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.

Sarepta, Biomarin Move Over- Here Come tcDNAs

In a head-to-head comparative study in NatureMedicine, Goyenvalle and colleagues claim that tricycloDNAs (tcDNAs), a relatively unexplored constrained nucleic acid analogue commercialized by SYNTHENA have superior efficacy over 2’-O-methyl oligos and PMOs for therapeutic splice modulation in mouse models of Duchenne Muscular Dystrophy (DMD). 

In addition to ~3 to 5-fold enhancements in dystrophin exon skipping in various muscles compared to the competing chemistries, the authors report that only with tcDNAs there was splice modulation also for the dystrophin isoform expressed in the brain.  This was accompanied by improvements in the behavioral and cognitive abnormalities in this model.   Apparently, these neurological defects are another important treatment goal in DMD.

Splice modulation was accompanied by ~2 and 20ug/g oligo concentrations in brain and muscle, respectively, following the administration of relatively large weekly doses of 200mg/kg that were necessary particularly for the correction of the neurological symptoms.

Interestingly, such delivery and target modulation was achieved without encapsulation or further modification technologies.  Whereas a 2012 publication by some of the same authors in collaboration with ISIS Pharmaceuticals explored the use of tcDNAs for RNaseH-mediated gene knockdown in conjunction with the phosphorothioate backbone known to greatly improve biodistribution and cell uptake, tcDNAs here were applied in their naked form.

The authors attribute this to an apparently spontaneous tendency of tcDNAs to self-assemble into ~100nm nanoparticles.   

The results seem to warrant the development of tcDNA for DMD exon skipping.  Critical to their success in the clinic will be the safety and tolerability of tcDNAs in Man with the kidney predicted to be the dose-limiting organ.  

The study is also a reminder that there are now a number of other chemistries, including the high-affinity CRN chemistries by ISIS Pharmaceuticals and Marina Biotech, the latter with a stated focus on DMD, which similarly promise improvements over the trail-blazing 2’-O-methyl and PMO chemistries.  

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.

Oligonucleotide Therapeutics Companies Crowding into GalNAc-Conjugation

Following Alnylam’s achievement of making subcutaneous administration work for RNAi gene knockdown in the liver by conjugating RNAi triggers to the GalNAc sugar, antisense companies have started to copy the approach.  As RNAi Therapeutics have made great progress in targeted delivery, antisense companies are starting to realize that in order to stay competitive and improve the safety of systemic uses of antisense, they need to get away from the notion of 'naked'/unformulated delivery that relies on swamping the body with phosphorothioated oligonucleotides.

This has become apparent at the AsiaTIDES meeting here in Tokyo where both Santaris and ISIS Pharmaceuticals disclosed their great interests in GalNAc conjugation.

In collaboration with Axolabs (the part of Roche RNAi Therapeutics that was not acquired by Arrowhead Research and that had familiarity with GalNAcs), Santaris presented phosphorothioate-LNA Factor VII (liver) knockdown data showing 80% gene knockdowns in mice following a single dose of 0.1mg/kg.  Even more potent knockdowns were seen at 0.25mg/kg and above. 

In another presentation by ISIS Pharmaceuticals on their cardiovascular franchise, the company noted that they will follow up on their initial Apo(A) (‘little A’) candidate with a GalNAc-conjugated version.  With this, they expect to increase potency by up to 10-fold, thus allowing for 10-30mg (~0.15-0.45mg/kg) dosing.

This illustrates the utility of the GalNAc receptor (ASGPR) and how the competing RNAi and antisense technologies are fertilizing each other.

Regulus Therapeutics, of course, is the first antisense (anti-miR) company of sorts that has adopted GalNAc conjugation for their liver-directed programs, most notably anti-miR122 for HCV that is about to enter clinical development.  Regulus obviously has a license to GalNAc from Alnylam.  Whether this also applies to ISIS Pharmaceuticals, remains to be seen.  The word on the lab floors is that GalNAcs per se are not patent-protected, so ISIS may use an entirely different linker strategy to Alnylam just as Arrowhead Research does with its GalNAc-targeted DPCs.

What it means for Tekmira and Marina Biotech

Since some of you are following my investment strategy, here is what I think this means for the liver-directed efforts by Tekmira and Marina Biotech (both of which I own). 

Marina Biotech could obviously follow the same path as ISIS Pharmaceuticals and Santaris in adopting GalNAc conjugation with its CRN technology.  As such, there should be no change in the competitive value of CRN compared to Santaris and ISIS antisense.  It could also attach GalNAcs to their liposome-based SMARTICLES for which delivery to the liver remains to be demonstrated.  To do all this, however, Marina Biotech needs to grow and establish in-house R&D.  

For Tekmira, it means that RNaseH antisense are getting close in potency for gene knockdown compared to the 2^nd gen MC3 SNALP LNPs (85-90% TTR gene knockdown in humans at 0.3mg/kg).  With the 3-fold more potent 3^rd generation SNALP LNPs which should enter the clinic this or early next year (TKM-ALDH2, TKM-HBV), Tekmira should stay well ahead of its competition with the most potent gene knockdown technology for the liver.  This means more addressable diseases and in most cases higher treatment effects as well.   And if it incorporated GalNAc-conjugated lipids into their liposomes, too, maybe that would extend that lead even further.

If gene knockdown in the liver is not a great example for why you need a competitive free market economy, then I don’t know what is. And, of course, there is no better example of why you need a lab ;).

Oligonucleotide Therapeutics for Spinal Muscular Atrophy Impresses in Clinical Study

In addition to the continued validation of RNAi in Man, the other big winner of 2013 in the field of oligonucleotide therapeutics was single-strand phosphorothioate chemistry in the CNS.  Today, ISIS Pharmaceuticals announced clinical data from the most prominent candidate in that effort, namely ISIS-SMNRx for spinal muscular atrophy (SMA), a genetic muscle-wasting disease.  Following intrathecal administration of the splice modulating oligonucleotide, time- and dose-dependent improvements were observed not only in muscle function, but also in SMN protein production (biomarker), thus laying the foundation for an accelerated approval pathway.

