Saturday, May 16, 2015

Aptamer-Targeted RNAi Trigger Delivery

In honor of 25 years of aptamers, or better the SELEX process which underlies the discovery of aptamers, I thought it might be a good time to revisit aptamers for the delivery of RNAi Therapeutics.

Aptamers are nucleic acids that have been selected to preferentially recognize a target, usually a protein, via their 3-dimensional structure in analogy to how monoclonal antibodies recognize their targets.  Aptamers are showing most promise in therapeutic development for the targeting of extracellular proteins in the eye for applications like wet AMD and diabetic macular edema (see Fovista from Ophthotech). 

Its success for systemic applications has been much more modest, however, with short circulation times and unexpected adverse events in a recent phase III study (likely due to the PEG portion of the aptamer drug) largely accounting for it.

Aptamers have also been considered as cell-targeting agents for RNAi Therapeutics.  Early reports suggested efficacy in HIV and cancer models.  Skepticism around the on-target mechanism in these examples was considerable though largely due to questions around how they were supposed to escape the endosomes.

I also fell into the camp of doubters (and still have some reservations), but have adjusted my view to a more productive one after it became clear that IF you had highly productive endosomal uptake like ASGPR/GalNAc and a highly stabilized RNAi trigger, gene silencing is possible even without explicit endosomal release chemistry.

Time to try the next iteration: Aptamer-DPCs

As there may not be another ASGPR-type receptor in the body and to compensate for lower drug exposure compared to the liver, in the quest to make aptamer-delivered RNAi Therapeutics more robust, the new learnings of RNAi trigger stability are probably best applied within the context of DPC delivery technology by Arrowhead Research.

Accordingly, the perhaps 10x lower uptake in say PSMA-expressing prostate cancer cells will be compensated by adding the RNAi trigger-aptamer complex (as one or separately) to a masked endosomal release polymer.  In case that the target cell receptor is only abundant, but does not support productive endosomal uptake, another aptamer may target a second co-receptor on the same cell (akin to some bispecific antibodies, co-receptors in viral cell uptake).

Following endosomal uptake, the masking groups come off, endosomal permeability increased so that the RNAi trigger may escape into the cytoplasm.  In certain configurations, a Dicer substract-type RNAi trigger structure may simplify design and increase stability.

Tuesday, May 12, 2015

Dicerna Keeps Searching for Its Identity

Dicerna Pharmaceuticals recent move from Watertown to Cambridge is symbolic for its continued search for a place in the RNAi Therapeutics landscape.  Following some setbacks in its cancer and home-brew LNP efforts, the company now pins its hope on that it can compete head-on with Alnylam in the development of GalNAc-RNAi trigger conjugates for gene knockdown in the liver.

Oncology on hold

Like others in the field, confidence in its cancer program (DCR-MYC in phase I/II studies for solid cancers and HCC) seems to be low.  In the absence of clear-cut early development-stage cancer responses and confirmation of bona fide tumor-wide gene knockdown, cancer drug development remains a hit-and-usually-miss for the Oligonucleotide Therapeutics industry.

As a result, Dicerna seems to view their own mouse data with skepticism just as I myself have yet to see data supporting tumor penetration and bona fide knockdown in well-controlled studies.  The company has to be credited that it is now setting the bar for DCR-MYC quite high when clinical data from higher-dose cohorts is expected to emerge around year-end.  If DCR-MYC does not make the cut, Dicerna will likely cut its losses in cancer drug development and LNP research in general.

DCR-PH1 close call

Dicerna management was also surprisingly frank about their hesitations about the technical success of their most interesting current program, namely DCR-PH1 for the treatment of hyperoxaluria type I. 
After reviewing the latest non-human primate studies, it now appears that at least an 85% mRNA knockdown of the HAO-1 target gene will be required to see the key oxalate biomarkers ‘move’, and over 90% for more robust movement.  Based on rodent data, the company had thought that 75% might be sufficient.

In NHP studies of DCR-PH1, an 84% average peak knockdown was seen following a single dose of 0.3mg/kg of a Tekmira SNALP LNP formulation with 68% knockdown remaining at week 4.  0.3mg/kg seems to be the current well-tolerated upper dose of Tekmira’s LNP formulations and almost identical (protein) knockdowns were observed with 0.3mg/kg of Tekmira LNP-formulated ALN-TTR02. 

