Arrowhead Publishes SubQ Delivery Technology to Go Beyond the Liver

In late 2012, Arrowhead Research shocked the Oligonucleotide Therapeutics world when it presented spectacularly potent and prolonged gene knockdown data in non-human primates using a subcutaneously administered single-molecule Dynamic Polymer Conjugate (DPC) formulation.  This arguably represented the most elegant delivery technology at the time.  Moreover, also due to its small, but not too small size (10-20nm) and slight negative charge, it provided us with a glimpse into the future of systemic RNAi delivery for regulating genes beyond the liver.

It certainly got my full attention and made me invest almost 100% of my stock portfolio back then.

Unfortunately, despite the validation in non-human primates which suggested clinical readiness would not be far off, the subQ DPC technology has seemingly struggled to reach clinical/commercial maturity. Not only Arrowhead’s lead development candidate, ARC520 for HBV, but also its second development candidate, ARC-AAT for AAT-related liver disease, was still based on the intravenously administered two molecule DPC version.  Although the reasons for the delays were never really disclosed, a few comments here and there made it seem very likely that chemistry and manufacturing issues were behind the delay.

Back to the Future

Last week, Arrowhead Research finally published a paper showing that single molecule DPC is still alive and kicking (Rozema et al.2015) and is progressing towards clinical application.  In essence, the new single-molecule subQ DPC prototype comprises of a membrane-active polymer which has been masked from premature cytotoxic interactions by pegylation and cell-targeting ligands that are added via protease-sensitive bonds; as before, the highly modified/stabilized RNAi triggers are appended by disulfide chemistry. 

The DPC is made in a 4-step process followed by a purification step to remove unwanted side-products and reactants.  The latter step is apparently important when going into primates.

The new old DPCs are thus distinguished from the intravenous version not only in that it combines the RNAi trigger and endolysosomal release polymer in a single molecule, but most importantly by the nature of its triggered release mechanism.  Whereas in the former DPC generations triggered release was dependent on changes in pH such as they occur when a DPC is endosomally taken up, they are now responsive to the presence of certain proteases in lysosomes. 

pH-dependent formulations apparently suffered from instabilities both in the body and during storage.  This was adequate for targeting genes in the liver because of the ready access of macromolecules in the circulation to this organ following intravenous administration, but not when the DPC first has to reach the circulation from the subcutaneous space and when less well accessible target organs are the ultimate destination.

Accordingly, non-liver single-molecule DPCs of the latest publication had impressive circulation half-times of the intact, protected molecule of 11 hours.  Similarly, such DPCs are stable for at least a year both in solution and when lyophilized. 

The extra-hepatic potential thus facilitated by increased stability now needs to be demonstrated by finding suitable targeting ligands and I’m sure Arrowhead has been busy working on that.  It should be noted that for target tissues where high concentrations comparable to the liver are unlikely to be achieved following systemic delivery, the extra kick that comes from an explicit release chemistry could provide a critical advantage over competing approaches.  These include simple conjugates of the GalNAc-type and probably also self-delivering RNAi trigger chemistries which incorporate ‘milder’ release chemistries (like lipid tails).

Knockdown lasting for weeks and months

The most impressive demonstration of the single molecule DPC performance in the Rozema paper came from the primate studies.  Here, a single administration of 0.5mg/kg 2’-O-methyl/F-modified RNAi trigger led to a highly potent knockdown (peak knockdown >95%) of liver expressed Factor VII with >80% knockdown of 2 and 4 months following subcutaneous and intravenous administration, respectively.

Following the 2012 delays and some uncertainties around what was really new and old in the recent publication, I am somewhat hesitant to declare that subQ DPC is now fully de-risked and ready-to-go.  In that regard, it would be helpful to learn more about the tox profile of the new molecules and related to that which polymers will be eventually used (e.g. 2-molecule with melittin-like peptide, a polyacrylate in the publication).

Nevertheless, since Arrowhead has said that the new 2015 development candidate may be from the subQ line of DPCs (or if not going after a extra-hepatic target) one would think that the most important challenges have now been overcome.

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.

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.

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, 1^st and 2^nd 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 2^nd 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. 

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.

Alnylam’s Second-Generation GalNAc Data Impress

Earlier this week at the American Society of Hematology meeting in San Francisco, Alnylam presented first multi-dose knockdown data in humans for its second-generation GalNAc-siRNA conjugate technology (ESC-GalNAc).  Accordingly, an almost 60% knockdown was seen in the first (and so far only) patient dosed at 0.045 mg microgram per kilogram ESC-GalNAc siRNA with the knockdown yet having to reach its nadir.  Moreover, further knockdown benefits are likely to accrue with dosing beyond 3 times weekly as was the case in this study.

At these low doses, no remarkable adverse events were reported, including injection site reactions or increases in liver enzymes which were seen with first-generation GalNAc-siRNAs in humans at much higher doses.