In the open-label phase Ib/IIa study in ~30 children with the ‘less severe’ form of type II and III SMA, functional improvements of 1.5, 2.3, and 3.7 points on the HFMSE scale were seen at the 3mg (3 doses), 6mg (3 doses), and 9mg (2 doses) cohorts, respectively.  The changes were thus largely consistent with results from a previous similar, but single-dose phase I study where a 3.1 point increase could be observed at the 9mg dose.

Despite the generally positive news, the data raise a number of questions.  For example, optimal dosing frequency remains uncertain as there were similar functional improvements regardless of whether a single dose had been given or 2-3 doses.  This could have been due to the  long half-life of the drug and the time it takes from SMN protein production (as a  result of the splice modulation) to impacting motor neuron function.  Similarly, in the prior phase I study no positive changes in HFMSE scores were observed at the 3mg and 6mg doses whereas in the present study, improvements were reported.  Clearly, larger patient numbers are required  to settle on the optimal dose, and in fact this dose may not have been reached yet (note: a 12mg cohort has been initiated and children from the phase Ib/IIa trial are allowed to roll over to an additional dose of 12mg).

Case for accelerated approval?

Possibly foreseeing such issues due to small patient numbers, ISIS Pharmaceuticals and BiogenIdec recently developed an assay that allows them to measure SMN protein abundance in the cerebral spinal fluid (CSF).  It is the results from these measurements that provide a strong case for why ISIS-SMNRx should be made available (pending the 12mg results) before a larger phase III study will have been completed.  This is because the functional improvements were accompanied by increases in the SMN protein which also were dose-dependent with a more than doubling of SMN protein at 9mg.

In SMA, the SMN1 protein is missing due to mutations.  The therapeutic approach of ISIS-SMNRx takes advantage of the fact that humans have a pretty much identical gene to SMN1, SMN2.  The problem with SMN2, however, is that only ~10% of its precursor messenger RNAs is spliced into a functional SMN protein due to a difference in essentially just one nucleotide in exon 7.  The severity of the disease, i.e. whether somebody belongs to type I (most severe), type II, type III, or type IV of the disease depends on the copy number of SMN2 genes: 2 copies in type I, ~3 copies in type II and III, and at least 4 copies in type IV.

Therefore, doubling the protein output for type II and III patients (the patient population in the present phase Ib/IIa study) would appear to put the children into the type IV category in terms of protein output (correponding to ~6 SMN2 copies).  In contrast to type I-III, type IV results in no differences in life-expectancy and only in rare cases causes patients to be wheelchair-bound late in life.  

Severe disease of high unmet need, strong biomarker data with highly suggestive functional results, all dose-proportional…the ingredients for an accelerated approval. 

Just in: ISISis reporting preliminary data from a parallel multi-dose phase II study in the most severe, infant form of SMA (type I).  Although small in numbers, the fact that the 4 babies at the starting 6mg dose are still alive and without permanent respiratory support at an average age of 12.5 months appears to be much better than expected.  According to natural history data, you would have expected 2 babies either dead or on permanent ventilation by month 10.  

And finally...the ISIS-SMNRx results increase the value of Marina Biotech's CRN chemistry.  This chemistry competes with the ISIS 2'MOE chemistry employed in ISIS-SMNRx and appears to be of higher potency/affinity, but much less defined safety.

Big Pharma Panic over Nucleic Acid Therapeutics

News this week of Roche licensing antisense technology from Santaris 3 years after having written down a related $500M+ investment in RNAi Therapeutics, is symptomatic for the apparent panic and resulting schizophrenic behavior that grips Big Pharma when it comes to Nucleic Acid Therapeutics (NATs).  Can NATs help rekindle their flagging discovery efforts or will NAT companies leave them in the dust as they advance to the top of the Pharma food chain?   

Meanwhile, Big Biotech in the form of BiogenIdec has also recognized that NATs are critical for their growth in the form of a partnership with Zinc Finger Nuclease specialist Sangamo Biosciences for the treatment of red blood cell disorders (sickle cell and beta-thalassemia).  This follows significant (~$150-200M) recent investments in ISIS’ antisense technology for diseases of the CNS and a deal with microRNA Rx company Regulus Therapeutics.

If you sit back and consider the clinical and preclinical developments in the space (look out for the upcoming RNAi Therapeutics Investment Guide 2014), there can be no doubt that nucleic acid therapeutics (including oligonucleotide therapeutics) are about to materialize as the 3^rd major chemical class of drugs following small molecules and recombinant proteins.  In fact, their mechanistic versatility (gene up- and down-regulation, modulation of RNA processing etc) means that in a few decades, there will be many more NAT-based new molecular entities than small molecules and recombinant proteins combined, in many cases for genetically defined patient populations.  

Interestingly, in 2013, only 2 monoclonal antibody new molecular entities (NMEs) received marketing authorization by the FDA (see here).

Investors do not have to take such a very long view as a number of commercially attractive Oligonucleotide Therapeutics are gearing up to enter the market, including for TTR amyloidosis, Hepatitis B infection, spinal muscular atrophy, and hypertriglyceridemia.

For those interested in the more particular relevance of yesterday’s deals to RNAi Therapeutics stocks, the Roche-Santaris deal ($10M in upfront plus the usual biobucks and royalties) represents another blow to ISIS’ claim that it owns the IP in the space, especially in light of the ongoing litigations and patent battles between the companies and the fact that not long ago, Roche partnered with ISIS on Huntington’s Disease.  This should provide further comfort to those, including myself, speculating that Marina Biotech’s CRN chemistry is a valid equivalent, if not superior alternative to the ISIS and Santaris antisense chemistries.  Regarding the deal between Sangamo and BiogenIdec ($20M upfront plus the usual biobucks and royalties), it is a validation of the attractiveness of the hemoglobinopathy market that forms an important part of Alnylam’s pipeline options.

In additional RNAi Therapeutics developments...

