Tuesday, December 24, 2013

The Retina within Sight of RNAi Therapeutics

 From the highly prevalent diseases such as the age-related macular degenerations (dry and wet) to the rarer, but more numerous diseases such as the retinitis pigmentosa, the eye is the subject of a significant and growing unmet medical need.  From a genetic point of view, the application of RNAi Therapeutics to these diseases is very attractive.  However- yes, you guessed it- delivery challenges have made it difficult to exploit its potential.  In 2013, I have come across at least two pieces of evidence, one in synthetic and one related to DNA-directed RNAi, which make me believe that the time for ocular RNAi Therapeutics is nigh.

A bit of history

Following an early rush into ocular diseases that saw 3 wet AMD RNAi candidates, one each by Opko Health, Quark Pharmaceuticals (partnered with Pfizer), and Sirna Therapeutics/Merck (partnered with Allergan), speed into phase II and III studies, considerable doubts about their scientific foundations killed off the enthusiasm.  

Firstly, it was thought that the preclinical validations of the wet AMD candidates rested on TLR3-activation artifacts.  While I have not seen this claim more widely supported and chemical modifications and short double-strandedness should readily get around this issue, the more vexing question to me has been how were these either unmodified or simply 2’-O-methyl modified, unformulated RNAi triggers supposed to enter their target cells?

Moreover, for ddRNAi where Genable Technologies is readying an AAV-based candidate for retinitis pigmentosa to commence clinical trials, vector distribution following needle administration represents serious safety and efficacy issues.  Because the AAV and lentiviral gene therapy workhorses do not diffuse on their own from intravitreal injection sites to the back of the eye, ocular gene therapy has largely involved subretinal injections which a) is a relatively dangerous procedure that can seriously harm retinal architecture and integrity, and b) limits vector diffusion and therefore therapeutic activity to a small area surrounding the subretinal administration site.

Smartly evolved AAV can penetrate from the vitreous into the retina

In order to develop viral vectors capable of overcoming the physical barriers between the vitreous and retina, Dalkara and colleaguespublished earlier this year a study on the selection of AAV2 variants capable of doing just that. 

The selection process of this now popular method of directing AAV to various tissues and cell types starts out with large libraries of more or less randomly mutated AAV variants.  In each selection round, the viral DNA is extracted from the target cells and re-amplified for the next round of selection such that the AAV variants that most efficiently transduce the target cells eventually become highly enriched.
The 7m8 AAV that they identified was thus capable of broadly transducing retinal cells following intravitreal administration in mice, from the inner ganglion cells to the outer retinal pigment epithelial cells.  In non-human primates, 7m8 also greatly enhanced retinal penetration from the vitreous compared to old gold standard AAV serotypes.  However, retinal cells were not transduced as broadly as in mice suggesting that either additional candidates from mouse evolution experiments need to be characterized in non-human primates or that the selection itself should be performed in non-human primates.

I view such progress exceptionally promising for retinal degenerative diseases in which rescue of only a fraction of cells should be therapeutic (e.g. by getting rid of a mutant mRNA that leads to the death of the cell expressing it), but potentially also for the more challenging disease settings where RNAi action would probably have to occur in the majority of cells in order to be therapeutic.
Along these lines, after deciding on the best AAV variant, an important task will be to determine the more precise percentage of cells of each cell type that can be transduced to then match them up with potential indications.

Sticky self-delivering RNAi triggers penetrate deeply into the retina

In the field of synthetic RNAi Therapeutics, a peer-reviewed paper came out by RXi Pharmaceuticals (Byrne et al.) which confirmed earlier claims that self-delivering RNAi triggers (sd-rxRNAs as they call their own versions) were able to fully penetrate the retinal cell layers in both the mouse and rabbit following intravitreal injections.  The rabbit is an important model because their eye volume, believe it or not, is close to ours (~1.5ml vs ~5.0ml).  Formal proof of RNAi-mediated gene silencing was then confirmed in the mouse.

The self-delivering RNAi triggers had guide strands of ~19 nucleotides and passenger strands of less than 15 nucleotides.  An extended phosphorothioate (PS) single-stranded tail on the guide and additional hydrophobic modifications such as sterol groups were supposed to enhance tissue penetration and functional cell uptake.  The 6-8nt PS tail obviously has been borrowed from standard antisense chemistry.  Therefore, a battery of tests was performed to exclude visual abnormalities resulting from these extensive modifications.  No notable tox findings were made.
Despite the similarities in chemistry, sd-rxRNAs appear to be superior to ISIS-type PS-ASOs (RNaseH mechanism).  This is because in the Byrne et al. study, ~3 microgram RNAi trigger was required for 50% gene knockdown, whereas 50 micrograms phosphorotioate antisense oligos were required for a 50% knockdown of MALAT as presented by ISIS at OTS 2013 in Naples (report still available).  To wit­, MALAT as a nuclear RNA can be expected to be far more susceptible to RNaseH ASOs than your average mRNA, so the potency difference could be even bigger.  Also, it would be interesting to determine the safety implications of administering 3 micrograms versus 50 micrograms or whatever the equivalent dosages in humans.

