Monday, March 19, 2018

Ionis Pays to License TTR Drug

When it comes to reaping the financial benefits of its efforts, Ionis ranks at the bottom of the industry and last week provided a new low point in this ongoing saga.

Licensing drugs for commercialization purposes is normal in the biotech space, especially when a smaller company lacks the resources to do so.  In return, the licensor typically receives an upfront fee and other milestones in addition to a royalty on sales.

Ionis Pharmaceuticals has just broken with this sacred tradition.  In fact, it ended up giving $200M to Akcea Therapeutics for it to market TTR amyloidosis antisense drug candidate Inotersen for which regulatory approvals are expected this summer.  The two companies will share the profit/loss from the upcoming commercialization of Inotersen and the GalNAc-conjugated follow-on compound in early-stage development.

To put it in simple terms, Ionis is transferring billions of (stock) market value (à Alnylam’s ~$15 billions market cap largely rests on its TTR franchise) to Akcea in return for Akcea's recently established sales infrastructure for which it might have spent $50M.  As I’ve been saying all along: building commercialization capabilities does not involve magic and for orphan drugs certainly don’t require Big Pharma footprints.  All it requires is the will to just do it.

Unfortunately, Stan and his longtime followers at Ionis only feel comfortable playing in their early-stage sandbox and don't seem to really care about creating shareholder value.

No other takers?
Stating that they have just transferred billions of stock market value may also be partly wishful thinking. 

Last August, when GSK declined to license Inotersen, Ionis said that pharmaceutical companies had instantaneously started to line up to license the drug.  Then after nothing happened in the coming months, Ionis changed to wanting to keep the US to themselves and licensing rest of world.

And now this: it is ‘licensing’ the drug to its own spin-off company to which it already controlled more than 2/3 of the shares in addition to important veto powers regarding Akcea’s corporate development.

Ionis says that they were forced to give the nod to Akcea because the drugs were racing towards approval and other companies wouldn’t have been able to ready Inotersen for commercialization in time.  This, of course, doesn’t make any sense since why was Akcea more ready to do so?  Couldn’t Ionis have sent its TTR commercial team which it is transferring now to Akcea to just about any other company as well?   

Clearly, nobody was substantially interested in Inotersen and my guess is that this is not due to Alnylam’s Patisiran believed to have much better commercial prospects than Inotersen.  Instead, it is Alnylam's RNAi GalNAc compound which greatly limits the absolute value of both Patisiran and Inotersen as it looks like a vastly superior TTR knockdown drug (~quarterly subcutaneous dosing, much greater knockdown) and may be approved within the next 2 years already, much earlier than Ionis' GalNAc follow-on.  

Sunday, March 11, 2018

Dicerna Supremely Confident About Clinical Pharmacology of its GalNAc Platform

Dicerna has just entered its GalNAc-RNAi conjugates into the clinic and by the looks of it, seems extremely confident about being able to forecast its performance in humans.  

Single-dose study

At least this is what I am forced to interpret into their remarkable decision to merely conduct a single-dose phase I/II study with DCR-PHXC for primary hyperoxaluria before going straight into a planned (multi-dose) pivotal study in 2019.

There is, of course, precedent from Alnylam’s ample experience with a related GalNAc-RNAi conjugate format and how animal studies have translated into humans and how repeat-dosing in man have increased and extended the knockdown compared to single dose administrations.
Dicerna thus believes it will be able to predict the optimal dosing schedule for the all-important registrational study based on single-dose monkey-to-human translation and the effect of repeat dosing in monkeys.  

You’ll probably be scratching your head already how accurate such modeling by triangulation can be.  Complicating matters, the primary aim is not to achieve a predetermined level of target knockdown (lactate dehydrogenase A/LDHA), but in fact oxalate knockdown which is downstream from LDHA.

So a lot of moving parts between a single-dose gene knockdown and therapeutic lowering of a toxic metabolite following prolonged and pronounced multi-dose knockdown.  And don’t get me started on the impact of RNAi trigger formats, the nature of their chemical modification as well as the target gene identity on gene silencing duration…and what about the small issue called 'safety'?

Dicerna: if this rushed design is an effort to catch up with the competitive program by Alnylam to better compete for patients for the pivotal trial, it’s probably not worth it.  Either you are greatly increasing the risk of phase III failure or, more likely, you'll be sent back into earlier-stage multi-dose studies by regulators (similar to what happened to the Alport program by Regulus Therapeutics).

Dicerna talking down value of mystery program

Following DCR-PHXC, Dicerna plans to bring two additional drugs into the clinic in the near future: one against HBV and another one for an undisclosed orphan disease.

Aside from the fact that I believe that there is little point in keeping the target identity a secret since they have pretty much given it away by characterizing it as one with >100,000 patients in the US alone (à alpha-1-antitrypsin-related liver disease), it is remarkable that the CEO has said that they are looking for a ‘risk-sharing’ partner at this early stage already.

