Wednesday, April 30, 2014

ISIS Wasting No Time to Find Out Clinical Utility of Spinal Muscular Atrophy Drug

Yesterday at the 2014 Annual Academy of Neurology (AAN) meeting, ISIS Pharmaceuticals provided an update (presentation here, press release here) on their splice modulation antisense drug candidate ISIS-SMNRx for the treatment of spinal muscular atrophy (SMA).  The data were largely consistent with those presented about two months ago.  

Disease progression, including deaths in the infant trial, however, dashed hopes that this drug would be on its way to Accelerated Approval.  In light of the small number of subjects (15) in this trial, these events make it difficult to determine the impact of ISIS-SMNRx.  Similarly, the open-label nature of both the infant (type I SMA) and children (type II/III SMA) studies leaves open the possibility that apparent treatment benefits seen in motor-function outcomes could have been a placebo effect.

As a result of these concerns, the company has taken the bold step to run placebo-controlled, blinded pivotal phase III trials in infants and children to ascertain the tantalizing signs of efficacy seen thus far.  Most importantly, the drug more than doubled target therapeutic SMN protein levels (based on measuring surrogate levels in the cerebrospinal fluid) thereby genetically converting type I into type II/III SMA and similarly type II/III into near-healthy status.   In addition, the motor function increases seen were not only clinically relevant, but were also dose-related and hardly, if ever seen in the natural history of the disease.

Clearly, the apparent disease progression in the infant study would seem contrary to this conclusion.  Type I SMA babies have a mere life expectancy of 10 months, whereas type II/III children are faced with only somewhat shortened life expectancies.  The reason for this discrepancy is probably that in a treatment paradigm, SMN protein levels only catch up with type II/III SMA a few months after birth, whereas in normal development the SMN gene is already expressed in the womb.  The fact, however, that in the mouse model of the disease, ISIS-SMNRx restored mice to near-healthy status when given after birth, supports the notion that the drug should be efficacious when given post-delivery.

In the case of the infant study, drug administration commenced around months 4-5.   Considering that rapid functional decline and death occur soon after this in the natural history of the disease, the more optimal use of the drug would be when given starting right after birth.  However, until whole genome sequencing at birth becomes a routine screening tool for genetic disease (it should be routine already in my opinion), such optimal use has to wait for probably another 7-10 years.  Nevertheless, since ISIS-SMNRx seems safe and was shown to successfully address the disease at its root in babies and children- which also means that it could synergize with other future treatments- regulators should consider the full potential of this drug, present and future, when making a decision as to its approvability in 2016/2017.

One thing is clear, ISIS and partner BiogenIdec want to conduct the most rigorous trials possible to do ISIS-SMNRx justice when it could have taken the present data and pressed for accelerated approval in type I SMA largely based on the increases in SMN protein.  Knowing the real benefit of a drug can only benefit SMA patients and their families, and as we have found out in the case of Sarepta and DMD, the timelines ultimately do not have to be that different.     

Monday, April 28, 2014

Big De-Risking of ALN-TTR02 and SNALP Delivery Platform

Today, Alnylam reported (PR here, presentation here) first data from its phase II open-label extension study of ALN-TTR02.  ALN-TTR02 is developed for the treatment of TTR amyloidosis (FAP form) and with a phase III study underway is the industry’s lead blockbuster candidate.  There is no doubt that its results will have a big impact on the perception of the technology.   Importantly, the new data revealed at the International Symposium on Amyloidosis show that ALN-TT02 not only maintains consistent knockdown potency following multiple (>2) administrations, but even more importantly, indicate that the biggest risk, long-term safety, will not be a problem.    

Phase II promising, but with efficacy and safety questions

The new data follow on from a 2-dose phase II study (somewhat euphemistically labeled 'repeat administration) showing that ALN-TTR02 can achieve ~80% TTR knockdown levels not only following a first dose, but also following a second dose.  This was good to see because there was theoretical concern that SNALP LNPs could provoke generation of neutralizing antibodies to the PEG component which might compromise efficacy following repeat dosing.  Indeed, TTR levels seemed to return back to normal more quickly following the second compared to the first dose and was responsible for Alnylam switching from a 3-week to a 4-week dosing interval.