The potency difference would have been much bigger still if RXi were not so married to their less than 15bp double-strandedness, a misguided decision driven by old IP considerations (when the Kreutzer-Limmers were still a concern).  I therefore expect other RNAi companies with more active R&D to thank RXi for the validation and come up with more optimal RNAi reagents for ocular applications.
Ocular RNAi Therapeutics- keep an eye on it in 2014 and beyond.

Wednesday, December 18, 2013

ISIS Demonstrates Wider Utility of RNaseH ASOs for Nuclear Targets

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

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

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

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

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

Why Marina Biotech could be the 2014 high-flyer

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

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

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

A shameful title

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

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

Reduction of Nuclear-Retained RNA

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

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

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

Monday, December 9, 2013

Silenseed Lifts Secrecy of First Clinical RNAi Slow-Release Formulation

Last week saw the first peer-reviewed publication of the LODER RNAi delivery system developed by Israeli biotech Silenseed (Khvalevsky et al. 2013).  Following a ~17-subject phase 0/I study in pancreatic cancer patients that was initiated in 2010 and a more recent phase I study with siG12D in ~100 patients with locally advanced, unresectable pancreatic cancer, LODER (Locally Drug EluteR) had become the first matrix-assisted slow-release RNAi Therapeutic formulation in clinical development.  Nevertheless, I have struggled to understand the basics of the technology largely based on the patent literature which is often ambiguous.

Slow-release RNAi Therapeutics

Slow-release RNAi formulations promise to minimize the need for and frequency of repeat drug administrations.  This is of particular value when systemic delivery options are limited and direct access to the diseased site difficult and/or dangerous to the patient.  Ocular applications are one such area as large molecule drugs are commonly administered by intravitreal needle injections which carry a cumulative risk of injury to the retina and other complications when given every month or two as is common today.  Other areas are wound healing applications (e.g. sites of broken bones) where you basically get the chance to apply the RNAi just once and pharmacology is only needed for a few months, or for diseases of the pancreas where surgical manipulations carry the risk of potentially life-threatening pancreatitis.

While RNAi activity in non-dividing tissues is remarkably extended- it now seems that with stabilizing RNAi trigger modifications and efficient delivery you should be able to achieve potent silencing in the liver for 2 to 3 months following a single administration- slow-release strategies are attractive if the goal is to go beyond that.
Slow-release strategies typically involve matrices with embedded RNAi triggers that dissolve over time thus releasing the RNAi payload.  A major challenge is to find matrices and formulations that are not only biocompatible and bioresorbable, but that do so gradually.  This is because for most matrices you initially get a great burst of activity with a relatively quick drop-off in drug release thereafter.

LODER technology

At the basis of LODER technology is the PLGA (polylactic glycolic acid) workhorse of the medical device industry.  Staying with simplicity, it appears as if the RNAi triggers are simply embedded in the ~1-by-4mm pellets in unmodified Tuschl RNAi trigger format.  As the PLGA dissolves, the RNAi triggers are liberated with about 55% released in the first week, followed by another 25% or so over the next 60 days. 

The release kinetics appear acceptable and it is good to see the RNAi trigger being protected from degradation while inside the matrix (albeit not totally unexpected).  What seems to be far from optimal, however, is the apparent reliance on intracellular delivery by naked, unmodified RNAi triggers alone.  It seems that a combination of the PLGA matrix with self-delivering RNAi triggers or other cellular delivery formulations is called for (shameless self-advertisement : I can always be had for consulting projects).


Nevertheless, the PNAS publication by Silenseed reports good evidence of gene silencing in mouse models, one involving luciferase gene silencing in a transgenic mouse with luciferase expression in the liver, others involving ectopic and orthopic pancreatic tumor masses.

Importantly, performing insightful analyses of the relationship between distance from the implanted pellet(s) and gene silencing, it was found that gene silencing was marked in a sphere up to 2mm away from a pellet.  In the pancreatic cancer models, this was accompanied by local necrosis as expected from the specific knockdown of mutant KRAS which is thought to drive the majority of pancreatic cancers.  

Given that silencing is so locally restricted, this makes me wonder how best to apply the technology in the clinic.  In the pancreatic cancer trials by Silenseed, resectable and non-resectable cancer settings have been tested, in single- and multi-dose regimens.  Intuitively, I could imagine that post-operative settings are attractive, where the pellets are deposited at the border between cancer and normal tissue following the excision of the bulk tumor to kill any remaining cancer cells much in the same way that radiation therapy is often indicated following breast cancer surgery.  In cases of non-resectable pancreatic cancer, it would seem that stuffing the pancreas with LODER pellets once and then hope for the best (maybe in combination with gemcitabine and the like) is the go-for strategy.

I am encouraged by this new way of applying RNAi Therapeutics, but also see a number of simple ways of how to improve upon this first generation LODER formulation.  This would further resolve potential IP issues that come with the use of a prototypical Tuschl-type RNAi trigger. 