Though the data from this phase I study of ALN-AT3 in hemophilia patients is still early and there will be gene target-dependent differences in knockdown potency, they do support Alnylam’s claim that second generation GalNAc is indeed considerably, as much as 50x more potent than first-generation GalNAcs.  Only last week I had speculated that it may be more appropriate to estimate 2^nd gen GalNAc to be ‘only' 5x more potent than 1^st gen GalNAcs.

I was wrong.

In non-human primates, ALN-AT3 had an ED90 of 0.5mg/kg with weekly dosing.  Based on the phase I data thus far, I expect the corresponding ED90 dose in humans to be a ~ weekly 0.075mcg/kg 0.075mg/kg for a ~7-fold improvement in potency in humans versus non-human primates, a relative potency improvement that is not seen for first-generation GalNAcs.  Add to this the inherent 5x improved intra-species potency of second- versus first-gen GalNAc (Nair et al 2014), it is indeed possible that ESC-GalNAc enjoy an up to 50x improved potency advantage.

In other words, it should be possible to now achieve highly potent knockdown with a once-monthly dosing regime and sub-1 ml subcutaneous injection volumes. 

The value of this for the ALN-AT3 program, which harnesses a unique mechanism in an otherwise crowded hemophilia field which in general is moving towards less frequent dosing/infusion regimens and less immunogenic molecules, remains to be seen.  The slow enrolment pace of the phase I trial, ~5 hemophilia patients enrolled in 6 months, gives cause for commercial concern.     

The competition

While the improved potency is great for Alnylam, the gene knockdown competition is unlikely to yield the liver to Alnylam.  Highly potent knockdowns are possible with other platforms by Arrowhead, ISIS, Tekmira, and possibly Dicerna, too. Beyond route of administration [subQ for Alnylam GalNAc, ISIS (GalNAc-) ASOs, Arrowhead’s single molecule DPCs, and Dicerna GalNAc versus intravenous for Arrowhead’s 2-molecule DPCs and Tekmira’s SNALP LNPs], differentiation will come from safety/tolerability and dosing frequencies.

The next datapoints in this regard will come from the R&D Day by Dicerna early next week (Dicer-substrate GalNAcs) and the 4mg/kg phase I data from the immensely exciting anti-miR122 program by Regulus Therapeutics (employing GalNAc-antisense chemistry) in January 2015.

Tekmira Presents Solid Pre-clinical Package for Upcoming HBV Clinical Candidate

Yesterday, Tekmira Pharmaceuticals presented the long-anticipated RNAi candidate for the treatment of HBV infection at the Annual Oligonucleotide Therapeutics Society conference (click here for the corresponding slide deck).  Accordingly, it was shown that TKM-HBV mediated solid knockdown of all HBV viral RNAs and proteins.  This included data in the challenging (and costly) mouse model carrying humanized livers (comprised of a mixture of mouse and human liver cells) competent of supporting the full HBV viral life-cycle.

In these mouse models, repeat doses of 0.3mg/kg resulted in ~90% reductions of both the critical HBV surface antigen (HBsAg) and viral DNA.  This may be an underestimate of the true potency of TKM-HBV as suggested by data targeting the human apoB gene in this model.  These suggested (although not proved) that it is much more difficult to achieve potent knockdowns of genes expressed in the human liver cells as compared to genes expressed in the neighbouring mouse cells of the same liver: around 10x the amount of RNAi trigger was required to achieve comparable knockdowns for the human ApoB gene relative to the mouse ApoB gene.

Based on these results, I expect an approx. ~85% knockdown of HBsAg in single-dose studies at doses that I conservatively expect to be very well tolerated (~0.2mg/kg).  As indicated by the recent clinical results with ALN-TTR02 and chimpanzee studies by Alnylam/Merck, both of which involved Tekmira's SNALP LNP delivery technology, these knockdown numbers are likely to improve with more prolonged repeat administration.

In case that Tekmira is able to safely dose escalate to higher dosages, say 0.5mg/kg, significantly more potent knockdowns can be expected.  One ought to, however, keep in mind that such higher doses are not necessarily supported by the clinical history of SNALP LNP which indicates that innate immune stimulations could become an issue around 0.3mg/kg. On the other hand, the otherwise conservative Tekmira management has been surprisingly optimistic as to 3rd gen SNALP LNP-enabled TKM-HBV being devoid of innate immunostimulatory activity.

Comparison with Arrowhead's ARC520

The results support the notion that Tekmira's HBV candidate will be more potent than Arrowhead's competing HBV candidate, ARC520.  However, there are many uncertainties in making such a prediction, most importantly the dose levels found to be safe and well tolerated in the clinical studies.  To wit, ARC520 is still dose-escalating and so far has exhibited a very good safety profile meaning that 90% (1log)-type knockdowns are well within reach, especially with repeat dosing.