Bad news for Benitec

In a recent paper by Lisowski et al. from Stanford (Kay lab) which appeared in Nature, very strong evidence was presented that the AAV8 serotype is far from ideal when it comes to transducing human hepatocytes.  This is in contrast to preclinical results mainly in mice that have shown highly efficient, almost 100% transduction of hepatocytes, the transduction level probably needed to achieve an RNAi cure of HepC.

Based on the preclinical work, the AAV8 serotype was readily embraced by gene therapists and adopted for various liver-related clinical studies. Surprisingly, however, the data so far in hemophilia did not support a significant advantage of AAV8 over the old AAV2 workhorse.

The study by Lisowski et al. shows that this is very likely the result of poor AAV8 transduction of human hepatocytes.  Among the multiple striking results, in mice with chimeric human/mouse livers, basically only the murine hepatocytes could be transduced whereas the adjacent human hepatocytes were not.

This is an unfortunate development that Benitec cannot be held responsible for.  It could be a double-whammy though for the company as in addition to the commercial concerns about the HepC indication for TT-034, results from the ongoing phase I study may not even support the delivery technology for other liver applications.  There is, however, light at the end of the tunnel as there are plenty new AAV serotype that appear to be as good in transducing human hepatocytes as AAV8 is in transducing murine hepatocytes.

Investor Appetite for Expanding the Nucleic Acid Therapeutics Tool Box

The last few days saw two more eye-catching examples of investors daring to dream big by committing significant early-stage capital to building new Nucleic Acid Therapeutics platforms. 

First, start-up mRNA Therapeutics company Moderna Therapeutics took advantage of the hype it was able to create in the wake of a deal earlier this year with AstraZeneca which involved $240M in upfront monies alone to raise another chunky $110M in a private round.  This brings the total raised by Moderna to over $400M in the last 2 years or so.  Then on Monday of Thanksgiving week, a consortium of VCscommitted up to $43M to start up Editas Medicine, a company built around genome editing harnessing the recently identified CRISPR adaptive immune system in bacteria.

Counting in IPOs and private rounds by nucleic acid therapeutics companies (e.g. Bluebird Bio in gene therapy, Prosensa in exon skipping), well over half a billion raised by RNAi Therapeutics companies in 2013, partnership monies earned by ISIS etc, we are talking here probably about approx. $1.5B raised by the industry so far this year.  And what is best about this in my opinion is that these fund raisings were not intended to help with commercializing a newly approved product or running a large phase III trial for a late-stage clinical candidate- no, they were mainly the result of broader interests in the platforms.

What a departure from the post-2008 world of biotech and oligonucleotide therapeutics when pipelines were commonly regarded as a financial liability and the platform concept was the ultimate biotech heresy belonging to the 2000 genomics bubble era.

If you like to see the glass half empty and secretly hope that the world is coming to an end soon (e.g. in the form of a stock market collapse), good luck to you!   While I expect some volatility as the industry moves towards bringing meaningful drugs onto the market and cash flow positivity (just witness the recent Prosensa and Sarepta stumbles) , looking at the nucleic acid therapeutics pipelines and a healthcare environment friendly towards targeted therapies that are the sweet spot of nucleic acid therapeutics, it is hard to come up with scenarios in which this nucleic acid therapeutics revolution can still be halted.  Moreover, the strong cash balances of some companies mean a virtuous cycle of value creation for companies like Arrowhead Research which are capital constraint, not technology constraint, and should also allow them and their investors to weather short-term volatility.

Having said that, the time for some healthy pruning will ultimately come, likely in the wake of the next major upheaval in the normal economic cycle, and I expect some investors to throw in the towel even before some of these technologies have had the time to prove themselves.  You think that making delivery work for RNAi Therapeutics strained some investor patience, then what about getting a protein, RNA, and DNA into the nuclei of target cells all at the right amount and time for the correction of single-gene disorders as appears to be the first therapeutic frontier of Editas?

   

But until then, the fact that investors dare to dream of medical breakthroughs again means that the future of biotechnology which lives off such bold concepts remains bright.   Nucleic acid therapeutics will play a critical part in that future.

Marina Biotech as a bet on the oligonucleotide therapeutics tool box

As the economy improves and interest rates remain low, I expect money continue to move into the higher risk end of the market.  In terms of the stock market this generally means that while the 'safe' companies were the first to recover following the collapse of the housing bubble, the more innovative and 'risky' groups such as social media and biotech followed with even larger returns.

Thinking of the oligonucleotide therapeutics space, the ultimate high-risk play that has yet to respond to the improved market conditions is Marina Bio.  In hindsight, the two main reasons for Marina Bio's spectacular share price erosion were (1) that it promulgated the idea of an oligonucleotide therapeutics supermarket concept when nobody wanted to hear of it, and (2) that it did so after it had lost its credibility in the markets after many broken promises (largely under previous leadership) and then tried to re-define itself by the year.

Most would consider it dead now, but with a number of licenses to companies like Novartis, Monsanto, and Tekmira, two products in the clinic that utilize its SMARTICLE delivery technology (one for a microRNA Rx mimic by Mirna Therapeutics, one for an DNAi Therapeutic by ProNAi) and an in-house clinical candidate for an orphan indication (transkingdom RNAi for FAP cancer) in a suspended (for financial reasons) phase I study that one ought to be able to revive, it should have more inherent value than the $3-4M current market cap suggests.   In addition, it retains access to usiRNAi triggers and high-affinity antisense chemistry for RNaseH gene knockdown and steric blocking applications that I see on par with the technologies by ISIS Pharmaceuticals, Santaris, and Regulus.

As appetite for all things oligonucleotide therapeutics grows, this could be an interesting play.

Marina Biotech to Stage Comeback

Arcturus Therapeutics Acquires usiRNA Technology from Marina

Today, Marina Biotech announced that it is assigning, i.e. is selling usiRNA technology to San Diego RNAi Therapeutics start-up Arcturus Therapeutics.   In addition, the company detailed recent progress in its patent estate encompassing various RNAi trigger- and delivery-related technologies.  Based on these accomplishments, and after extending the maturity date of a critical loan to 2014, it now wants to resurrect itself as a real biotech company by raising capital and relocating to, you guessed it, Cambridge, Mass.  