Tuesday, December 3, 2013

Delivery Advance Illustrates Influence of Cosmetics Skin RNAi Therapeutics

The skin has always been a target organ of considerable interest to the RNAi Therapeutics industry due to its apparent accessibility for delivery purposes plus the fact that there are various unmet needs ranging from the severe genetic disease (e.g. epidermolysis bullosa, pachyonycia congenita) to cosmetic desires.  Interestingly, it is the latter that in many ways is driving skin RNAi Therapeutics these days.

Motorized microneedle array with unprecedented silencing efficacy
In an important advance in the rate-limiting area of delivery, Hickerson and colleagues from TransDerm and various other collaborators recently published 80% gene silencing efficacy in a mouse model for epidermal gene expression using a motorized microneedle array borrowed from the cosmetics industry (in particular the Triple-Mby BomtechElectronics of cosmetics hot-spot South Korea).  This compares to 50% and 33% gene silencing in the same model using simple (static) microneedle arrays and intradermal needle injection, respectively, before.  Accordingly, this represents a 2.5 to 3.5-fold increase in gene silencing efficacy when considering how much of the undesired target protein you are left with!

I have to admit that I did not double-check that indeed the same siRNA sequences and self-delivering RNAi trigger modifications were used in the various studies which could have affected results.  However, since these results have all been reported by TransDerm and the goal of TransDerm was to compare delivery efficacies of various technologies, I am willing to accept the comparability claim by the authors. ­

The trick with the motorized microneedle array appears to be that following penetration of the stratum corneum barrier motion (oscillation) allows for a larger volume of drug to be deposited in the epidermis than with a static needle array.  Moreover, the depth of administration can be adjusted for optimal epidermal delivery and to make it pain free as well, unlike the original high-pressure hypodermic needle attempts by TransDerm.   With this, it should be possible to deposit low single-digit milligram of RNAi triggers to an area the size of a tip of a thumb- which is quite a bit.

A possible limitation of such microneedle arrays is that the administration itself causes microinjuries to the skin.  Therefore, you want to make sure that you do not end up making things worse, especially in applications where wound healing and restoration are the goal.  Since the technology is apparently used in the beauty industry already, it is unlikely that its application will leave insightly scars and the likes.

I look forward to seeing a technology like motorized microneedle arrays in conjunction with self-delivering RNAi trigger formats being used in the clinic.  Initially, the technology is most amenable to applications where the focus is on locally defined areas such a skin parts prone to blistering.  However, taking advantage of imaging technologies and 3-D printing, I envision a future in which the technology would also be possible to treat large areas of the skin, if not the entire body surface.  As TransDerm illustrates, combining the capabilities of existing technologies from disparate areas often enables the biggest advances.

RXI-109 for dermal anti-scarring now available under the ‘Specials’ provision in the EU

Anybody that has gone to a dermatologist knows how blurred the lines between medical and cosmetic applications have become when it comes to the skin (cosmeceutical concept).  Taking advantage of the regulatory grey zone, it is skin applications that are leading the charge in the commercialization of RNAi gene silencing in WoMan.  Following a claimed treatment for skin blemishes marketed as Britena Whitening & Anti-blotch Cream by Biomics (partnered with Benitec on HepB), it is now RXi Pharmaceuticals that has signed a distribution agreement for its dermal anti-scarring drug candidate RXI-109 with Ethicor

The goal of this arrangement is to drive early sales based on an exception of European drug legislation that allows for the use of experimental drugs prior to proper marketing authorization.  All it apparently takes is a judgment call by the treating physician.  I can see the point of this ‘Specials’ provision for severe, orphan diseases as a form of compassionate use when there is intriguing early clinical evidence of efficacy and safety, but for an anti-scarring treatment, mmh...you can easily see how consumers willing to take risks in the quest for beauty will make their physician give them an injection of the stuff.

But then again, when you see how much unproven, potentially harmful potions and lotions are being sold on the cosmetics market, it is hard to argue why you should make an exception with RNAi as long as care is being taken that somewhat riskier (depending on chemistry) systemic exposures remain low and yours truly does not have to pay for it via increased insurance premiums.  I guess my biggest problem with all this is that the company distributing RXI-109 calls itself ‘Ethicor’ just as I get nervous when somebody starts a sentence with ‘to be honest’ and what follows is more often than not a lie.

Thursday, November 28, 2013

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.

Wednesday, November 20, 2013

Silence Therapeutics to Validate Endothelial RNAi Knockdown in Man

This Monday, Silence Therapeutics held an investor evening in London.  To my surprise, interest in the company and technology was such that 80-100 largely analysts, investors, and fund managers crowded the elegant Victorian-style room at the Royal Institution.  In stark contrast to the quaint setting, the main message of the evening was that the company won’t play it conservatively when it comes to this cutting-edge medical technology and is about to test whether their lipoplex-based delivery technologies can knock down genes expressed in endothelial cells…in Man.