Beyond potency, it should be noted that TKM-HBV comprises of 3 different RNAi triggers, both to cover the vast majority of viral sequence variation and to minimize the potential of breeding drug resistance.  To my surprise, such resistance mutations were observed in a woodchuck model that Tekmira conducted together with HBV powerhouse Bristol Myers Squibbs.

Oh, BMS? You can bet that should RNAi Therapeutics be able to meaningfully increase HBV cure rates from the low bar set by current standard of care (~15% with ill-tolerated immune stimulants), not only will BMS, but also the likes of Gilead be very interested to swoop in to pick up one or both of these compounds and/or companies.

An IND filing for TKM-HBV is on track for year-end 2014 with first drug administrations in early 2015.

Disclosure: I am long both TKMR and ARWR.

Arrowhead’s HBV Candidate Requires Further Dose Escalation

Today, we learned about some hard HBsAg knockdown numbers from the phase IIa Hong Kong study of ARC520 in chronically infected HBV patients.  The data relate to the first 2 cohorts in this ongoing dose escalation trial.  Accordingly, the mean HBsAg knockdown at nadir for the starting dose of 1mg/kg was 39% within a range of 22-57% (n=6) while it was 51% within a range of 46-59% for the 2mg/kg cohort (n=6).

ARC520 was given as a single dose to patients already stably on polymerase inhibitor entecavir.

It should be noted while numerically the improvement in knockdown from 1mg/kg to 2mg/kg was only 12%, this is likely the result of the apparent high variability at the lower dose level with the increased tightness of the knockdown range at 2mg/kg indicating that the RNAi mechanism is starting to be solidly engaged with the expectation of a steepening dose response going forward.

While clearly missing the company’s own guidance of a 1 log reduction at 2mg/kg, the good safety profile-no SAEs at all in the study with all AEs rated to be unrelated to ARC520- in addition to the steepening dose-response curve following 2mg/kg means that ARC520 is far from being out of the HBV knockdown race.  Still, the stock market over-reacted, punishing ARWR stock with a percent decrease that matched the reported knockdowns.

Although even I ended up willing myself into believing that a 70-80% knockdown was possible following a single ARC520 dose of 2mg/kg, revisiting the chimp study which involved 2 doses of ARC520 (first one at 2mg/kg then one at 3mg/kg), it should be noted that at the time the 3mg/kg dose was administered, the HBsAg levels had only declined by 50%...about the same as achieved in the phase IIa study.  It is thus possible that Arrowhead gave the 2^nd dose just as HBsAg levels were about to go up again, consistent with the already rebounding levels of HBV DNA and HBeAg in that study.

As a result, my expectations for the single 3mg/kg dose are now 70-75% based on the ~75-80% peak HBsAg knockdown in the chimp study following the 2mg/kg and 3mg/kg doses.  This also means that in order to reach that 1log knockdown goal the company had set for itself, 4mg/kg will most likely be needed.  Importantly, in the concurrent phase I dose-escalating study in healthy volunteers, this quite large amount of drug seemed to be well tolerated and the company is awaiting approval to adopt this dose in the Hong Kong study.

This projection is not much off the 90% knockdown achieved in the ARC-AAT program at 3mg/kg in non-human primates.  The improvement of this 2^nd DPC-based candidate about to enter the clinic is possibly explained by progress in the potency of 2-molecule DPC delivery technology.  I add this as today many were confused about what the interim phase IIa results meant for the platform and the value of the company.

Overall, as long as 4mg/kg is an acceptable dose from a tox point-of-view, ARC520 is still in the game to be first-in-class in HBV knockdown.  It would have been much worse if say a 70% knockdown had been reported, but worrisome safety signals emerged.  On the other hand, the continued need for a dose escalation would seem to delay Arrowhead’s broad-based phase IIb study plans, meaning that the competition, in particular Tekmira's TKM-HBV is coming closer.

At a market cap of ~$400M, the market has almost fully discounted the potential of ARC520 given the $150M+ in cash as well as the IND-ready, first-in-class ARC-AAT for which we can expect solid knockdowns in the clinic.  Interestingly, data for this candidate were selected for an oral presentation at AASLD while the ARC520 data will be in less prestigious poster form. Finally, should the single-molecule DPC which got me excited about the Arrowhead RNAi platform in the first place finally reach the clinic, it would necessitate an upward revision of the value of the company.

Disclosure: Long ARWR.  I sold most of my holdings at $11 and change given the underwhelming results and increasingly negative market reaction, but got back in below $6 when I considered the sell-off to be a gross over-reaction and imminent 3mg/kg data having the potential to surprise the market to the upside from now much lowered expectations.  Add to this ARC-AAT, the platform...