In clinical 3-weekly multi-dose studies of ALN-TTR02, this translated into sustained 80-85% target gene knockdowns.  This means that Dicerna now relies on the safety of DCR-PH1 to allow for doses of around 0.5mg/kg.  Not impossible, but probably a close call given the history of SNALP LNP and further exposes DCR-PH1 to competitive threats.

GalNAcs coming

Given the stage of their internal cancer and LNP efforts, Dicerna is now pinning its hopes on taking on Alnylam with GalNAc-RNAi trigger.  This is where Dicerna is currently investing most of its R&D efforts in.

It has now disclosed non-human primate data from those efforts, with 5 consecutive daily doses of 2.5mg/kg GalNAc-Dicer substrates resulting in ~70% knockdown of HAO-1 2-3 weeks after this loading dose.  Given the larger molecular size of the extended Dicer-substrates versus Tuschl-type siRNAs, this corresponds on a molar basis to ~1.5mg/kg of Alnylam’s GalNAc-siRNAs.  

This is somewhat less than what Alnylam presented for their PH1 program at OTS 2014 (ED80s in rodents of ~2.5mg/kg weekly) and Dicerna's GalNAcs would seem to require some further refinements to be competitive.

But in this case, they will end up with something that has little pharmacological distinction, is 3-4 years behind Alnylam, which in turn is not shy to put legal/IP pressure on its competition.

In my opinion, Dicerna management and Board need to put in quality time to find their true identity.

Disclosure: I am short DRNA as a relative valuation short for my ARWR long position. DRNA has a slightly larger market cap than ARWR, but ARWR has a distinguished, more mature DPC pipeline with ARC-520 and ARC-AAT two attractive candidates in the clinic whereas DRNA has nothing in the clinic it apparently has confidence in.  It's possible that both stocks are grossly undervalued, but relative valuation is one of my main RNAi investment methods and this is why I'm applying it here. Nothing personal.

Sunday, May 3, 2015

Arrowhead Publishes SubQ Delivery Technology to Go Beyond the Liver

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

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

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

Back to the Future

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

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

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

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

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

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

Knockdown lasting for weeks and months

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

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

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

Wednesday, April 29, 2015

HBsAg Rules at International Liver Congress

Now that the HBV world has gathered extensive clinical experience with interferons and polymerase inhibitors (NUCs) and with the resolve to finally find a cure for a serious disease afflicting hundreds of millions worldwide, the hepatitis B surface antigen (HBsAg) has become recognized as the key determinant for treatment outcome.  This is being confirmed by trial after trial investigating combining the actions of both NUCs and interferons, either one after the other or together at once.

Some of these studies were presented at the International Liver Congress last week in Vienna (ILC2015).  Emerging from them are actionable HBsAg rules which can predict fairly well whether a patient will eventually seroconvert to (or at least lose) HBsAg.  No matter the excitement around CRISPR technologies, HBsAg seroconversion remains the gold standard outcome in HBV treatment in the foreseeable future.

These rules can be divided into pre- and post-IFN treatment onset.

In the pre-IFN setting, it is those patients that have below ~500 IU/ml serum HBsAg as a result of NUC treatment that will most likely respond to interferon treatment/immune stimulation with s-antigen seroconversion (see earlier blog entry).  Since NUCs alone hardly do anything to promote s-antigen seroconversion despite its dramatic lowering of viral HBV titers, it appears to be their slow impact on HBsAg levels ( 0.1 log per year HBsAg reduction) that has the synergistic effect with interferon: with HBsAg lowering you take off the foot on the immune brake, with interferon you step on the immmune gas pedal.

As such, HBsAg knockdown by RNA(i) Therapeutics would seem to do the same for interferons as NUCs do, only in a more rapid and potent manner.  Of course, both could be used concurrently as a run-in to IFN treatment.

However, once on IFNs (post-IFN onset), it is the relative HBsAg decline that has high positive predictive value in prognosticating who will seroconvert.  Of note, the HBsAg decline comes before any adaptive immunity can be detected.  This supports that HBsAg decline in itself contributes to seroconversion rather than it being a mere correlation.  In that setting, it is a 1 log decline in HBsAg the first few weeks after IFN treatment onset that separates the winners from the losers. 