On the safety side, infusion-related hypersensitivity reactions are the major concern with SNALP LNP as with most other infused therapeutics, nucleic acids, protein, or small molecules alike.  While the steroid pre-treatment may have ensured that no major immune reaction was seen in the phase II study, infusion reactions had been recorded in 3 of 20 infusions at the key 0.3mg/kg dose.  Intriguingly, when a micro-dosing pre-treatment strategy was employed (increasing the length of infusion from 60 to 70 minutes) no such reactions were seen in the 18 infusions thus administered.  This is probably related to the fact that infusion reactions in general are essentially restricted to the first dose and are dose-related.

Phase II open-label extension data provide highly positive answers

In thinking about a headline for today’s blog entry ‘spectacular’ was on my mind a lot.  However, I refrained from using this term as the scientific results show very comforting consistency. 'Spectacular consistency' may be too oxymoronic.   In stock market terms, however, this consistency may very well be called ‘spectacular’ both for the much increased likelihood that ALN-TTR02 will make it across the finish line and for the safety demonstration of Tekmira’s SNALP delivery platform in general for which the major concern has always been safety, not efficacy.

Importantly, the results revealed today show that the ~80% knockdown potency is maintained following an aggregate of 119 doses of 0.3mg/kg ALN-TTR02 compared to an aggregate 38 doses before.  In the patient who has been on therapy the longest, this was the case following 9 doses over half a year.  The integrated knockdown level over time may have indeed been slightly higher than 80% since TTR levels were measured at their nadir, just before the next dose.  One can therefore conclude that the enhanced recovery from gene knockdown following the second dose did not intensify over time and that sustained and consistent knockdowns can be achieved over the long-term.

Regarding safety, just 3 instances of mild-moderate adverse events were reported in the extension phase that were deemed possibly treatment-related.  Probably only the 2 instances infusion reactions in a single subject call for attention.  Even so, none of them were deemed severe enough that the infusion rate had to be slowed as it is normally done.  The other mild-to-moderate AEs were an ‘increase of diarrhea’ and an 'impairment of taste'.  Maybe not all that bad in a disease like FAP.

Further indicative of the tolerability of ALN-TTR02, Alnylam projects 27 out of the initial 30 patients to participate in the open-label extension study.  First functional results from this OLE are expected to be reported by the end of 2014.

Disclosure: I could not resist but buy back some TKMR today based on the recognition that today’s data represent a great de-risking of the SNALP LNP delivery platform the company depends on.

Friday, April 25, 2014

Celgene in Surprise $710M Upfront Antisense Deal

Hands up if you had heard of Nogra Pharma and antisense therapeutics before yesterday; or of Giuliani International Limited and antisense, Nogra’s original name?

I can’t imagine that before the $710M upfront licensing deal with Celgene was announced yesterday many would have heard of the company, and for a good reason. 

Substantial scientific doubts…

Nogra Pharma has been developing an antisense oligonucleotide for the treatment of inflammatory bowel diseases with a pivotal phase III study apparently planned this year.  The candidate in question, GED-0301, is a simple first-generation phosphorothioate DNA oligonucleotide targeting Smad7 for gene silencing.  It does not even have a gapmer structure for increased potency, an industry standard for more than a decade now:

‘Phosphorothioate single-stranded oligonucleotides matching regions … and 107–128 (5'-GCTGCGGGGAGAAGGGGCGAC-3', oligo 4) of the humanSmad7 complementary DNA sequence (GenBank accession number AF010193) were synthesized in the sense and antisense orientations and used as described’

Although this was not the case in this original 1999 publication which provided the mechanistic rationale for GED-0301, later publications on a preclinical model of IBD in mice and subsequent phase Iresults state that this oligonucleotide had been then modified to rule out non-specific immune stimulation, although the functional confirmation of this was not presented.

Also interesting is the fact that in the phase I study which was conducted in 15 subjects, the only evidence for systemic exposure of this oligonucleotide came from only one subject in which it was ‘barely detectable… suggesting that the drug is not probably absorbed following oral administration.’

…but maybe it does something after all

On the other hand, I get the fact that this oligonucleotide, provided orally in enteric coated tablet form, is supposed to act on the intestinal epithelium and mucosa, including associated immune cells.  The drug would therefore in theory not have to reach systemic circulation in order to be effective.  Nevertheless, I would still expect it to show up there following uptake by the intestinal lining as a result of normal oligonucleotide drug elimination typically involving the break-up into smaller pieces which then get released into the blood to be renally excreted. 