Alnylam Once Again Clutches at IP Straws to Support Valuation Gap (with correction)

(21Aug14) Yesterday, I mistakenly stated that Alnylam wrongfully concluded that Dicerna was infringing on a newly issued Tuschl patent.  Following comments in the comment section below, it came to my attention that indeed there was a claim that I missed, claim 81 (and some contingent claims), that covers RNAi triggers of 25 base-pairs as follows:

81. An isolated double-stranded RNA molecule, comprising:

(i) a sense strand and an antisense strand that form a double-stranded region of up to 25 
base pairs, said sense strand having an identity in the double-stranded region of at least 85 
percent to a target RNA molecule; and

(ii) at least one strand having a single-stranded 3’-overhang, wherein said 3’-overhang 
has been stabilized against degradation; and

(iii) at least one nucleotide analogue, 


wherein said RNA molecule is capable of target-specific RNA interference. 

Note that Dicerna's RNAi triggers make use of the 2'-O-methyl modification which sometimes is found in the 3' overhang and can also have stabilizing activity.  Taken together, this claim indeed questions Dicerna's RNAi triggers, and although I would expect vigorous debate around whether 25 base-pairs are covered by the patent's description requirements should it come to a patent litigation, the assumption is that Alnylam's new patent rightfully questions many, if not most of the RNAi triggers used by Dicerna currently.  

Since I'm at it, the new patent also comes awfully close to the asymmetric RNAi trigger designs by RXi Pharmaceuticals and others (asiRNAs).  RXi e.g. uses dsRNA lengths of below 15bp with the guide strand having a long 3' overhang.  I am a bit surprised that Alnylam got just enough extension both below and above their traditional 19-23bp stronghold to start overlapping with some asiRNA and Dicer-substrate designs.

Regardless, I stand by my point that Alnylam has re-invigorated their patent-related press releases in order to explain the valuation gap to its peers in the public markets.  The original blog entry follows here:



This morning, Alnylam greeted the competition with another IP-related press release.  It wrongly claims that a patent it just obtained covers competing technologies.  This suggests that it either lacks an understanding of RNA technology basics or that it is afraid that the market will come to understand that the valuation difference to its peers has no basis in either a commercially more attractive clinical pipeline, a superior patent estate, or simply better technology.

Dicerna’s Dicer-substrate technology not in 14-24bp range

Today’s press release concerns US patent application 13/725262 which is part of the Tuschl patent estate covering certain RNAi triggers with 3’ overhangs.  Although the patent has not finally been published, based on the latest submitted claim set, the RNAi trigger covered by the main claim should comprise the following features:

a)      a dsRNA length of 14-24 base-pair; 

b)      at least 1 3’ overhang;

c)       at least one ‘nucleotide analogue’;

d)      and the dsRNA is non-enzymatically processed.

Clearly, in citing the Rose et al. and another paper by Dicerna (actually their scientific founders from the Rossi lab at the City of Hope) as proof of Dicerna’s infringement, Alnylam hopes that its investor and business development audience does not actually read scientific papers. 

‘Specifically, the newly allowed patent application broadly covers small interfering RNA ("siRNA") molecules of various designs, including so-called "dicer substrate" RNAi triggers (Amarzguioui et al., Nat Protoc.2006;1(2):508-17; Rose et al., Nucleic Acids Res. 2005 Jul 26;33(13):4140-56)…’

Otherwise, it would quickly become apparent that Dicerna’s version of RNAi triggers have a dsRNA length of 25 base-pairs and, well, are enzymatically processed: Dicer substrates!

[Note: in the original entry I mistakenly said Dicerna's triggers were 27 base-pairs; to be precise, they are 25/27 designs with 25 base-pairs and a 2 nucleotide 3' overhang on the guide.]

So as the actual clinical pipelines of Arrowhead Research and Tekmira are about to look more attractive in terms of commercial value (HBV alone), look forward to more Alnylam patent-related press releases to help the market understand why Alnylam has a market cap of $5 Billion and its competition only about 1/10^th of that.

PS: the claim that usiRNAs infringe on this and other patents by Alnylam largely depends on the definition of ‘nucleoside analogue’ and ‘modified nucleotides’.

PPS: this patent does not change Alnylam's position as very similar ones related to 3' overhangs have already issued.  However, by slicing and dicing a patent application, it is possible to get issued a set of highly similar patents which, of course, is great fodder for the PR department.

Dose of ARC520 HBV Drug Candidate to be Increased to 3mg/kg

Today, Arrowhead Research reported preliminary phase IIa safety and efficacy results of ARC520 in patients infected with HBV.  The goal of this study is to determine the level of viral knockdown, especially HBsAg, following a single dose of ARC520.

Efficacy in-line with animal studies

The results for the 1mg/kg and 2mg/kg cohorts indicate that knockdowns are in-line with what has been seen with 2 molecule DPC-enabled RNAi in non-human primates, including the HBV-infected chimpanzee.  The company could not be more specific about numbers since it is still a blinded study and the knockdown curves apparently haven’t stabilized yet after 8 weeks in the 2mg/kg cohort suggesting remarkably prolonged pharmacology.