The usiRNA modification arguably allows you to circumvent the Tuschl siRNA structure and related patent estate by Alnylam and is claimed to even improve upon the Tuschls by allowing for greater specificity.   In addition to Arcturus and Marina, Tekmira, and likely Arrowhead Research (through Roche), have access to such RNAi triggers.

Financial details of the transaction were not disclosed.  Through the assignment of the patents, Arcturus stands to collect the milestone and royalty streams from Marina’s existing licensees.  This includes Tekmira which in its quarterly filing disclosed this week that it would have to pay $3,250,000 in milestones plus single-digit royalties for the technology.  Although these numbers pale in comparison to what Alnylam has asked for RNAi trigger licenses in the past, this suggests that the undisclosed financials and likely upfront payment by Arcturus should have been substantial for a company like Marina…at least enough to continue to pay its patent prosecution and other bills. 

How Arcturus paid for it is unclear to me given that its first significant capital raise involved merely $1.3M.   

For Arcturus the deal seems to make a lot of sense.  If the usiRNA workaround theory holds up, you would be very hard pressed to find such inexpensive RNAi trigger IP (because from a distressed seller) allowing you to broadly go after your targets of choice.  Obviously, this is to complement the liposomal delivery technology on which it was founded.  With the right financial support and scientific talent, Arcturus will be an interesting story to follow.

Mirna Therapeutics Brings First MicroRNA Replacement Therapy into Clinic

It has been a long wait, but 5 years following the initiation of anti-miR122 development for the treatment of HCV infection by Santaris, a second microRNA Therapeutics has now entered clinical development.  MRX34 by Mirna Therapeutics is a miR-34a replacement therapy for the treatment of liver cancer or cancers with liver involvement.  

MicroRNA replacement therapy is technically very similar to RNAi Therapeutics.  It involves adding to cells naturally occurring microRNAs to orchestrate typically a range of processes deemed to be therapeutic.  It is added to cells in the form of double-stranded RNA triggers very much alike RNAi triggers and can therefore largely utilize the same types of delivery approaches.  The delivery technology for MRX34 is the NOV340 SMARTICLE technology owned by Marina Biotech.  This liposomal delivery technology is distinct from SNALP, most notably by employing ionizable ‘amphoteric’ lipids, lipids that can take on both positive and negative charge depending on pH, and not ionizable cationic lipids, lipids that merely become positively charged at acidic pH, as in the case of SNALPs. 

An extensive literature supports miR-34a as an exciting microRNA for replacement therapy in cancer rivaling the most famous let-7.  Accordingly, miR-34 emerged as Mirna Therapeutics’ top priority based on extensive screening conducted at Ambion (now Life Technologies) from which Mirna Therapeutics was spun out.  Under transcriptional control by the guardian of the genome, p53, its pleiotropic effects range from cell cycle inhibition, to counter-acting anti-apoptotic mechanisms and to sensitizing towards chemotherapy.  The choice of liver-related cancers was thus not based on cancer biology (many cancers cancers would apply), but largely a function of where the company thinks NOV340 can deliver to.

This to me raises again the question of whether liver cancer is closer to normal liver or whether it is closer to solid tumors in general in terms of delivery.  MRX34 thus follows Alnylam’s reasonings as manifested by ALN-VSP02, but goes against what is known about blood supply differences between normal liver and liver cancer and what is practiced by the likes of Tekmira and Dicerna.

The phase I study will be a typical dose-escalation study seeking to determine the maximally tolerated dose.  Given the importance of delivery, close attention should be paid to the pharmacokinetic and biodistribution data from this trial.  These should start to become available in the first half of 2014.

The development is positive for at least two other companies.  As the provider of the delivery technology, Marina Biotech obviously stands to gain financially and otherwise from such clinical milestones.  Whether it will be sufficient to pay off its debts that have come due and consequently avert bankruptcy is an open question.  Due to the financial distress, Marina Biotech struggled to enter into deals giving it fair compensation for its technology.

Although the most direct competitor to Mirna Therapeutics, InteRNA as the other major microRNA replacement company in oncology should also benefit from the initiation of the phase I study as it helps to validate its approach.  The question will be whether among its stable of microRNA replacement candidates, there are some with as robust activities as miR-34a.   

BMS Partners with Santaris

In other recent news related to microRNA Therapeutics, Big Pharma Bristol-Myers Squibb partnered with LNA antisense company Santaris under which the Danish company collected $10M upfront.  Although the press release did not specify much the aims of the the alliance, referring to RNA Therapeutics broadly, a few factors speak in favor of microRNAs being involved.  

Most notably, BMS had terminated an phosphorothioate RNaseH antisense collaboration with ISIS Pharmaceuticals.  As Santaris in turn had terminated their PCSK9 phosphorothioate RNaseH antisense program as well, most likely due to kidney toxicity (--> phosphorothioate chemistry as also in Prosensa; van Poelgeest et al. 2013), the first suspicion that BMS sought out Santaris as a more potent PCSK9 alternative becomes less compelling.  Moreover, ISIS Pharmaceuticals is suing Santaris over US patent infringement of RNaseH technology which should hinder the ability of Santaris to enter into relationships with US companies for RNaseH antisense purposes.  Of course, the deal could also indicate that a settlement is in the making...

The Time for the U(nusual)siRNA Strategy Has Come

As Tekmira and Arrowhead Research will unveil their next RNAi Therapeutics development candidates later this year, an interesting question will be whether these will involve one of their RNAi trigger options that some consider to be unencumbered by fundamental IP related to traditional designs (esp. the Baulcombe and Tuschl II IP).  These decisions could have important strategic consequences for the competitive landscape, from targets and indications to Big Pharma involvement.   