At the very least, this apparent absence of oligonucleotide in the blood indicates that cellular uptake is inefficient.  Combine this with the inherent inefficiency of first-generation RNaseH, and you will have a hard time imagining that there would be potent on-target gene silencing.  Nevertheless, an interaction of the phosphorothioate oligonucleotide with particularly gut phagocytic cells is likely and this might have a therapeutic immune-modulatory effect on the disease.  

To convince me of an on-target silencing effect, I would have needed to see much more extensive PK/PD studies, additional control oligonucleotides, as well as a detailed characterization of the non-specific immune modulatory effects of GED-0301.  Just switching it from a non-modified, to a methyl-cytosine modified oligonucleotide without supporting characterization seemed a bit quick.

Moreover, in order to firmly establish the delivery strategy, I would have liked to see RNaseH silencing by the same chemistry and route of administration for a gene that is unrelated to immunology. 

The press release indicated that the phase II results from a blinded study for the treatment of Crohn’s Disease were positive and that they will be presented in a major publication and medical meeting.  It is likely that Celgene liked what it saw in the results and that this explains the enormous deal value.  After all, if Celgene has been able to turn cancer drug Abraxane (albumin-conjugated paclitaxel) into a commercially successful drug (closing in on being a blockbuster), their sales force should also do well in selling another drug of uncertain mechanism and debatable risk/benefit.   

Tuesday, April 22, 2014

Pharmaceutical Mega-Deals Could Delay RNA Therapeutics Partnerships

Pharmaceutical mega-deals are en vogue again.  Though not official, rumor is that Pfizer intends to acquire AstraZeneca for $100B, and deal engine Valeant has gone hostile on Botox maker Allergan with a ~$45B bid.  As if that weren’t enough for what was supposed to be a quiet Easter weekend, double-digit billion figures are being moved across the table in an asset swap between Novartis and GSK.   

The motivations for all these deals are essentially the same: squeezing out short-term profits by slashing R&D.  Valeant is an interesting example as it never pretended to be in the R&D game in the first place.  Instead, it exists on the notion that R&D is inefficient and risky and financial engineering through M&A instead of drug development is the only way to Big Pharma bliss.  Considering its spectacular rise to a ~$50B market cap company and a relentless increase in its share price, it has the goods to show for it. 

Pfizer, on the other hand, like all Big Pharmas likes to tout its R&D prowess webcast after webcast, R&D day after R&D day, but in fact is the worst offender when it comes to squeezing profits from slashing R&D.  In just 5 years following its acquisition of Wyeth, the R&D budget of the combined companies has been cut in half.  AstraZeneca is partly a juicy target because it was forced to be more risk-taking in its R&D as it gained the reputation to be the Big Pharma with the least innovative and effective R&D. 

As a consequence of this, AstraZeneca has become one of the most active Big Pharma in RNA Therapeutics with deals in antisense (ISIS), microRNAs (Regulus), RNA modulation (PTC Therapeutics), and most famously the 2013 $240M upfront mRNA Therapeutics deal with Moderna

Unfortunately/fortunately, depending on whether you think Big Pharma involvement in RNA Therapeutics is a good thing or not, the other two deal protagonists from this weekend, Novartis and GSK are also amongst the Big 4 Pharmas in RNA Therapeutics (Sanofi/Genzyme being the 4th).

In addition to cost savings by cutting R&D outright, RNA Therapeutics deals could also be affected by Big Pharmas becoming pre-occupied with re-organizing.  This is based on experience as the narrative is that when Pfizer acquired Wyeth in 2009, Wyeth had by far the superior RNAi development effort, but that this fell victim to the acquisition.  Similarly, when Roche acquired Genentech the same year, RNAi Therapeutics quickly fell down the priority list.

What deals may be canceled or at least delayed as a result of these developments? 

mRNA delivery is the first one that comes to mind as I believed AstraZeneca to be under pressure to do something in this area after having spent probably $300M on mRNA Therapeutics by now.  

We have already heard about Novartis which had been another top pick for a delivery deal to go with its target picks from Alnylam.