In the chimp study, HBV load in serum was reduced by 1log at 2mg/kg, but determination of the HBsAg knockdown following a single administration was complicated by the fact that Arrowhead gave a second dose of ARC520 of 3mg/kg before the HBsAg knockdown at 2mg/kg had leveled off.  With 2 doses of 2mg/kg and 3mg/kg 2 weeks spaced apart, the final knockdown was ~80%.  This level of knockdown was likely an underestimate of the true efficacy of ARC520 since one of the two siRNAs was a mismatch and the chimp had very high viremia to start with.  For the non-human primate study with ARC-AAT, Arrowhead’s new development candidate for alpha-1 antitrypsin, the knockdown with a single dose of 1.5mg/kg was ~75%.

Taken together, I expect that the knockdown at 2mg/kg to be somewhere around 70-75%.

Arrowhead extending to higher doses

While this level of HBsAg knockdown in such a short period of time, would be superior to anything before in the HBV space, for comfort and competitive reasons, it is not all that exciting.  What is more exciting is that Arrowhead is doing what I’ve always said they should be doing, namely testing higher doses than 2mg/kg.

This is because for 2-molecule DPC-RNAi, it is the amount of the endosomolytic peptide that is rate-limiting for knockdown efficacy. As shown in animal model after animal model (e.g. Wooddell et al. 2013), the efficacy achieved with 2mg/kg was well below maximal knockdown efficacy.  However, when slightly extending the dose to 3mg/kg or 4mg/kg, the depth of knockdown increases tremendously. 

In the case of ARC-AAT for example, a 75% knockdown at 1.5mg/kg became a knockdown of 90% at 3mg/kg, which was the same knockdown as with 6mg/kg indicating that a plateau had been reached.  In the case of HBV, the plateau, based on 6mg/kg endosomolytic peptide was a virtual elimination of HBsAg in the serum.

Despite the various genes and doses, the picture is that the dose-response becomes very steep soon after 2mg/kg.  Whether it is 3mg/kg or 4mg/kg is another question.  Arrowhead is currently gearing up for these doses following phase I extension studies in healthy volunteers,   

The most important news today therefore is that 3mg/kg in healthy volunteers was as well tolerated as 1mg/kg and 2mg/kg before (4mg/kg in the works).  Indeed, it was even better tolerated since the skin reactions disappeared with the transient use of an oral anti-histamine. 

Results from the 3mg/kg cohort in this dose-finding study should be presented at or around AASLD in November. Stay tuned.

Fed-Induced Sell-Off Offers Attractive Values in RNA Therapeutics

For whatever reason, Janet Yellen does not like cheerful biotech investors and between her first policy speech as new chairwoman of the Fed in April and comments last week decrying biotech and social media stocks as inflated she caused two major sell-offs in RNA Therapeutics stocks.  As a result, industry bellwethers ISIS Pharmaceuticals and Alnylam are trading at less than half their 52-week highs, though better than ‘second-tier’ RNA Therapeutics companies such as Tekmira and Arrowhead Research which are trading down even more than that.

When the technology has matured to the point that it can bring significant value to patients, pipelines rapidly progress and expand, and with companies flush in cash by historical standards, this sell-off offers in my opinion great risk:rewards.  Here is a run-down of my five favorite plays.

1.       $ISIS. ISIS Pharmaceuticals is my current RNA Therapeutics core holding that I would not want to be out of.  With ligand-targeted technologies offering much lower tissue exposures and therefore much better safety margins, multiple mechanisms of actions and a pipeline that rivals any in the industry, this company is on track to become the most valuable in the industry- if not economy (subject to the vagaries of the healthcare policy directions). 

At a $3B market cap, no foreseeable financing needs, and a healthy newsflow (especially regarding partnerships), the downside should be relatively limited, and I will sleep tight even knowing that Yellen (who seems to confuse the Dow and large cap biotechs with the broad biotech industry) might open her mouth again to talk about something she obviously understands very little about.

Best long-term risk/reward.

2.       $TKMR. Tekmira is the most beaten-up stock of the bunch that gets credit for almost nothing.  This is mainly the result of the Ebola trial results which were a disappointment- little doubt about that.  However, translating these results from the unthankful ‘Haertetest’ to the rest of the pipeline is unwarranted.  This is because a highly most potent knockdown technology for the liver, should be able to carve out some market for itself.  And if the HBV product won’t require transient immune suppression and/or if its use is deemed acceptable in HBV with its expected finite treatment period, there is an enormous opportunity for which the favorable newsflow is only about to heat up with the presentation of the preclinical dataset..

It is the newsflow from new product candidates (esp. HBV)), clinical trial starts (liver cancer, HBV, alcohol dependency), clinical trial results (ALN-TTR02 OLE, TKM-PLK1 interim phase II with little to no expectations by the markets), and business development (mRNA), that makes TKMR an attractive buy at these severely depressed levels ($31 in April, now trading at $9).  And with the Ebola Haertetest on Clinical Hold, TKM-EBOLA does not scare me anymore as an investor.  It even offers a potential near-term catalyst should the Hold be lifted.