Whereas RNAi Therapeutics have more or less conquered the liver, opening up a whole host of indications to RNAi Therapeutics, despite the apparent accessibility of the vascular endothelial system to delivery and promising animal studies, it has proven a more difficult tissue to firmly establish gene-specific knockdowns.  Part of this technical problem is due to the fact that the vasculature, especially the capillaries which are of most functional importance, is tightly interwoven into the tissues that they supply.   This causes experimental difficulties of obtaining pure endothelial cell populations, a particular concern when genes are also expressed in the more abundant host tissue cells.  Moreover, unlike the liver, proteins (and RNA) expressed in the vasculature are not commonly found in the serum.  The latter is of particular importance in clinical studies where taking appropriate biopsies is either not technically feasible or would be deemed unethical.

Similar to how the clinical demonstration of target gene knockdown in the liver has turned around the fortunes of the likes of Alnylam and Tekmira, Silence Therapeutics also wishes to remove remaining doubts by conducting a second phase Ib/IIa study with lead candidate Atu027, this time not in pancreatic cancer (impossible to obtain adequate biopsies in advanced pancreatic cancer patients), but for head and neck cancer (anticipated regulatory submission in 2014).  Head and neck cancer is one of the few cancers for which the tissue is readily accessible.  And while they are at it, they also will take muscle biopsies to look for PKN3 target repression, and look at a whole slew of other assays, some serum-based, for their ability to assess gene expression in vascular endothelial cells.

In addition to the clinical efforts, I also expect the company to more strongly adopt non-human primates for their delivery studies.  When it comes to liver-directed RNAi, non-human primates have been accepted to be a highly predictive surrogate for performance in humans and one can expect the same to be true for endothelial gene knockdown.

The strategic changes are accompanied by continued corporatere-organization of which the most notable overall change may be the increased clinical focus.  This effort is spear-headed by Dr. Michael Khan who is trained in internal medicine and thus has a good feel for selecting interesting indications of unmet medical need and conducting the appropriate clinical studies.  On the scientific front, the most notable change is the departure of long-time CSO Dr. Klaus Giese (due to family reasons), succeeded by long-time comrade Dr Joerg Kaufmann.

In addition to picking up details like the ones above, such investor events are also an invaluable opportunity to gather insights into the investor base and other people associated with the company.  In that regard, the new CEO Ali Mortazavi has done an remarkable job not only at expanding the technical, clinical, and business development expertise of the company, but also at putting the company in a position to become a sustainable stand-alone biotech company which, if you have followed the fate of UK biotech, is not an easy task.  With Atu027 clinical efforts in high gear and Atu111 for acute lung injury likely to join the clinical pipeline in 2014, the coming period will not only test the organizational skills of management, but also their ability to react to share-price moving clinical events.  Expecting success, Silence Therapeutics is striving for a full listing on the LSE thereby opening up the company to an even larger investor base.        

To learn more about Silence Therapeutics and related events, please follow this link.

Friday, November 15, 2013

Arrowhead Research Patent Application Shows Ample Experience with Triantennary GalNAc-siRNAs

[Warning: this blog entry is not about to discuss a very recent development, but rather is intended to compare the liver gene knockdown technologies by Arrowhead Research and Alnylam based on a review of the patent literature; for the non-technical folks, a mention of Novartis towards the end might be of interest]. 

It has become clear that the DPC technology by Arrowhead Research, especially their 2-molecule-version used in ARC520 for chronic HepB, and Alnylam’s GalNAc-siRNAs share a number of features.  Based on patent application by Arrowhead Research that published last summer, there is evidence that the company has ample first-hand experience with the platform used by Alnylam.  Importantly, the data show that the addition of an endosomal release agent greatly increases the potency of GalNAc-siRNAs.

Large increase in potency with endosomal release polymers

Previously, I had speculated that simple GalNAc-siRNA conjugates as advertised by Alnylam have insufficient potency.  Accordingly, patent application US2012/0136042A1 by Alnylam showed that whereas simple GalNAc-siRNA conjugates had no or very little knockdown activity, the addition of a lipidic pharmacokinetic modulator with some endosomal release activity such as cholesterol allowed for more robust activity (see first image below).
Demonstrating the superiority of DPC delivery technology for gene knockdown in the liver, at least in terms of potency, the patent application by Arrowhead Research shows that even so, the activity of a GalNac-lipid-siRNA pales in comparison to its use along an endosomal release polymer: no knockdown with GalNAc-palmitoyl-siRNA alone, but an 80% knockdown when given together with the polymer (see table).

Note that a range of lipids, including cholesterol were evaluated in that patent application.  Also note that the preferred GalNAc-conjugation was the same triantennary GalNAc structure as used in Alnylam’s programs.  

Intellectual property consideration

While the Alnylam patent application claims priority to sometime in 2007, the Arrowhead patent application claims priority to sometime in 2010.  Given that the data suggest that Arrowhead should have chosen the triantennary GalNAc-cholesterol-siRNA backbone for ARC520 for maximum potency with the 2-molecule DPC approach, instead of the cholesterol-siRNA that they eventually chose, it is possible that IP concerns played a role in that decision. 