Fortunately, RNA(i) Therapeutics is in a different position from what it was in 2009.  Cashed up and with robust, clinically validated technologies, a number of companies do not depend on dilutive Big Pharma deals any more- at least for now.  Let the deals therefore happen.  They will only accelerate the demise of the old pharmaceutical model to be replaced by innovative biotech companies.  

Saturday, April 19, 2014

Dicerna Trying to Succeed Where Novartis Has Admitted Defeat

This week, newly public RNAi Therapeutics company Dicerna initiated its first phase I study of a Dicer-substrate-based RNAi Therapeutic.  DCR-MYC targets the well-known Myc oncogene utilizing a liposomal delivery formulation (EnCore) for targeting a variety of cancers, solid and hematological (à Myc and lymphoma) malignancies alike, but with a planned focus on primary liver cancer in future studies.

The cancer trial start coincides with Novartis’ bitter, brake-slamming exit from internal RNAi Therapeutics development, largely blaming lack of suitable delivery technologies.  In particular, in classic Big Pharma style, Novartis seems to have selected its 31 RNAi trigger picks under the 2005 Alnylam license not based on where delivery is most advanced, but based on where it wished to strengthen its disease franchises.  It is this putting the cart-in-front-the-horse attitude that is at the root of Big Pharma’s miserable failure with an emerging platform technology that has its own mind of where it wants to go first.

According to commentary by Alnylam, cancer appears to have been a focus of Novartis’ target selection.  With regard to delivery to cancers, I would agree with Novartis to the extent that it is not as far developed as for example for the liver.  A problem with it is the inter- and intra-cancer heterogeneity of the EPR effect that most current cancer delivery approaches rely on.  You therefore have to be quite careful as to which cancers you select.  The same heterogeneity applies to target receptor expression (e.g. LDL-receptor, folate receptor) and Tekmira will have its good, not necessarily publicized reasons for why it chose neuroendocrine (NET) and adrenocortical carcinoma (ACC) for its ongoing phase II trial with TKM-PLK1, preliminary results from which are expected this year.

I’ve had the pleasure of attending the European Symposium of Controlled Drug Delivery in the Netherlands this week and presentation after presentation showed that for most liposomal formulations, tumor penetration is a major issue.  The good news is that EPR is very real, but the field has come to a point where it needs to establish the rules for which cancers are amenable and which strategies (size, lipophilicity) can be employed to aid in tumor penetration.

Imaging studies presented at the conference and the recent (conditional) European marketing approval of the companion-diagnostic/folate receptor-targeted cancer drug pair by Endocyte (Vintafolide) strongly suggest that patients should be pre-selected based on whether they have cancers amenable to EPR.  For example, pre-treatment with a small dose of the drug co-formulated with a diagnostic contrast reagent would both visualize amenable tumors as well as have the side benefit of de-sensitizing the patient to hypersensitivity reactions that are typically observed for infused drugs during the first administration.

So while I remain uncertain about the specific prospects of DCR-MYC partly due to concerns around the target and partly due to the relative inexperience of Dicerna in liposomal delivery, RNAi Therapeutics will become a reality in the treatment of cancers.  Just don’t expect clumsy Big Pharma R&D to rise to the challenge.

Monday, April 14, 2014

Welcome to 'The Wait'

With Tekmira sliding today 15-20% and the rest of RNAi, and in fact biotech sector, trading weaker by the hour, I will acknowledge the technical damage and view this cementing the end of the RNAi Therapeutics Revival Era (2011-2014).  The new 3-year segment can likely be called ‘The Wait’ as following various human proof-of-concept gene knockdowns, we have accepted that RNAi Therapeutics are real, but still would like to see first products approved to fully declare victory.

RNAi Therapeutics sentiment follows 3-year cycles with striking regularity: it all started with the 2002-5 Geek Phase, one of benign ignorance of the technology, and was followed by the 2005-2008 era of Irrational Exuberance when Big Pharma gave away money regardless of technical obstacles. This then foreshadowed the 2008-2011 era of Doubts and Despair when no matter how good the scientific news, it fell on deaf investor ears.  Finally, we are still all too familiar with the 2011-2014 Revival where those that persisted reaped life-changing rewards.