Support for freedom-to-operate claim

One of these designs is the usiRNA from Marina Biotech.  These comprise at least one ‘unlocked’ nucleic acid monomer (UNA) in the double-stranded RNA molecule.  While I have reservations about the scientifically tenuous claim (see here why) that UNAs are not to be grouped with most of the other nucleotide modifications for RNAi use because they lack an intact ribose group, usiRNAs were held to be sufficiently non-obvious and of specific utility that the USPTO issued fairly broad claims in 2012.  Moreover, Marina Biotech once commissioned an external IP lawfirm perform a freedom-to-operate analysis on usiRNA, and (surprise, surprise) came to the conclusion that, indeed, usiRNAs have FTO.

Overcoming target picking limitations

This view seems to be shared also by others in the industry. Notably, Roche RNAi (now part of Arrowhead Research) in 2009 gained access to Marina’s usiRNAs, meroduplex siRNAs, and Dicer-substrate RNAi triggers.  This came as a surprise given that Roche had spent over $300M just two years earlier to gain access to RNAi trigger IP held by Alnylam.  Given that none of the three licensed RNAi trigger forms and related IP poses any FTO threat to traditional Baulcombe-Tuschl designs, the most likely explanation for the move is that it was about allowing the company to escape the target picking limitations under the license from Alnylam.  This included the 31 targets exclusively held by Novartis, some Tekmira exclusive target picks, and some targets pursued by Alnylam that Alnylam exempted from competition.  Whether the last of Alnylam’s Big Pharma licensees, Takeda, might pursue a similar strategy is an interesting question.

Facilitating platform partnerships

When Alnylam and ISIS sued Tekmira for infringing on their RNAi trigger IP by collaborating with Bristol-Myers Squibbs on RNAi delivery, it became a priority for them to have access to or control over non-Alnylam RNAi triggers.  As a consequence, they obtained an exclusive license to Halo-Bio’s multivalent RNAi triggers (more than two strands).  Subsequently, they gained access to Marina’s usiRNAs, including the ability to sublicense.   This now puts them in the position to engage in platform partnerships with Big Pharma companies that do not have access to Alnylam IP.

The same strategy would likely also apply to Arrowhead Research with its various RNAi trigger options that it inherited from Roche, especially if Alnylam provided Roche with only product-specific sublicensing rights, if at all.  As RNAi Therapeutics enjoys a return of pharmaceutical interest, this one-stop-shop option by the two leading delivery companies could be critical to bringing new companies into the space.

And for Alnylam, these developments would not only diminish the royalty it might earn from licensing its IP, they could undermine their own product candidates, including ALN-PCSK9 (hypercholesterolemia) and ALN-AT3 (hemophilia).  Accordingly, the preclinical data strongy suggest that subcutaneous DPCs can do everything that Alnylam’s GalNAcs can do, only much more potently and with less frequent dosing. 


 

The RNAi Therapeutics Money is in the Product Candidates

If you believe, like I do, that the RNAi Therapeutics money ought to be in delivery, the track record suggests that you are mistaken: with the exception of what was euphemistically referred to as a $65+10M 'restructuring' of the agreement between Tekmira and Alnylam, over the last 4 years there has not been one deal where an RNAi delivery company reaped substantially non-dilutive funding for their delivery technology.  By contrast, the money was to be made in RNAi triggers and especially in partnering/licensing out RNAi Therapeutics candidates (for more details, see the RNAi Therapeutics in 2013 Report).

The failure of companies like Tekmira, Arrowhead Research, Silence Therapeutics, and Marina Biotech (plus many others not so much in the spotlight), to capitalize on the uncontested value of delivery may be due to one of the following factors:

1) their respective delivery technologies do not meet the expectations of the pharmaceutical industry;

2) RNAi Therapeutics has lost its attraction as a platform technology. Consequently, an investment in platform technologies such as delivery is not compelling;

3) Potential partners want a One-Stop Shop. Licensing in delivery AND the RNAi triggers separately can be burdensome and may mean decreased potential profits down the line (royalty stacking);

4) intellectual property issues around the payload when monetizing delivery; Alnylam and ISIS have famously sued Tekmira for their delivery deal with BMS (litigation terminated now) claiming that Tekmira was indirectly selling RNAi triggers it did not own.

I believe that all the above factors have contributed to some degree with the relative weight of the issues varying depending on the specific technology, geographies, and other company-specific factors such as the trade secret litigation between Tekmira and Alnylam that has delayed deal flow related to the most advanced RNAi delivery technology.

However, RNAi Therapeutics is regaining favor as a platform technology and I am hopeful that this will translate into the long overdue transactions, also involving the SNALP and DPC technologies by Tekmira and Arrowhead Research, respectively, which have technologies of clinical maturity (disclosure: I am a shareholder of both companies).  The two most likely customers here are Novartis and Merck.  Novartis has an active interest in RNAi Therapeutics, but the scientific and patent literature suggest that they have no tangible delivery technologies and their internal efforts are not even half-hearted so that I expect them to go out and buy in the technology instead of replicating Merck's inreasingly costly mistake of investing hundreds of millions in internal delivery research, including SNALP and DPC lookalikes, when the combined market caps of the originator companies is a fraction of that (please somebody explain that logic to me).

Nevertheless, RNAi delivery companies cannot rely on such platform partnering and need to push ahead with creating RNAi Therapeutics candidates.  This last mile is currently the most rewarding way to monetize on their delivery technologies.  Alnylam has long understood this (see recent partnering around TTR, PCSK9 and VSP), and is now reaping the rewards. 

What Alnylam has done, however, is no magic, far from it: identify genetically attractive gene targets, formulate into established delivery tech (e.g. SNALP, GalNAc), and do some biology around them to build a scientific story to be sold to the pharmaceutical and investor world.  With an established delivery technology, the hard work, or maybe better, the most uncertain factor has been removed, so it's pretty smooth sailing from there as long as the gene target is good and desired by the industry.