It is uncertain to me, however, whether 1 log is a precondition to s-antigen seroconversion as the non-responders do not even come close to that (maybe 0.3log).  It is therefore possible that anything that pushes HBsAg below say -0.3-0.5log could have a dramatic effect on s-antigen seroconversion rates.

An RNAi Therapeutic for HBV used simultaneously with IFNs may therefore aim at helping IFNs to get to the  0.5-1log reduction threshold, and rapidly at that.

Ergo, there are now a number of obvious strategies that one can apply regarding the use of RNAi Therapeutics in HBV with various knockdown goals, both absolute and relative.  The exact strategy would depend on how the RNA agent is combined with polymerase inhibition/NUCs or immune stimulation. 

While a number of other HBV targets were reported at the conference such as core assembly and entry inhibitors, HBsAg (and HBV mRNA knockdown in general) lowering remains the most distinguished and the mechanism predicted to be most synergistic to existing treatment approaches.  As combination treatment is strongly predicted to be the future of HBV, HBsAg lowering should become a pillar of those treatment regimes.

Disclosure: long ARWR, looking for lower entry in TKMR.

Monday, April 27, 2015

Regulus Therapeutics RG-101 Continues to Have Potential in HCV Treatment Landscape

Having attended the International Liver Congress last week in Vienna, Austria, it has become clear to me that HCV is not going away soon.  Even in the US where progress towards its ‘eradication’ may be considered most advanced with about 1/5 of the known patient population treated last year alone (~250k), it will be an uphill battle to identify, treat, and pay for the millions more infected. Worse still, it is not enough to simply cure the existing pool of HCV patients, but also stop the cycle of re-infection (largely the result of injection drug use).

Treatment cost is one challenge and the current drug rationing approach leads to the counterproductive warehousing phenomenon where current medical intervention is focused on the patients with more advanced liver disease.  This is not only the hardest-to-treat population, but also allows the liver health of the previously less sick patients to deteriorate.  This obviously makes little sense also from a pharmaco-economical perspective when getting rid of HCV early on has now been shown over and over again to dramatically reduce HCV-related cirrhosis and liver cancer.

Another problem is the fractured treatment landscape that exists for the various patient populations (split up according to fibrosis/cirrhosis stage, genotype, co-morbidities, the rapidly growing concerns around drug-drug interactions, available/accessible meds etc) making it difficult for even the learned gastroenterologist to keep up with the latest developments and putting HCV treatment practically out-of-reach for the general practicioner.  

12-24 weeks remains the standard drug treatment duration with docs worrying about shorter treatment regimens being sub-optimal.  A triple regimen by Gilead after 4 weeks of treatment merely achieved a 27% SVR12 which in the DAA world is practically synonymous with a cure.  The best shot at shortening treatment duration may therefore come from Achillion with 6 week of DAAs achieving high cure rates in 'easy' patient populations.

While interferon is on the way out, it could make an at least transient comeback for the hard-to-treat genotype 3 where, in addition to cirrhosis, cure rates with the all-oral DAAs low (60-80%).

To sum it up, the liver community has expressed multiple times at ILC2015 that a short-acting pangenotypic regimen is an important goal in the development of new medications for HCV.   And if they paid attention at the oral late-breaker on Saturday, RG-101 is poised to play a critical role in filling this unmet treatment goal due to its long duration of antiviral activity following administration, regardless of genotype.

RG-101 update: more relapses, but thesis intact

The clinical investigators of Regulus Therapeutics presented a 20 week update on the phase I study in genotype 1, 3, and 4 patients with good to moderate liver health.  28 patients received study drug RG-101, 4 placebo.

At the primary endpoint on week 8 (reported in earlyFebruary), slightly more than half (15/28) of patients treated with RG-101 were below the level of quantitation (BLOQ).  According to the company, most of them were not only BLOQ, but undetectable (by sensitive PCR) at that.  This is a remarkable feat given that the GalNAc-conjugated phosphorothioate antisense molecule had been only given once.

According to the latest update, half of those patients eventually relapsed (7-8 depending on whether you count the patient that was lost to follow-up), most of them shortly after week 8.  Although the relapsers are slightly disappointing as in the short-acting DAA world undetectable virus for 8 (or better 12, SVR12) weeks following cessation of treatment is more or less equivalent to a full-blown cure.

