compete for some of the same targets, the most common pattern you will likely see is that ISIS has a first-mover advantage (à IP and experience) with non-GalNAc generation 2.2 candidates due to their formerly somewhat fool-hardy, but now genius-looking pursuit of the cardiometabolic area.  When there is direct competition, the gen2.2-based drugs will likely be outcompeted by Alnylam’s GalNAc-siRNA conjugates due to their a) longer duration of action, and b) their possibly superior safety profile.

However,  as ISIS Pharmaceuticals is giving their cardiometabolic franchise a GalNAc overhaul, the company will also likely have the once monthly dosing frequency and a safer alternative turning it into a head-to-head race between Alnylam and ISIS Pharmaceuticals with winners that could differ from target to target.  Long-term, ISIS Pharmaceuticals may another ace in the competitive race as the single-stranded phosphorothioate oligonucleotide approach currently seems more amenable to oral dosing than double-stranded RNAi approaches.
   
While Tekmira’s SNALP LNP technology may be competitive when it comes to multiplexing targets, it is Arrowhead Research that is best positioned to surpass both Alnylam and ISIS Pharmaceuticals should they succeed in progressing their single-molecule subQ DPC technology into the clinic as indicated in last quarter’s conference call.  The endosomal release chemistry gives it a potency, and potentially also dosing frequency advantage over Alnylam’s simpler GalNAcs. 

Expect the CEO of Alnylam to increasingly attack the Arrowhead competition by raising safety concerns as he did in the recent RBC Healthcare conference presentation. I find this remarkable given that Arrowhead Research has not released the full safety data from its phase I study of ARC520.  But if you don't think you can win on potency, it may be best to sow seeds of safety doubt based on innuendo.
  

So watch this space. Next up are results from ISIS-GCCRRx (diabetes) and ISIS-ANGPTL3Rx (lipid disorders), clinical results from which are imminent.  Head-turning ALN-PCSsc results could be out in Q3. 

Tuesday, February 24, 2015

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.

Wednesday, February 11, 2015

The Tide May Have Turned for ARWR

Arrowhead Research emerged as a major RNAi Therapeutics player due to its- at least publicly- single-minded focus on HBV.  During this time (early 2013-early 2014) it saw a meteoric rise in its stock by more than 10-fold.

Management got so caught up by their own campaign of pushing Arrowhead Research as an HBV stock that they set themselves up for failure by setting overly ambitious goals for that program. 

As a result, the stock plummeted almost as rapidly as it had risen first by the Fed-induced biotech sell-off in spring 2014, and especially after first clinical results (see here and here) of ARC520 in HBV-infected patients did not live up to the hyped-up expectations.  90% HBsAg knockdowns had been the stated goal for a single-dose 2mg/kg.  This was despite preclinical studies which suggested that more than 2mg/kg of the endosomolytic DPC component was needed to achieve such robust knockdowns.

While my jaws certainly dropped in disbelief when I heard this, in my mind this has to be chalked up to a lack of full understanding of their company's own technology rather than gross misconduct.

…but for me it has always been subQ, subQ, subQ, extrahepatic

While I very much liked the fact that Arrowhead Research was at the very cutting edge of the ‘HBV-The-Next-HCV'  wave, what originally got me all fired up about Arrowhead Research was an OTS presentation in late 2012 where they presented impressive (robust and long-lasting) knockdown in non-human primates with a subcutaneous, most likely single-molecule version of their DPC delivery technology.  Knockdown that was more potent than anything out there (Alnylam GalNAc-STC at the time) combined with the convenience of subcutaneous instead of intravenous administration.  The latter is practiced with their more advanced two-molecule DPC version underlying ARC520 and ARC-AAT in the clinic already.

Single-molecule DPCs should also be the foundation for reaching tissues beyond the liver, making the transition back to single-molecule DPC all the more valuable.  Given that the liver has been solved for oligonucleotide therapeutics with Alnylam’s and ISIS’ GalNAcs, opening up new tissues to RNAi is obviously all the more attractive.

It is unclear what held the company back from taking the non-human primate achievements almost 3 years ago into the clinic.  Scale-up manufacturing issues rank highest on my list of possibilities.

Company guides for 2015 IND for either subQ liver or extrahepatic i.v. candidate  

During this week’s Q4 earnings conference call, the company indicated that they have finally achieved long-awaited technological breakthroughs so that we can now expect them to file an IND for either a liver target using for the first time a subcutaneous DPC formulation or an IND for an extra-hepatic target. 

Correction/clarification (2 Feb 2015): The company contacted me to clarify that what they said was that they will file an IND in 2015, and in addition to that, nominate a new development candidate that will either be extrahepatic or a subQ liver candidate.

Interestingly, if the extrahepatic program should make it to the finish line first, it would still be administered intravenously, which leads me to believe that it is a target in the kidney which I consider the only other obvious target tissue amenable to 2-molecule DPC.  If the target cell is not the proximal tubule cell, it would suggest that Arrowhead has identified a GalNAc-ASGPR-type ligand-receptor pair for the kidney.

ARWR 2015 playbook

Be it as it may, the prospect of both a highly competitive delivery technology for the liver and the availability of a new target tissue makes this a highly attractive re-entry point into ARWR.  At $6+ down from the mid $20s not even a year ago and with almost half of its valuation in cash, I do not see much downside from the 3-4mg/kg results of ARC520 to be reported in Q2 2015. 

Personally, I expect an 80-90% knockdown at 4mg/kg, but since I have no idea how the market would react to an 80% knockdown, the results are a coin toss to me, but with a somewhat larger upside (up to $14) than downside (down to $5) from here.

If the stock trades down, but somewhat dependent on the safety data, it may be an opportunity to snap up ARWR for the ARC-AAT phase I results coming up by the end of the year.  I consider ARC-AAT a very robust program with increased knockdown potency compared to ARC520 and much less ambiguity around what an X% knockdown means.
 

Right now, Arrowhead Research is an ARC520-only story and that should change once ARC-AAT becomes recognized as a medically and commercially very attractive product candidate (e.g. an orphan indication with an estimated 100.000 patient population in the US alone).  And I am convinced that I'm not the only investor to recognize subQ and extra-hepatic as the ultimate value drivers for ARWR all of which could propel the stock back to its 2014 highs over the next year.
By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.