It is thus ironic that platform companies get loved for their specific product candidates (not just in RNAi Therapeutics it seems), and not for the technologies that critically enabled them. For RNAi delivery companies, it is important to swallow this scientific toad and invest the additional $5M or so it takes to build that IND-enabled package to reap disproportional rewards.

Big Agriculture Bankrolling RNAi Therapeutics

After years of pouring millions, if not billions into RNAi-related intellectual property (IP) and the development of double-strand RNA delivery, the RNAi Therapeutics industry is now harvesting returns from an unlikely source: agricultural companies.

Most notably, Alnylam reported yesterday an IP license and collaboration agreement with Monsanto which is widely known for its transgenic seed business.  Particularly eye-catching was the $29.2M in upfront monies, an amount not seen in RNAi Therapeutics for a long time.

However, Alnylam is not the only RNAi company that has been approached by Big Ag.  Admittedly somewhat flying under my radar, Devgenclosed a similarly upfronted RNAi collaboration with Syngenta in May of this year.  Interestingly, that deal came after Devgen’s 4-5 year RNAi partnership with Monsanto had ended in 2011, earning the Belgian (ag) company tens of millions.  This suggests that there is an RNAi scramble in the Ag space reminiscent of what happened in RNAi Therapeutics in 2006-8.  Moreover, Marina Biotech, also in May, exclusively licensed RNAi IP to Monsanto, and Tekmira mentioned in their last two conference calls that it was undertaking evaluative work with a large agricultural company: Monsanto or Syngenta?

The fact that Tekmira is involved in this business development opportunity for RNAi Therapeutics companies suggest that general RNAi IP is only one reason for Big Ag’s approach.

At first, this left me scratching my head: how would you apply double-strand RNA delivery by LNP in a commercially meaningful way in agriculture?  After some research though, it became obvious that Monsanto, Devgen and Syngenta are interested in using orally ingested dsRNA to fight insect pests such as the Western corn rootworm (WCR).  The need of finding new solutions for WCR has dramatically increased as the long-standing transgenic Bacillus thurigiensis toxin-incorporating crop by Monsanto has been plagued by resistance.

Another compelling reason for using non-transgenic approaches in agriculture is the fact that it should speed up the regulatory process as RNA is Generally Regarded as Safe (GRAS) by the FDA. This much reduces the hurdles compared to transgenic plants which might spread in the environment and further express biologically active proteins.  Moreover, unlike a toxin like Bt, the RNAi trigger can be highly specific to the targeted pest species.

The question, of course, is whether this approach, despite its attractions is technically and financially feasible in the first place.  The seminal work by Devgen and Monsanto (Baum et al., Nature Biotech2007) suggests that this is in fact the case: sub-nanogram per cm2 amounts of relatively cheap T7 in vitro transcribed RNA were sufficient to specifically and effectively silence essential genes in the entire body (!!!).  As a result, the growth inhibition caused by the pest was much reduced after ingesting the RNA.  I guess that the delivery work is aimed at even further reducing the required amount of RNA by a log or two.

The mechanism of this amazingly efficient gene silencing is likely the same as the early finding in nematode worms (another group of agriculturally important pests no less) that feeding them with E. coli bacteria expressing dsRNAs can cause potent and long-lasting silencing.  This phenomenon is referred to as ‘systemic RNAi’ and involves RNA amplification.  Although such systemic RNAi is unlikely to operate at the same high efficiency in all pest species, harnessing it in a species like WCR would already be highly commercially lucrative.  Monsanto apparently is close to commercializing such an RNAi-based insectizide.

Transkingdom RNAi and ddRNAi

When thinking about RNAi in plants, DNA-directed RNAi (ddRNAi) usually comes to mind, the type of RNAi where long hairpin RNAs are expressed from a transgene inserted into the host genome.  Certainly, a ddRNAi approach e.g. in corn against the same transgenes is also possible and indeed this has proven to be equally effective when compared to sprayable RNAi in the 2007 Nature Biotech paper.  It should also be added that unlike in your typical protein-expressing transgenic crop, ddRNAi per se does not involve transgenic protein expression, thereby lowering the regulatory hurdles.

When thinking about oral RNAi, especially in light of the RNAi history of feeding dsRNA-expressing bacteria to nematode worms (the first ‘transkingdom RNAi’ example), one may also consider the ‘Transkingdom’ RNAi technology by Marina Biotech (originally from Cequent).  One can speculate that Monsanto’s interest in Marina Biotech is related to this as part of a wider RNAi initiative by the Ag giant. An issue of feeding pests with such bacteria, however, is that again you release transgenic organisms into the wild.  While this may not be so much an environmental or health problem, you know that there are many out there that are religiously against anything ‘GM’, smashed windows and all.

Has Tekmira vs Alnylam been settled?

If we assume that LNP delivery is part of the package in the Alnylam-Monsanto deal and that Monsanto is the Ag company that has been working with Tekmira (until at least just two weeks ago), one can come up with at least three hypotheses for how the deal reflects on the Alnylam-Tekmira litigation:

1)     Tekmira and Alnylam competed, and Alnylam won;

2)     Monsanto will also tap Tekmira to cover all bases;

3)     There is an understanding that Alnylam will use the $30M to settle the lawsuit, and as part of the settlement/M&A, Monsanto will gain access to Tekmira technology.  Announcing the Monsanto deal before settlement is beneficial as it further bolsters Alnylam’s reputation and balance sheet. In that line of reasoning, the Regulus IPO should come SRTL.

The next weeks will tell.

Gradalis Swiftly Moves ddRNAi-Enhanced Cancer Vaccine Candidate through Clinic

I’ve been reminded a number of times by the staunch Benitec-supporters here that Texas-based biotech company Gradalis has been moving a ddRNAi-enhanced cancer vaccine candidate (‘FANG’) aggressively through clinical development. Virtually out of nowhere, Gradalis initiated clinical trials two years ago and there are now two active phase II trials, one in ovarian cancer and one for advanced melanoma. A peer-reviewed publication on the phase I trial was also just published (Senzer et al.) arguably making FANG the lead RNAi candidate in oncology.