Of course, the prognostic rules for a long-acting agent like RG-101 with a slower onset of antiviral knockdown ought to be different.  The notion that the viral rebounds were simply due to waning drug levels in the liver (and not due to viral escape mutations!), was supported by the biomarker analysis in the healthy volunteer part of the phase I study, also presented at ILC2015, where the trough in viral knockdown (~day 28) more or less coincided with maximal total cholesterol lowering as a predicted by miR-122 biology.

Of note, there was no apparent benefit of increasing the dose from 2 to 4mg/kg which was consistent with preclinical evidence that showed a declining liver/kidney drug ratio at 4mg/kg and maximal cholesterol lowering at 2mg/kg in humans.  This indicates that ASGPR receptor binding becomes saturated when too much GalNAc antisense is given at once.  The increased drug liver concentration at higher concentrations observed in earlier preclinical studies probably indicate uptake in non-productive compartments of the liver, including Kupffer and sinusoidal endothelial cells.
The hope is that with a second dose of RG-101 28 days after the first shot, maximal viral suppression can be maintained for at least another 4 weeks to stave off any viral comeback as seen in the single-dose study.  This is supported by both the healthy volunteer part of the study and the chimeric PXB mouse experiments presented which showed that such a second dose not only maintained drug potency, but in fact led to a step-up in efficacy.  I am therefore optimistic that with 2 doses of RG-101 monotherapy alone ~50% cure rates can be achieved in patient populations similar to that in the phase I study.

This, however, is not even the goal.  The ultimate goal would be to establish a simple pan-genotypic 4-week treatment regimen.  Accordingly, the combination of RG-101 with a DAA(s) (sandwich regimen) can be expected to result in a very, very deep viral knockdown by week 4.  At this point, a second shot of RG-101 would be administered to give the immune system another 6 weeks or so to finish off the virus.  I believe a very realistic scenario, and depending on which patient populations you are looking at a very compelling alternative to current HCV medications and those in development. 

PS: Open questions

Unfortunately, given that cholesterol lowering was still close to maximal at week 8, it would have been comforting to show a mutation analysis from the clinical study to confirm that viral relapse was not explained by the virus successfully developing resistance against RG-101.  This is such an obvious question that one wonders why Regulus did not present the data (yet). 

Another question mark around the current data set is why Regulus is not disclosing the differential effect of RG-101 on good and bad cholesterol and instead is reporting total cholesterol lowering.  The study investigator said that they are still analyzing the data from the multi-dose healthy volunteer study  (months after completing dosing???) and are planning to publish those.  I am mildly optimistic that this could unexpectedly bring to the fore the cardiovascular potential of miR-122 targeting, although in this case (à mostly chronic treatments) the liver cancer concern around miR-122 inhibition may be more valid than it is for the 2-shot HCV treatment goal. 

Thursday, April 23, 2015

Absolute HBsAg Levels, Not Percent Decline May Be Goal of HBV RNAi

I just walked into an early morning session at the International Liver Congress in Vienna and may have learned the most important nugget of information regarding RNAi treatment for HBV.

During the discussion in the ‘Banishing B’ session, Dr. Joerg Petersen referred to clinical analyses to be presented this Saturday showing that patients who achieve HBsAg levels of less than 500, or even better 200 IU/ml and then are given an interferon have a much better chance of eventually losing HBsAg, i.e. being functionally cured, than those that do not.

Dr. Petersen has been involved in clinical studies combining nukes and an interferon, and data presented at last year’s American Liver meeting (AASLD) showed that 9% treated with the combination for 1 year lost HBsAg in the year following combination therapy compared to just 2.8% receiving interferon alone.

Note that currently only interferons are thought to give you a chance of functionally curing HBV by medication and that HBsAg seroconversion attributed to interferon treatment may occur in the years after cessation of interferon therapy.  It will therefore be important to see whether this increase in seroconversion with combination treatment continues to hold up in subsequent years. The nukes are ‘only’ thought to protect the liver from the ongoing damage from HBV replication and may have to be given indefinitely.

I am not sure whether the new insight comes from a fresh clinical study or are the result of a more detailed subgroup analysis of the previous study.  Regardless, it hammers home a message that can be heard again and again, even more so in Vienna this year than at the London meeting last year: it is all about HBsAg lowering.