Best 6-12 month risk/reward (until release of phase IIa HBV knockdown results).

3.       $RGLS.  I’ve never liked Regulus much as a stock, mainly because of its anemic pipeline that its own management does not even seem to be excited about given that it now calls the potent GalNAc-targeted anti-miR122 product candidate for HCV merely a proof-of-concept for the company.  However, given that the HCV market emerges as one with a long-tail, not all is lost for this pan-genotypic, potentially one or two-shot treatment when used in conjunction with other HCV drugs. 

When HCV-competitor Achillion recently surged on the back of the Merck takeout of HCV play Idenix as it reminded investors of the long-tail nature of the market, Regulus was forgotten.  It may reach investors’ consciousness when they report phase I results possibly early next year.  Solid financials with more than $100M in cash and a reasonable $300M market cap given its prominent position in the microRNA Therapeutics industry.

Speculative buy with regard to single catalyst.

4.       $ARWR. All eyes are on the outcome of the ARC520 phase IIa study in HBV-infected patients which could be announced any day now.  My prediction is a ~80% HBsAg knockdown at the 2mg/kg dose.  My problem is that I have little idea about how the market will respond to that given that the trial is not designed to achieve the ultimate goal for this therapeutic candidate: a functional cure.

Most investors seem to expect an easy double (or more) from current levels, an notion that I do not want to necessarily reject for an 80% knockdown.  It all seems to depend on how the results will be framed by the analysts and how successful the dueling hedge funds are in painting the tape to their advantage. 

With more than 10% of the float short and given ARWR's historical trading pattern, great volatility is a given.

Highly speculative buy, so much so that options may actually be the best way to play it.

5.       $SRPT. No matter the negative market reception to the recent release of the 144-week study results, Sarepta and patients will get their accelerated approval for eteplirsen.  The debate has reached a point that the drug development clock for Duchenne Muscular Dystrophy cannot be set back another 5-10 years by rejecting the current class of candidates of which Sarepta’s looks to be the most promising- despite the highly anecdotal nature of the results.  This is because eteplirsen seems amazingly safe, so the potential harm from giving a potentially non-effective medicine is limited.  This is clearly not the case for Prosensa’s exon skipping drug candidate, and don’t even get me started about PTC Therapeutics …

Solid 12-month risk:reward juiced by the large short position (>30%).

RNAi Trigger History Revisited as Alnylam Once Again Gets Tough on IP

Last month, Alnylam lectured  Arrowhead Research that they infringed Alnylam's RNAi trigger IP and added that the use of UNAs would not protect companies using them (Tekmira, Arrowhead Research, Marina Biotech, and Arcturus) either.  So as Alnylam is once again trying to intimidate the competition and their investors by claiming that they control RNAi triggers, it might be worth revisiting some RNAi trigger history.  Doing so suggests that in fact they have been one of the egregious infringers of 3^rd party IP themselves and raises questions as to their own freedom-to-operate and validity of IP.

Sirna and Silence Therapeutics early proponents of modified RNAi triggers

The early RNAi days were marked by the competition for RNAi trigger supremacy between star-studded start-up Alnylam and working-class Sirna Therapeutics which had just averted bankruptcy following failed attempts with ribozymes.  Silence Therapeutics was another company that had ambitions to cornering important RNAi trigger IP and like Sirna had a history in failed attempts with oligonucleotide therapeutics.

Due to their prior experiences in nucleic acid-based drug development, it came natural to Sirna and Silence to apply nucleic acid modifications and soon earned a head-start in creating IP related to the use of modified RNAi triggers.  The belief was that in order to endow RNAi triggers with pharmaceutical properties, they had to be modified.

Sounds familiar? If so, then it is probably because this has become Alnylam’s new mantra, too.  Of course, this comes with a 12-year delay and only after acquiring Sirna’s IP estate and a history of claiming that they want their RNAi triggers to be as ‘natural’, i.e. unmodified, as possible, not due to IP limitations, but because of superior performance and considering safety.  In fact, Alnylam has not only been infringing Baulcombe IP for a short while, but also Merck/Sirna IP for probably as long as they were starting to see decent in vivo knockdown results with their highly modified GalNAc-siRNAs.

Although this clearly shows that Alnylam’s publicly claimed control over RNAi trigger IP has simply been a mirage, to their credit they make efforts in eventually gaining access to IP they are glaringly lacking.  Also, while at some point and for some delivery strategies the notion of minimally modified RNAi triggers had its merits, the emergence of RNAi trigger conjugates has increased the value of RNAi trigger modifications.  One might also criticize companies like Sirna/Merck, Silence, and RXi Pharmaceuticals (one of the first practical adopters of highly modified RNAi triggers and conjugates) for standing still instead of developing their initial technologies to their logical conclusion.