The phase I study involved over 40 patients with advanced solid tumors and demonstrated the safety and logistic feasibility of the approach. Although evidence of suggestive of efficacy was presented such as a clear correlation between an immune response and survival, it would be premature to conclude anything with regard to efficacy. Having now followed a number of cancer vaccines, most of which have eventually failed, it seems to me that correlations such as this could be just as well as a reflection of the fact that those with more responsive immune systems will do better anyway.

‘FANG’ comprises of plasmid DNA from which a single RNA polymerase II promoter drives the expression of an upstream GM-CSF open-reading-frame followed by a pair of downstream RNAi hairpins. This plasmid is introduced by electroporation in a petri dish into the patients’ own cancer cells which have been obtained from a tumor resection. After allowing some time for the expression of the transgenes, the cells are irradiated so as to kill off their proliferative potential and are then re-introduced like many other vaccines by intradermal injection.

The GM-CSF component, wildly popular in the cancer vaccine field and also part of Dendreon’s famous prostate cancer vaccine PROVENGE, is supposed to serve as an attractant, proliferation and maturation factor for dendritic cells which are supposed to ingest, present and thereby stimulate an immune response against the antigens unique to a tumor; the pair of ‘bifunctional’ hairpins meanwhile both target furin which is thought to be an important protease for the maturation of the various isoforms of TGF-beta, a well-known immunosuppressant often overexpressed in cancer.

‘Bifunctional’ here means that one hairpin is perfectly matched and therefore mostly relies on the so-called Ago2/cleavage-dependent mode of RISC activation, whereas the other hairpin contains a central bulge due to mismatching changes introduced in the passenger strand arm of the hairpin thus relying on the non-cleavage pathway of RISC activation which can be facilitated by all four human Argonautes (both predicted to yield the identical guide strand). This strategy of distributing the RNAi between the various Argonaute proteins is certainly an interesting idea, but I’m not sure whether even Gradalis knows what consequences of this is both in terms of efficacy and safety.

A general lack of detailed molecular mechanistic studies is probably my biggest concern with this candidate and when thinking about Gradalis in general. It also at least partly explains why FANG has been moving so rapidly through the clinic. I find it particularly troubling that I have seen no detailed studies by Gradalis looking at the relationship between furin knockdown and TGFbeta inhibition which is key for Gradalis' strategy. This already has caused difficulties in interpreting some of the phase I data where possible assay problems complicated reconciling apparently only modest reductions in furin with much more pronounced down-regulations of TGFbeta. This not only makes it more difficult to make the right development decisions, but also when it comes to finding a partner for the program. On the other hand, you could argue that a cancer vaccine candidate involving both GM-CSF expression and TGFbeta inhibition already has a good chance at succeeding, and sweating out the technical details would only cause delays without making us much the wiser.

As I had mentioned, the Benitec supporters are following Gradalis’ development with much interest as such an advanced ddRNAi candidate may be a prime licensing opportunity for Benitec which controls an important part of the ddRNAi patent landscape. I’ve certainly looked at the hairpin structures involved in light of Benitec’s patent claims (esp. the ‘099 Graham patents) and there is a good chance that Gradalis ought to take a license as it further monetizes this candidate, although their structures may give them a bit of wiggle room.

Mirna Therapeutics selects Marina Biotech’s SMARTICLE delivery tech

In another notable development last week, cancer microRNA Therapeutics company Mirna Therapeutics said that it would use Marina Bio’s SMARTICLE liposomal delivery technology for the development of microRNA replacement therapy for cancer. Based on conference presentations, the two companies had been collaborating on the delivery of microRNA mimics before announcing the deal. An attraction of the SMARTICLE delivery technology, which Marina had acquired from Novosom, is certainly the fact that there is already clinical experience after SMARTICLE-enabled ‘DNAi’ compound by ProNAi has begun dosing a year ago. Similar to related agreements between Mirna and Silence, and InteRNA and Silence, insightful details about the financials were not disclosed. For Marina, which have diluted shareholders by what seems like a 100-fold over the last 3 years (unreal, really), it is good news as its extensive technology offering is finally getting takers.

Tectonic Shifts in RNAi Therapeutics

As consolidation in RNAi Therapeutics in the Old Economies continues, the balance of power is rapidly shifting towards the resource-rich and growing economies of the Far East where national RNAi champions are set to make their mark on the international RNAi Therapeutics scene.

After some notable mergers between private and public RNAi companies (Intradigm-Silence, Cequent-Marina Biotech), and the decision by some, albeit not all, Big Pharma companies to turn their backs on RNAi Therapeutics development in-house, a contraction of the publicly traded pure-play RNAi companies seems inevitable. Arrowhead Research (ARWR), despite its name, has long stopped internal RNAi research and its technology is getting stale by the day, the captains of RXi Pharmaceuticals (RXII) have decided on a course that is entirely incompatible with it continuing to be an RNAi platform company, Marina Biotech (MRNA) despite its good intentions signaling to the world almost daily that it is in distress and has not found anything worth focusing on, and the executives of Rosetta Genomics (ROSG) personally making sales calls as the company continues to bleed money.

Some of these companies do have interesting technologies worth funding in my opinion. RXi’s sd-rxRNAs are well differentiated and complementary to the established RNAi trigger structures, Rosetta had established a prolific microRNA diagnostics machine, and Marina Biotech built a very able and what seems to be enthusiastic RNAi Therapeutics team, but probably invested too aggressively hoping for an early turnaround in RNAi sentiment that would lift all boats. There may be a rationale for conserving some of that value by a) spinning out (RXi) and/or merging technologies that are synergistic (ROSG); and b) selling themselves for a small premium for its practical RNAi research expertise (MRNA).