Implications for HBV RNAi

The implications of the new analysis for RNAi approaches for the treatment of HBV is obvious: use RNAi to get HBsAg below the threshold. In other words, it may be less about getting a magical 1log knockdown, but more about getting patients below 500IU/ml. 

For this, Dr. Petersen recommended using 2 nukes so that the tiny and very slow HBsAg declines observed on nukes continue ( < 0.1 log per year). With RNAi agents, you would likely achieve this goal for a patient with an HBsAg at baseline of 1000IU/ml within a month, even with a single 2mg/kg dose of ARC520 from Arrowhead Research as reported last year. 

The absolute knockdown potency of an RNAi agent would determine which fraction of the HBV population fall within this sweet spot. With a 1log knockdown e.g. you could start RNAi with patients with as much as 5000IU/ml.

For the clinical development of RNAi agents for HBV, the first step will be to determine the HBsAg decline on a background of nukes (just what Arrowhead is doing right now).  For pivotal trials, an immunostimulatory agent such as an interferon should be added to the nukeà RNAi/nuke treatment regimen to finish off the virus.

Stay tuned to learn about the fold benefit of HBV cures in patients falling below the 500IU/ml threshold, and the 3-4mg/kg single-dose results for ARC520 from Arrowhead Research to be reported later this quarter (note to Arrowhead PR department: next Monday may be a good time to do so).

Wednesday, April 22, 2015

First RNAi Therapeutic Nearing Finish Line

ALN-TTR02 for the treatment of TTR amyloidosis is the most advanced RNAi Therapeutic in clinical development and has been carrying the torch for the field as whole. Expectations are therefore high and a stumble in this program as a result of the therapeutic hypothesis underlying the program not panning out would likely trigger a temporary*, but steep sector-wide sell-off.  

* it should be clear, however, that with the current ability to robustly knock down genes in the liver, RNAi Therapeutics will result in a number of successful treatments.

It therefore came as a relief yesterday when Alnylam presented (press release here, data slides here) 12-month data from an open-label extension phase II study of ALN-TTR02 in the polyneuropathy form of the disease (FAP) showing

a)      continued robust gene knockdowns for more than a year (88-80% reductions peak/trough in 3-week cycle);

b)      disease stabilization (if not improvement) when the Natural History of the disease would have predicted marked deterioration (predicted mNIS+7 at 12 months of +18 in Natural History vs ~-2.5 on ALN-TTR02).

Furthermore, the safety of this liposomal formulation enabled by Tekmira seemed more than sufficient for a disease as severe as FAP TTR amyloidosis (5-15 year survival following diagnosis) with the most significant adverse events being related to the intravenous route of administration meaning that ALN-TTR02 should be given under trained medical surveillance.

There are some questions that remain open, some of which should be answered by the ongoing phase III APOLLO study which should complete sometime in 2016 (with an 18 month primary endpoint).

Firstly, it will be important to show disease stabilization to be strictly related to ALN-TTR02.  In the phase II study, most patients (20 of 27) were on tetramer stabilizers which have previously shown to result in very modest (tafamidis) to moderate (diflusinal) therapeutic benefits.  While neither tafamidis nor diflusinal have shown disease stabilization after 12 months, the concern remains that they could have contributed to the apparent therapeutic benefit seen in the phase II study.

To my surprise, the 7 patients not taking tetramer stabilizers on top of ALN-TTR02 seemed to do even better, at least numerically than those taking them (-6.5+/-9.2 vs -1.1+/2.5).  Although the number was quite small, the fact that this is the opposite result from what one might have expected, it is possible that a slight placebo effect may have played a role in this open-label study: those for which ALN-TTR02 was the only medical intervention might have had a greater ALN-TTR02-driven placebo effect.

Other more complicated explanations based on TTR lowering affecting the PK/PD relationship of tetramer stabilizers are also possible if this phenomenon is for real.

Fortunately, the blinded phase III APOLLO study will compare ALN-TTR02 to patients taking no tetramer stabilizers to treat their FAP.  Finally, it would be of interest to look at the effect of ALN-TTR02 on the spleen in the APOLLO study as spleen toxicity due to lipid stability might be the most important safety parameter with chronic dosing.    

In summary, yesterday’s 12-month data removed important overhangs over the RNAi sector and we are on track for the first commercial RNAi drug in 2017. Seeing is believing.
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.