Another, non-exclusive explanation might have been manufacturing cost concerns which should favor simple cholesterol conjugates over triantennary GalNAcs.  This would also be justified in that it is the toxicity from the endosomal release peptide and not the RNAi trigger that is expected to be rate-limiting in terms of toxicity.  In other words, to compensate for the inferior potency of cholesterol-siRNA along the release polymer, you just give more of it.

In any case, given the overlapping research activities of the two companies as evidenced by the patent applications, possibly partly the result of the former Alnylam-Roche partnership, it will be interesting to follow the patent prosecutions to find out to which extent the patents by Arrowhead Research could impair the freedom-to-operate and novelty of Alnylam’s platform, both with regard to GalNAc3-siRNAs and GalNAc3-lipid-siRNAs.

An interesting player in this convoluted situation is Novartis.  Assuming Novartis has access to GalNAc-siRNAs from Alnylam, they might be able to combine them with the endosomal release polymers from Arrowhead Research for optimal DPC2.0 knockdown activity (of course, that assumes they take some sort of license from Arrowhead Research).  It’s time for Novartis to show their RNAi delivery hand anyway lest they suffer the same fate as their peers' with their RNAi investments losing all of their value.

Single-molecule subQ DPC

The potentially convoluted IP situation is another, albeit secondary reason, why I greatly look forward forward to Arrowhead Research adopting for their upcoming development candidates the new old single-molecule DPC technology for which they had shown very impressive non-human primate data at last year’s OTS meeting. 

Because the GalNAc residues in the single-molecule DPCs are distributed along the peptide, there is no need for a triantennary GalNAc cluster for similar hepatocyte targeting potency.  Moreover, PK modulation can be achieved by modifying the polymer without the need for direct modification of the RNAi trigger.

And with regard to ARC520- don’t get me wrong. The intravenously administered ARC520 is still an exciting candidate with good activity, it’s just not as potent as it could have been.  I therefore look forward to seeing a second-generation candidate enter clinical development once clinical proof-of-concept for the immune reactivation hypothesis has been formally obtained.  Such a candidate would have much increased potency (at least 10x) and could be administered subcutaneously.  A high-quality problem to have.

Monday, November 11, 2013

Alnylam Solidifies Lead in TTR Amyloidosis Race

Over the weekend, Alnylam announced expanded data from the phase II study of ALN-TTR02 (aka PATISIRAN) in the FAP form of TTR amyloidosis at the ISFAP meeting being held in Brazil.  The data confirm the consistent knockdown potency of ALN-TTR02 and, most interestingly, suggest that a new dosing regimen can address the most rate-limiting safety issue encountered so far. 

Compared to the 19-patient dataset revealed at the Peripheral Nerve Society meeting at the end of June, the latest update includes data from 9 more FAP patients that received the highest dose (0.3mg/kg) in the once-every-3-week treatment regimen.  Previously only 3 patients received such dosing whereas the data from the 6 patients with the once-every-4-week dosing indicated an undesirable TTR rebound effect towards the end of the 28-day treatment cycle.

Data from the 12-patient once-every-3-week cohort now show that a ~80% persistent knockdown of TTR can be achieved although there still seemed to be a minor rebound effect at the end of the 21-day treatment cycle (down to ~75% knockdown).  It therefore needs to be watched whether the apparent rebound effect worsens or maybe gets better with dosing for more than the two infusions as performed in this study (open-label extension study ongoing).   

The most exciting revelation, however, from the new data was that there were no apparent infusion reactions in the 9 additional subjects.   Previously, 3 out of 7 in the once-every-4-week cohort of 0.3mg/kg experienced such reactions.  Infusion reactions thus far tends to rank as the rate-limiting safety issue in the development of SNALP-related RNAi Therapeutics and although they appear to be readily managed by slowing the rate of infusion, are dose-related, and generally occur only during the first infusion, it would put everybody at ease if there were no such risk.

Rather than being the result of a streak of luck, the absence of infusion reactions coincided with the institution of a 70-minute microdosing strategy which Alnylam labeled as ‘proprietary’.  If it holds up, it would definitely be good news for Alnylam and FAP patients.  Beyond that, Tekmira may actually be the major beneficiary of such progress as its pipeline rests on i.v.-administered SNALP RNAi Therapeutics such as ALN-TTR02.

By initiating a phase III study of Patirisan and further announcing fast-track designation for this product candidate, the company remains on track for an approval in 2016/7.  Data from the competing RNaseH antisense compound by ISIS and GSK at the same meeting remains to be publicized.

Monday, November 4, 2013

ARC520 for Chronic HepB: The Immune System…It’s Reactivating!

Usually, immune stimulation which manifest itself as flu-like symptoms and the like is something that you do not want to see with an RNAi Therapeutic.  Having said that, there are settings in which you want to see immune stimulations.  This is also the case for the treatment of chronic HBV with a HBsAg knockdown approach. 