A comeback for AtuRNAi triggers?

Silence Therapeutics left a lot of value on the table by limiting themselves to a modification pattern that involves alternating 2’-O-methyls with a 2’-O-methyl-modified base on one strand opposing an unmodified base on the other like in a zipper.  One reason for this limitation was that during patent prosecution, the attempt by Silence Therapeutics to get patents related to modification patterns in general and not limited to 2’-O-methyls failed.

Interestingly, the RNAi triggers in ARC520 that Alnylam lays claim on involve a modification pattern reminiscent of AtuRNAi, only that it is here 2’-fluoro that is the alternating modification (Wooddell et al. 2013).  Also, if you review Alnylam’s recent patent applications (e.g. WO2014089313), alternating 2’-fluoros seems to be Alnylam’s preferred modification pattern, too.  Could it be that these companies were inspired by AtuRNAi trigger design?   

In any case, AtuRNAi and Silence may hold the key to invalidating some troublesome modified RNAi trigger IP by Alnylam by rendering them obvious.  Even more exciting for Silence, albeit unlikely given that the opportunity may have passed is the prospect that Silence could revive some of the more general RNAi modification pattern claims, thereby affecting the freedom-to-operate by Alnylam (and Arrowhead Research).

And welcome to Amy Shuman, former general counsel of Pfizer, to the Board of Directors of Alnylam.

ISIS Pharmaceutical Reveals Dynamic PolyConjugate Efforts

When Arrowhead Research made a splash 1 ½ years ago at the Boston OTS meeting in late October 2012 with impressive subQ DPC knockdown efficacy in monkeys, there was a large number of meeting participants crowding the speaker after his presentation.  Although I sat a few rows away, the most eager questioner was an employee from ISIS Pharmaceuticals who managed to beat the Merck representative to the podium!

There were times when I believed that the interest of large companies in the technology of small companies boded well for partnership potential.  It has become clear to me, however, that while this may be true to some extent, the first instinct by the large guys is to get close to the innovators so that they can appropriate as much of the technology as possible without paying a dime.

While I have long shelved Merck into that category and DPCs will now be a research priority at Alnylam following their acquisition of Sirna/Merck, a now published patent application by ISIS Pharmaceuticals on melittin-based, GalNAc-targeted single-stranded antisense delivery (ssRNAi and conventional ASO) demonstrates that ISIS ticks no different.

With a priority date of WO 2014/089146 A1 of December 4, 2012, this poor employee and collaborating patent agent had to stitch together a patent application in just a month after returning home from the conference.  Unsurprisingly, the patent application lacks any actual experimental data to support the 'ínvention'.

I don’t want to be too cynical about this as this is how the industry and the patent system function.  It is an important lesson for small companies though that they should not get overly excited about interest they generate for their technology and they should only engage in deeper relationships once they have established that the larger party is not just trying to steal their technology by pretending to collaborate with them.

It is this unwillingness to share and attendant mistrust that in my experience impedes much business development that makes great sense on paper.  This ultimately delays timelines, leads to litigation, and makes the pie smaller for everybody.

And for the future of gene knockdown in the liver…if ~5mg per week may be possible for GalNAc-targeted gen 2.5 RNaseH ASOs, one can only wonder what a melittin-type escape mechanism would add to its potency, and safety. 

Comment on Seeking Alpha bear article on ISIS Pharmaceuticals

Last night, a detailed bear article on ISIS came out that shook the market in after-hours trading.  In summary, the thesis rests on the poor safety profile, especially immunogenicity of gen 2.0-based KYNAMRO (2’MOE gapmer) and that this is likely to translate to all other gen 2.0 drugs based on shared chemical composition and the (in my opinion idiotic) claim by the CEO of ISIS that KYNAMRO is a success and is representative for gen 2.0.  Talk about shooting yourself in the foot.

While I agree that the KYNAMRO data have raised legitimate questions around the safety of gen 2.0 phosphorothioate oligonucleotides, the bear article conveniently ignores the abundant clinical data that have emerged since for a number of other antisense drugs based on gen 2.0 chemistry.  These support the claim by ISIS that through improved screening, they are now able to better weed out the sequences that will likely prove immunogenic in the clinic. 

Importantly, in oligonucleotide therapeutics in general, while nucleic acid chemistry has a great influence on whether a molecule is immunogenic, it is the exact sequence composition that ultimately decides whether this is actually the case.

This is illustrated by the recent phase II clinical results for ApoCIII (no discontinuations noted), Factor XI, and GCGR.  Not only were robust gene knockdowns achieved, in sharp contrast to KYNAMRO, the company claimed that they were no flu-like symptoms, chills and other symptoms indicative of the immunostimulatory potential of oligonucleotides.  By contrast, about 1/3 in the KYNAMRO studies exhibited such events, with even higher numbers in the open-label extension phase.