The pure-play survivors may be the following: Alnylam, Tekmira, Silence Therapeutics, and Benitec. Alnylam is obvious, because of their cash and an aura that makes investors and pharmaceuticals partners pay a premium for their assets (I expect the VSP and Atu027 deals to reflect this). Tekmira as the delivery experts and also benefitting from diversification tendencies in the resource-driven Canadian economy, an investor base, however, that Tekmira needs to tap more aggressively. Silence Therapeutics with its recent progress in delivery, some valuable RNAi trigger IP, and supported by an investor base that has widened in the wake of its merger with Intradigm to cover the US, UK, and Germany. And finally Benitec which has positively surprised me by its recent recapitalization which puts it again into the category of drug developers and not just an IP play. Certainly, the re-issuances of a fundamental ddRNAi trigger patent have helped, but I don’t think this recapitalization would have been possible without resource-hungry China buoying the Australian economy.

Alnylam: RNAi trigger IP, brand and industry connectivity.

Tekmira: problem solvers, delivery powerhouse.

Silence: RNAi experience, broad investor base.

Benitec: ddRNAi powerhouse, Australian economy and proximity to China.

Benitec probably best symbolizes the shift in RNAi Therapeutics towards the countries with most economic growth. While its commercial focus may still be with the traditional markets for innovative medicines (US, Europe, Japan), its research activity, once in the US, has shifted to the East as illustrated by its collaboration with Biomics on HBV. This collaboration both taps into the geographic proximity with China as well as the growing scientific expertise that can be paid for with the strong Aussie dollar.

Don’t be surprised if the leading RNAi Therapeutics candidate for scarless wound healing will be developed in China (Sirnaomics), and not by RXi in the US, or if the first RNAi agent with human use will be marketed in the Far East and not the US or Europe just as it happened in gene therapy. Some of it may be explained by less stringent standards of patient protection in these countries, but it would be a mistake of complacency to use this as the only explanation.

Whether it will be Biomics, Sirnaomics, BMT, or others remains to be seen, but the flow of investment dollars firmly points towards a global shift in RNAi Therapeutics development and commercialization. Smart minds and outstanding technologies are one part of the equation, financial backers with deep pockets the other.

Marina Biotech Finds Success with Local Bladder Cancer Approach

Marina Biotech this week reported pre-clinical data supporting the use of local, intravesicular siRNA delivery for the treatment of nonmuscle invasive bladder cancer. The publication in Molecular Therapy comes weeks after this early-stage program was partnered with Swiss pharmaceutical Debiopharm which will be responsible for funding the rest of the development.

According to the National Cancer Institute, there are about 70,000 new cases of bladder cancer in the US alone, most of them related to smoking. Because bladder cancer typically starts at the epithelium lining exposed to the urine, simple surgical resection is often sufficient to stop the disease in its tracks. Unfortunately, in some cases the cancer recurs and progresses into a more aggressive, muscle-invasive form of cancer contributing to the 14,700 deaths from bladder cancer annually (US number). Current strategies to prevent recurrence include the instillation of immuno- and chemotherapeutics into the bladder. When this fails, the bladder often has to be removed. Clearly, more treatment options are needed to limit the progression of bladder cancer into the more aggressive forms and maybe also to provide an alternative for bladder removal once more aggressive cancers have developed.

In the present study, Seth and colleagues first screened a range of RNAi triggers against the cancer-related genes polo-like kinase 1 (PLK1) and survivin and were able to demonstrate that Marina’s usiRNA chemistry platform allows for very satisfactory knockdown efficacies with IC50 values in the 10 to 30pM range (bladder cancer cell lines in tissue culture). This triggered widespread apoptosis and, in the case of PLK1, a strong reduction in cell viability. The data therefore add to the notion that PLK1, incidentally also the target in Tekmira’s phase I clinical program TKM-PLK1, may be the single-most promising RNAi cancer target, a view apparently shared by Marina scientists as evidenced in the Discussion part of the paper. Nevertheless, survivin may still be a highly desirable drug target for sensitizing cancer to chemo- and radiation therapies.

The selected siRNAs were then formulated into positively charged multilamellar liposomes of around 100nm. Due to the negatively charged proteoglycan-rich urothelium, a formulation with a lipid containing a guanidinium group was deemed particularly promising in being able to penetrate the 6-7 cell-layered urothelium. Accordingly, these formulations, when instilled into the bladder, were able to very efficiently suppress the growth of nonmuscle invasive bladder cancers in mouse models of the disease. Although equally highly efficient in vivo knockdowns were reported, 90-95% with 1mg/kg (relative to body weight), in my mind there are still some unanswered questions as to how much of that merely reflected the reduction in the size of the tumor.

In terms of safety, no untoward reactions to the formulations were reported. One important reason for this should be the lack of systemic exposure from such treatment. The authors also stated that they were not able to find evidence of innate immune stimulation despite careful investigation. Ideally this analysis would have included a positive control, but then again, also taking into account the 5’ RACE analysis for sequence-specific target cleavage, the overall evidence strongly supports that RNAi knockdown was a main contributor to the in vivo efficacy. Actually, in the case of bladder cancer, having a bit of local immune stimulation may very well be a good thing as I was surprised to learn that bathing the bladder with a solution containing the Calmette-Guerin bacterium (BCG), the famous vaccine against tuberculosis, is part of the current standard of care for superficial bladder cancer and is thought to work by stimulating the immune system. Who knows, Marina may even want to adapt BCG to trans-kingdom RNAi for bladder cancer to combine the RNAi and BCG mechanisms of action into a single agent.

Study Adds yet Another Indication Suitable for Current RNAi technologies

Marina Biotech has made it into an art to select development programs amenable to their current technologies. Given the challenges of systemic RNAi delivery, in a relatively short period of time, the company has already identified and progressed three cancer applications where local approaches can probably be used: familial adenomatous polyposis (FAP; ingested trans-kingdom RNAi), bladder cancer (intravesicular LNP), and most recently malignant ascites (intraperitoneal LNP). Together with developments elsewhere in the field, this clearly shows that the time for RNAi Therapeutics is Now: a range of solid cancers (e.g. liver, lung, FAP, bladder, melanoma), hypercholesterolemia, hemorrhagic fever viruses (Ebola, Marburg), TTR amyloidosis, PHN, AMD, Huntington’s disease etc etc.