ARC520 is the lead candidate in this effort and yesterday the sponsor, Arrowhead Research, presented very exciting data in a chronically infected chimpanzee that had been treated with the RNAi agent.  The data are not only exciting because they presumably represent the fastest reduction of the HBsAg antigen ever seen in a real infection (note: only the chimpanzee is thought to reflect human HBV infection), no, what is even more exciting is that the data are consistent with a HBsAg-specific T-cell immune response.  

As the success of an HBsAg knockdown approach for the treatment of chronic HBV hinges on the hypothesis that by knocking down HBsAg it might be possible for the body to re-activate an adaptive immune response against the virus, the data in my mind are the biggest de-risking event in the development of ARC520.

The data

At the 2013 Liver Meeting of the AASLD in Washington DC, Arrowhead Research presented more detailed data on the chimpanzee that had been treated with ARC520.  Before that we had known that two doses of ARC520 (one of 2.0mg/kg and one of 3.0mg/kg) spaced 14 days apart was able to knock down HBsAg by ~80%, HBeAg by over 90%, and serum HBV DNA by 1-2logs.  The important knockdown here is that of HBsAg, an otherwise ‘undruggable’ target.  Reverse transcriptase inhibitors such as entecavir are not able to meaningfully reduce HBsAg.

The discrepancy of the degrees of HBsAg and HBeAg/HBV DNA knockdowns is likely explained by the prolonged half-life of HBsAg.  Repeat dosing for an extended period of time should lead to even further reductions in HBsAg.  Moreover, the treated chimpanzee was an unusually tough challenge, because old (HBV for over 35 years alone), heavy and with extremely high viremia (>10exp10 genomes per ml). 

Importantly, as predicted by the HBsAg knockdown-immune reactivation hypothesis, there was an apparent T cell-mediated anti-HBsAg immune response shortly after peak HBsAg knockdown levels were reached.  The peak HBsAG knockdown occurred somewhere between ~days 25 and 38 and there was a flare-up in liver enzymes around day 43.   
A liver-enzyme flare-up would be expected when anti-HBsAg cytotoxic T-cells start to attack HBV-infected hepatocytes.  Consistent with it being due to a T-cell response, markers of T cell activation, most notably interferon gamma, were also up-regulated around the time of the flare-up.  Interestingly, liver enzyme levels did not fully revert back to normal, but remained somewhat elevated compared to base-line suggesting that the RNAi knockdown kicked into gear a more persistent immune response.

Such delayed dynamics are consistent with what is seen following successful treatment with interferons.  In the ~5-10% of cases where interferons are able to achieve the gold standard HBsAg elimination (in the presence or absence of HBsAg seroconversion), the elimination usually occurs after the ~52 week course of interferon, in many cases years afterwards.

Of course, the present chimpanzee data do not show an elimination of HBsAg.  While I do not exclude the possibility that Arrowhead Research will come back in another 3 months or so to report that the immune system has finally overcome HBsAg, I prefer to keep expectations for such an event low and instead consider the present data as a nice starting point that indeed ARC520 is able rekindle the desired immune response after only two doses over 14 days.

Why it is unlikely to be a non-specific immune response

It is very important here to emphasize that what we are seeing here was not due to a non-specific innate immune response triggered by an immunostimulatory RNAi agent.  Similarly, some RNAi delivery strategies run the risk of causing direct damage to hepatocytes which would also manifest itself by increases in liver enzymes.

The most convincing argument to me is in the timing of the flare-up and cytokine elevations.  While non-specific responses usually occur in the hours and days immediately following RNAi administration, in this case, they occurred 3-5 weeks after the second dose.

Consistent with a ‘clean’ safety profile of ARC520, no such liver enzyme and cytokine elevations were seen in the phase I volunteer study for which Arrowhead reported initial safety data a month ago (2mg/kg highest dose in that study).  Nevertheless, as those data only focused on the safety in the first few days following drug administration for the above reasons and the 30-day follow-up still remains to be reported, one formally cannot exclude the possibility that the unique DPC chemistry is associated with liver damage and the like only weeks after drug administration.  I consider this quite unlikely though.

Going along with this theme, I expect the phase IIa study which will involve infected patients in Hong Kong and is scheduled to initiate enrollment in early 2014 to be ARC520 on top of an RT inhibitor such as entecavir.  As RT inhibitors stabilize the liver of HepB patients and in light of the phase I data, any flare-ups that would be seen in that single-dose study would presumably be the result of HBsAg-specific immune reactivation.  

Lots of exciting catalysts ahead over the next 6 months and who knows, due to intrapatient variability, maybe there will be a cure or two in the phase IIa study already.  

PS: For more background on RNAi knockdown for HBV and ARC520, please visit my cureHBV companion blog

Monday, October 28, 2013

Tekmira Grabs Leadership Position in Messenger RNA Therapeutics

Messenger RNA Therapeutics is the latest addition to the RNA Therapeutics tool box.  A simple concept, it has only been recently revived outside the therapeutic vaccine realm when it was shown (e.g. Kariko et al. 2012 and Kormann et al. 2011) that certain nucleic acid modifications can minimize, if not abolish innate immune responses triggered by these long RNAs.