I was prepared for this sentiment change to occur, but not in so drastic fashion.  Also, that Putin invading the Ukraine, a senator writing a Letter of Ignorance to Gilead, and a new Chairman of the Fed stumbling in her first important speech would get the ball rolling was unexpected.  It would have made more sense for Arrowhead Research to first demonstrate gene knockdown with DPC before assuming the waiting mode.

For investors this means less reliance that the general RNAi Therapeutics sentiment will elevate stocks.  Instead, attention needs to be paid to each company’s clinical trial catalysts.  For companies it means to stay fiscally conservative and focus capital largely on expanding pipelines instead of the technologies at their disposal.  Fortunately, the healthy cash balances of a number of companies (Alnylam, Tekmira, Arrowhead Research, and Dicerna) mean that they can afford to do so and are shielded for the moment from the need to raise capital.  Product-oriented deals such as in HepB are always on the table to supplement the balance sheet.

Novartis revealing today that it has given up on its internal RNAi Therapeutics pipeline development efforts  was both surprising and not.  Not surprising since it is obvious that these tired Big Pharma R&D organizations have even failed just to copy the leading RNAi delivery technologies from pure-play RNAi Therapeutics companies.  With the exception to some degree of Merck, the RNAi work from Big Pharma that has transpired has been nothing short of embarrassing.  Surprising in that one would have thought that Novartis would take their 31 target picks and marry them to delivery technologies from either Tekmira or Arrowhead Research.

The question now is who will get the picks.  Although rapidly deteriorating in value, the picks would give a company leverage over the very Alnylam that licensed them to Novartis.  This is because Novartis enjoyed preferential gene target picking rights.

And finally, full disclosure, I in fact did sell.  Not that it makes any sense scientifically.  I do not, however, want to make the mistake of ignoring the fact that the market has changed and ride it down any further.  I will continue to follow the science and markets here on this blog and hope you will do well in spite of me.   This is a very difficult post, but I know that in the end I will be measured by my ability to forecast.

Friday, April 11, 2014

McSwiggen Patents not Fundamental

Alnylam recently issued a press release regarding the upholding of a European patent (the ‘McSwiggen’ patent EP 1423406) that it had inherited from Merck as a result of the $175M+ January deal.  Given that Alnylam called the patent ‘critical for the development and commercialization of all RNAi therapeutics’, I thought it would be worthwhile pointing out that while valuable, it is by no means to be considered a fundamental RNAi trigger patent. 

The reason is that the patent claims contain a number of important limitations.  Remember that for an RNAi trigger to infringe, it would need to fulfill each of the various specifications.  Here is the main claim with my annotations in red highlight:

1. A chemically modified short interfering nucleic acid (siNA) molecule that down-regulates
expression of a target gene by RNA interference (RNAi), wherein:

a. the siNA comprises a sense strand and a separate antisense strand wherein said
antisense strand comprises a sequence that is complementary to RNA of the target gene
and wherein the sense strand comprises a nucleotide sequence that is complementary
to the antisense strand,

b. each strand of the nucleic acid molecule is independently 18 to 24 nucleotides in length
and the siNA duplex comprises 17 to 23 base pairs;
This encompasses most canonical (Tuschl-type) RNAi triggers, but not Dicer-substrates for example (means it already does not apply to Dicerna’s and Arrowhead’s Dicer-substrate RNAi triggers)

c. 10 or more pyrimidine nucleotides of the sense and/or antisense siNA strand are
chemically modified with 2’-deoxy, 2’-O-methyl or 2’-deoxy-2’fluro nucleotides,

10 or more modifications (on pyrimidines at that) is a lot, but not unprecedented.  Tekmira’s use of RNAi triggers utilizes fewer modifications since they do not rely so much on them for stabilization purposes; however, conjugate approaches such as DPCs and GalNAc-siRNAs are usually heavily modified

with one or more phosphorothiate internucleotide linkages and/or a terminal cap molecule
at the 3’-end, the 5’-end, or both of the 3’ and 5’-ends, being present in the same or
different strand.

A single, terminal phosphorothioate linkage is often employed in RNAi triggers for apparent stability reasons, although I have not actually seen a study that this is actually beneficial; self-delivering RNAi triggers often use more extensive phosphorothioates in addition to an already heavy use of modifications.  ‘Caps’ are used for stability reasons and to increase ‘guide’ over ‘passenger’ strand loading specificity. This is a nice tool, but not essential. For example a UNA (usiRNA) modification at the 5' terminus would do the same.