Granted, given that these were 13-week studies, it is impossible to disprove the thesis that things are bound to get worse over the long-run.  However, no flu-like symptoms versus 1/3 of patients exhibiting flu-like symptoms in studies of comparable duration is a dramatic difference and allows one to extrapolate that the safety of the follow-on drugs will similarly be greatly superior to KYNAMRO over time.

While I had been tempted to let the Seeking Alpha article by Dr. Anonymous pass as raising legitimate concerns, the blatant failure to mention the more recent experience with gen 2.0 and the after-hours action last night makes this article suspect and outright useless given the lack of new information or insight.

Alnylam Pulls Chair from Underneath Arrowhead Research

Machiavelli would have blushed. Feeling the heat from both RNAi and antisense competition for targets in the liver, Alnylam has made it clear in its recent McSwiggen patent-related press releases that it is determined to wipe out at least the RNAi competition through patent and contract strategy (see here and here).  

Whereas before it used to call out Tekmira/Marina/Arcturus by claiming that unlocked nucleic acid would fall under their patent estate, today it added Arrowhead Research to the club of companies that entered an RNAi trigger licensing contract with Alnylam, but then find that those contracts were not worth the paper written on: Merck, Tekmira, Arrowhead Research, and others.

In brief, the McSwiggen patents that Alnylam bought from Merck claims RNAi triggers that satisfy the following conditions:

1)      RNAi trigger with strands that have a length that fall within the classical range for siRNAs;

2)      At least 10 or more bases (often pyrimidines) of either or both strands have to be one of the following modifications: deoxy, 2’F, or 2’0-methyl.

Depending on the patents there are slight variations as to the strand lengths covered, additional requirements for phosphorothioate linkages etc.

Given the above limitations, it is strange that coincident with the acquisition of the McSwiggen patent estate, Alnylam repeatedly adds in the related press releases that it owns RNAi triggers, including those modified with acyclic nucleotide analogues (--> usiRNAs).  By contrast, it would appear that replacing any of those modifications with the very unlocked nucleic acid analogue would be a simple way of circumventing McSwiggen without any destabilizing effect on the RNAi trigger. 

Isn’t that odd?  A company in a position of strength would not do that.  But we all knew that Alnylam still wishes Tekmira to disappear from the face of the earth, so that’s not really new.

The real shocker may be to investors of Arrowhead Research (from Alnylam’s press release):

‘we intend to maximize the value of this newly issued IP solely through the advancement of ALN-HBV - our GalNAc-conjugated siRNA targeting the HBV genome for the treatment of HBV infection’

In other words, Alnylam says that the HBV target-specific license it gave to Arrowhead just 2 years ago does not include rights to the newly acquired McSwiggen patent estate.  And indeed, ARC520 by Arrowhead infringes the newly issued patent subject of today’s press release (US 8,618,277).  I will just use si-74 (one of the 2 siRNAs in ARC520) to illustrate why.

chol-siHBV-74 sense: chol-uAuCfuGfuAfgGfcAfuAfaAfuUfgGfuAf(invdT) 23 bases,

chol-siHBV-74 antisense: dTAfcCfaAfuUfuAfuGfcCfuAfcAfgdTsdT 21 bases.

I’ve highlighted the pyrimidine bases in red.  ‘f’ after a symbol stands for 2’-fluoro, small case is 2’-o-methyl, dT is deoxy-T.

1.       ‘277 claims an HBV-targeted RNAi trigger which meets the following requirements:

a)      Each strand 18-24 bases (applies to si-74);

b)      the sense strand comprises 10or more 2'-deoxy, 2'-0-methyl, 2'-deoxy-2'-fluoro, or universal base modified nucleotides (applies to si-74 where 21 nucleotides are accordingly modified in si-74 sense);

c)       the antisense strand comprises 10or more 2'-deoxy, 2'-0-methyl, 2'-deoxy-2'-fluoro, or universal base modified nucleotides (applies to si-74 where 21 nucleotides are accordingly modified in si-74 antisen);

d)      10 or more pyrimidines (i.e. U or C) of either strand modified by 2'-deoxy, 2'-0-methyl, 2'-deoxy-2'-fluoro nucleotides (applies to si-74 as each strand has at least 10 of those modifications).

Genius, by acquiring the Merck patents in January, Alnylam not only gave the withering Kreutzer-Limmer patents a new life given that Merck was in some cases the only party fighting it.  No, Alnylam thereby also pulled the chair from underneath Arrowhead given the reliance of that company on ARC520 for its valuation.  Of course, a crumbling valuation of Arrowhead could really help Alnylam as it tries to catch up and develop its own version of DPCs based on what Merck has been able to copy from Arrowhead.  Given that ‘277 will only expire in 2022/3, just waiting it out may not be an option for Arrowhead.

Sorry, Arrowhead, just because Alnylam really, really ‘dislike’ Tekmira and is calling you ‘a friend’ does not mean that you can trust them any more than Tekmira or that you are any more savvy in your drafting contracts.