Of course, in addition to representing an increased innate immune challenge compared to RNAi Therapeutics, like RNAi Therapeutics, the key technical challenge for mRNA Therapeutics is the effective delivery into the cytoplasm of target cells.  When AstraZeneca paid Moderna Therapeutics $240M in upfront alone earlier this year for a limited technology license, I half rolled my eyes telling myself ‘not again’.  

The ‘not again’ refers to Big Pharma getting distracted by supposedly gate-keeping IP claims regarding the RNA inducer all the while ignoring the critical importance of delivery.  As we know, this mis-attribution of value has caused much trouble in the history of RNAi Therapeutics.

Enter Tekmira

I further believed that the SNALP LNP technology by Tekmira is most readily adapted for mRNA delivery among the RNAi delivery technologies.  So it was pleasing when Tekmira disclosed last week at the 1st International mRNA Health Conference in Tuebingen, Germany, that they indeed have been pursuing mRNA delivery and presented first data indicating that they are most advanced in this effort.

As it is difficult to compare the amounts of proteins expressed with the different technologies due to the unique half-life of each mRNA and protein, the leadership hypothesis is partly based on an assumption, namely that there is a close relationship between SNALP LNP delivery of siRNA and mRNA.  More importantly, however, due to their ample experience of commercially translating SNALP LNP delivery for RNAi Therapeutics with over half a dozen SNALP-enabled candidates that have entered clinical development and with the demonstration of scale-up, they should have a first-mover advantage.

Liver and solid cancers

In particular, Tekmira presented data on mRNA delivery in mice for the liver and solid cancers.  The liver is of interest both as a target organ itself and also as a factory for the production of proteins secreted into the circulation.  The data showed that robust levels of the luciferase marker protein could be made in the liver.  However, the data also reminded me of one (certainly not insurmountable) challenge with mRNA Therapeutics: the relatively short period of time (<24 a="" as="" been="" boundary="" data="" designed="" expression.="" expression="" gene="" half="" has="" have="" hours="" however="" indicate="" life="" lower="" luciferase="" nbsp="" of="" ote="" p="" platform.="" protein="" reporter="" robust="" short="" so="" specifically="" that="" the="" to="">

In that light, the tumor expression data were particularly intriguing.  Not only were the tumor peak expression levels comparable to the liver, but they also were maintained over a longer period of time (~2 days) and generally declined more gradually.  Since the same mRNA was delivered, this observation would be consistent with delivery to the tumor over time, as one would expect if the EPR effect plays an important role here.  The data also support a depot effect following extravasation meaning that intratumoral SNALP-mRNAs can be stable so that they can be taken up in a delayed fashion and yet be functional.  Such observations incidentally should also prove quite useful for the development of RNAi delivery for solid tumors and I look forward to more such cross-fertilizations between siRNA and mRNA delivery.   

Tekmira the logical partner for AstraZeneca

The new disclosures would seem to warrant AstraZeneca partner with Tekmira on mRNA delivery.  After all, having spent $240M for IP puts them under pressure to do something with their rights.  As I do not think much of Moderna’s own LNP delivery efforts (order my latest OTS 2013 Report to see why), AstraZeneca would be well advised to look outside of that partnership for delivery solutions.

It also so happens that AstraZeneca’s IP rights relate to protein expression for metabolic disorders (--> liver as a critical metabolic organ) and cancers, precisely the two areas where Tekmira’s technology should be most useful initially.    

And who knows, maybe Big Pharma is not always that dense as it sometimes seems and all this had been in the making months ago and the CEO of Tekmira is about to make good on his partnership ‘promise’ (in that case, sincere apologies to AstraZeneca).

Sunday, October 27, 2013

OTS 2013 Meeting Report- Now Available

Want to learn how Oligonucleotide Therapeutics are emerging as the 3rd major drug discovery engine after small molecules and recombinant proteins?  If so, then read my report on the 9th annual meeting of the Oligonucleotide Therapeutics Society held this year from October 6-8 in Naples, Italy.  My hope is that by reading the report, corporate decision makers, investors, and scientists will learn about the key dynamics in the field to help them strategically allocate their time and capital.

Please refer to the Meeting Agenda for the presentations at the meeting.