In sum, the upheld McSwiggen patent has just too many modifications so as to present Alnylam’s competition headaches.  Most affected will be self-delivering RNAi triggers and RNAi trigger conjugates.  In fact, Alnylam may have needed the patent the most and I’m wondering whether it also needed it to do the deal with Genzyme-Sanofi.  Remember both the Alnylam-Genzyme and Alnylam-Merck deals were basically announced on the same day.

And no, this is no evidence that Alnylam's patent estate covers 'usiRNAs' as the company went to pains to point out in the press release.

Thursday, April 10, 2014

GILD by Association

Biotech stocks have suffered massive losses with the IBB biotech index down 20% over the last 1 ½ months.  This followed a sustained bull market with a 300% increase since the US Housing Bubble bottom.  RNAi Therapeutics stocks could not duck this trend and suffered similar, if not exaggerated losses: bellwether Alnylam down almost 50% since their $700M Genzyme deal, Arrowhead Resesarch down 40% since their all-time high, and even the most undervalued of them all, Tekmira, down a solid 30% off the pricing of their secondary barely a month ago.  Should investors worry?

The causes of the pullback in the biotech market can be attributed to at least three factors: 1) a general downturn in secular growth stocks that have done quite well recently; 2) worries that interest rates are on the upswing and could divert capital flow away from stocks with little or no current earnings; and finally 3) a sense that society will stop paying for expensive drugs. 

Although the era of ‘resource-constrained’ healthcare has long arrived in Europe, the fact that US lawmakers made an example out of HCV wonderdrug Sovaldi (sofosbuvir) as a wildly overpriced drug, sent shudders through the biotech investment community.  If a $84,000 price tag for a cure of HCV is deemed too much despite the fact that it will extend life by years for the average patient and save the healthcare system much more over the long-term in terms of reduced costs related to liver-related complications…then what about say orphan drug pricing for which $300-500k per patient every year has not become that uncommon?  To wit, orphan diseases represent a fertile ground for RNAi Therapeutics as illustrated by Alnylam’s phase III candidate for TTR amyloidosis, ALN-TTR02. 

‘Resource-constraint healthcare systems’ is certainly something that I occasionally hear here at the European Liver Meeting (EASL) which celebrates the very Sovaldi and general progress made in treating HCV, yet tries to deal with the problem of how to get it patients due to cost issues in light of the millions infected and that would be treated today if cost were not an issue.

Interestingly, nobody here criticizes the drug makers for overcharging.  I don’t think this is because they are paying for our lunches, but because the medical and long-term pharmacoeconomic and quality-of-life benefits of curing HCV are so obvious.  In general, I believe the Sovaldi issue will be short-lived and accelerate a transition to a value-based reimbursement system with the benefit of curtailing some of the drug pricing mis-behavior we have seen (you all know them).  However, beyond that, I expect that we will still be willing to spend much on our health and drug costs accounting for just ~10% of overall healthcare costs, the pharmaceutical industry should be able to make the case that innovative drugs that make a solid difference in patients' lives out to be rewarded financially.  Remember this when small, innovative biotechnology companies are undercapitalized to the point of becoming financially non-viable yet patients clamoring for new treatments.  RNAi Therapeutics was in that precarious position just 2 1/2 years ago and RNAi investors deserve every cent they raked in on the stock market when the sector recovered. Every cent.

If you look at the RNAi Therapeutics pipeline addressing the roots of and seeking cures for diseases ranging from the severe and orphan like TTR amyloidosis and solid cancers, to the chronic and debilitating like HBV and alcohol dependence, it will be RNAi companies that will stand first in line to benefit from the value-based cost model of healthcare.   The continued flow of clinical trial data (watch ARC520, TKM-PLK1, ALN-TTR02, and ALN-AT3 this year) should make that obvious and allow RNAi Therapeutics to break out from the biotech crowd and bounce back.  And even if the monetary policy makers increased interest rates, I don’t think it would be much in this deflationary environment, and a 1% short-term interest rate should not divert capital flow all that much.    

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.