Table of Contents                                                                                          Page

I.                    Introduction                                                                                  2

II.                  Themes and Trends                                                                     3
A.      Multiple high-impact therapeutic opportunities               3
B.      Thinking small: focus on oligonucleotide chemistry        4
C.      New antisense applications mushrooming                       5
D.     Few new oligo inducer structures and delivery                7
E.      The Duchenne muscular dystrophy phenomenon               9

III.                Highlights from the various oligonucleotide modalities              10
A.      Aptamers                                                                          10
B.      Immunomodulatory oligonucleotides                                11
C.      mRNA Therapeutics                                                         12
D.     RNAi Therapeutics                                                           13
E.      LncRNA Therapeutics                                                      17
F.       Therapeutics splice modulation                                       19
G.     MicroRNA Therapeutics                                                  22
H.     RNaseH Antisense                                                            23


(15% discount for those that have ordered the 2013 RNAi Therapeutics Investment Guide)

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My first name: dirk; my last name: haussecker

Wednesday, October 23, 2013

Regulus Borrows from RNAi Delivery Technologies…5 Years Late

With the gift of birth of having access to all the technology toys from parent companies Alnylam and ISIS, Regulus Therapeutics in 2007 was poised to speed into the clinic a new class of RNA Therapeutics: microRNA Therapeutics.  Today, Regulus has yet to put a single compound into clinical development.  This not only reflects the increased biological complexity of microRNAs as opposed to for example single gene knockdown approaches such as RNAi Therapeutics, it also reflects a fear of breaking with the dogma that for microRNA inhibition ‘naked’ antisense technologies should be used.

It turns out that only now, Regulus finds that in order to optimize the product profile for their lead program, anti-miR122 for the pan-genotypic treatment of HCV infection, they really ought to borrow from RNAi delivery, in this case GalNAc-conjugates from Alnylam.  With this, they will achieve more potent miR-122 inhibition as well as increase the therapeutic window through the targeted delivery.  This is opposed to saturating the target organ along with the rest of the body with ‘naked’ phosphorothioate molecules, a concept I'm struggling to get comfortable with. 

The case for such a facilitated delivery strategy is even stronger for an antiviral anti-miR candidate such as this one because hitting the virus instantly instead of only slowly reaching effective drug concentrations in the target organ reduces the risk of drug resistance.

As a result, Regulus will enter the clinic with RG-101 at a time when the first all-oral HCV therapeutics with high cure rates will have hit the market.  This is a commercial catastrophe for an otherwise scientifically sound target.

One already has to be thankful that a small organization such as Regulus is able to show such flexibility at all (I don't even want to know in which antiquated terms Big Pharma is thinking about microRNA Therapeutics).  This achievement almost makes me afraid to ask why they have not thought it through to the logical end and adopted more structured, and much more potent anti-miR structures along with these delivery technologies?  This armchair CEO would have had a SNALP/structured anti-miR strategy tested in 2008.

However, Regulus Therapeutics has a chance to redeem itself- at least partly.  As it evaluates GalNAcs and LNPs (SNALP?) for an anti-miR program in liver cancer (HCC), it could for example help the RNAi Therapeutics industry understand whether the GalNac-receptor (ASGPR) is suitable for RNAi Therapeutics candidates for the attractive liver cancer indication.  So as Tekmira has followed Arrowhead Research into HBV, maybe Arrowhead Research may want to follow Tekmira (TKM-PLK1) into HCC.

Disclosure: The idea for this blog entry came after I started to look into RGLS ahead of the AASLD meeting (Nov1-5).  I concluded that there would be a good chance that with presenting a promising profile for RG-101 at AASLD and maybe some new data for the Alport Syndrome at the Kidney Week also in early November (Nov5-10), we could see RGLS bounce back into the $9-10 range by mid-November.

Tuesday, October 15, 2013

From Platform to Products to Platform

Following a number of clinical proof-of-concepts with various RNAi Therapeutics candidates, investors have started to once again not just value RNAi Therapeutics companies for their lead candidates alone, but also their platform technologies.  Recent analyst notes, the $60M fund raisings each by Arrowhead Research and Dicerna, and the pipeline development conference call by Tekmira all support this conclusion.

This is a major change in the perception of the industry from just 2 years ago when it was left for dead by most.  The timely clinical validation of RNAi Therapeutics activity was the last straw left.  To their credit, Alnylam, with the crucial help of Tekmira’s SNALP delivery technology, managed the last-minute turnaround.  At the same time and in the absence of prospects for Roche-type platform deals, RNAi bellwether Alnylam emphasized its transition from platform to product company.

In addition to reminding us of the larger potential of RNAi Therapeutics, positioning yourself as a strong platform company also tells the market that you are ready to take advantage of the most attractive RNAi-amenable markets by developing best-in-class solutions.  I cannot imagine e.g. that a blockbuster RNAi Therapeutic for TTR amyloidosis will not prompt companies which believe to have the better delivery technologies to compete for the revenues.

In order to make a credible case of being a strong platform company, vibrant R&D operations are necessary.  In addition to being indispensable for technical improvements, trying to instead obtain your animal data and formulations from CROs can be dangerous.   One of the reasons why Arrowhead Research and Tekmira should do well in this environment is that they never suffered the drastic layoffs that particularly targeted the basic research organizations while the product-specific teams were mostly left intact.

Selling the platform dream to investors and achieve an acceptable cost of capital will be an important task for RNAi Therapeutics companies to bridge the time until real sales revenues come in.  Instead of hurting investors, a healthy cost of capital and cash cushion also lessens the risk of companies succumbing to a dilutive death spiral and allows their companies, cash-, but not technology-constrained, to capitalize on their technologies in a timely manner.   
By Dirk Haussecker. All rights reserved.

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