Even more surprising was the comment last week that Dicerna will even wait to partner the program before entering it into clinical development!  

This truly is unheard of for a company in the red-hot genetic biotechnology space where funding is relatively easy to come by these days for a company of a profile like Dicerna (clinically ready genetic technology, $700M market cap).  Here, the universally accepted name of the game is to get at least a couple of drug candidates into the clinic with minimal ownership dilution (e.g. by partnering) early on.  Developing an orphan candidate to clinical readiness and then idling it sends out a clear signal that the candidate is deemed to have disappointing prospects.
It would be easy for Dicerna, with the stock up 100% since the recent offering, to do another ~$100M raise to comfortably navigate three programs through proof-of-concept.

With these two unexplainable apparent unforced major errors, it got me thinking: can it be explained with the uncertainty around the trade secret litigation with Alnylam? According to the Q4 2017 conference call, a trial date has been set for April.

Thursday, March 8, 2018

Commonly Used RNAi Trigger Modification Can Integrate into Genome and Cellular Transcripts

To endow RNAi molecules with drug-like properties, they need to be modified (for stabilization, immuno-silence, RISC incorporation).  Modifications commonly used these days include 2’-O-methyl and 2’-fluoro (2’-F) modification of the ribose sugar ring and phosphorothioation of the phosphate connecting the constituent nucleotide monomers.

A study by Ionis and AstraZeneca scientists now shows (Saleh et al 2018) that 2’-F nucleosides are readily incorporated into RNA polymerase transcripts and the genome in tissue culture cells. By contrast, 2’-MOE nucleosides, a modification that Ionis chiefly uses for its antisense oligos, was highly refractory to such incorporation under the same conditions.

So regardless of the political motivation behind this publication- Ionis likes to paint the 2’-F modification used by competitor Alnylam as dangerous, whereas Alnylam likes to say same about Ionis’ phosphorothioates- the fact that turnover products from RNAi trigger degradation may be used in this way raises genotoxicity concerns that need to be taken seriously.

Even if minor degrees of 2’-F incorporations into transcripts and genomic and mitochondrial DNA turned out to be harmless, not undertaking the appropriate studies could catch companies in the space on the backfoot when regulators suddenly demand them.

It is possible that RNAi bellwether Alnylam indeed has responded to this concern as they have taken to minimizing the 2’-F content in their latest generation of GalNAc-conjugates while increasing 2’-O-methylation.  Although Alnylam justified this change with wanting to further increase the stability and thus longevity of the gene silencing, in light of twice annual administrations already possible with the old format (see inclisiran for PCSK9 lowering) and increasing 2'-O-methyl content making it harder to find intrinsically potent molecules, this move had me wondering whether it had actually to do with toxicity concerns instead.  This paper would support this notion.

Saturday, March 3, 2018

Antisense Technology Produces Huntington’s Disease Breakthrough

Huntington’s Disease (HD) is one of the most prevalent severe, ultimately fatal genetic neurological diseases of our times for which impactful treatments are desperately lacking.  Based on results from a clinical study aiming to knockdown the disease-causing gene using RNaseH antisense technology, this is about to change over the next 3 years.

IONIS-HTTRx study results presented at CHDI

At the major annual HD gathering this week, lead investigator Tabrizi from the University College London presented data from a phase I-II study of antisense drug candidate IONIS-HTTRx in patients with early symptoms of the disease.

IONIS-HTTRx (aka RG6042), developed by Ionis and partnered with Roche, targets both wild-type and mutant huntingtin protein to provide all patients with the most potent and safest sequence possible.  While mutant allele-specific approaches have been discussed and are being pursued by antisense rival Wave Life Sciences, the concern that suppressing wildtype huntingtin in adults seems to me a far-fetched theoretical discussion, if not wishful thinking given that antisense is unlikely to completely eliminate wildtype huntingtin and that the drug is being given to adults.  

To wit, the concern is based on genetic mouse models where complete huntingtin knockout causes embryonic lethality. Importantly, this is not recapitulated in mouse model where knockout is delayed until adulthood.

Call me cynical, but the choice of an allele-specific approach by Wave Life Sciences has likely been primarily motivated by allowing for some follower differentiation.  Ironically, by limiting themselves to a much reduced sequence space around co-segregating single nucleotide polymorphisms, the sequences may not only lack the potency, but also the apparent safety of IONS-HTTRx.

Good safety profile maintained until highest dose tested

In this study, IONIS-HTTRx was given monthly over 3 months.  Speaking to the safety of the approach, apart from transient side effects due to the intrathecal mode of administration, no adverse events of note were reported and all 46 subjects have subsequently rolled over into the open-label extension study.

Importantly, doses as high as 120mg monthly were well tolerated at which dose the knockdown effect seems to have plateaued.  This not only bodes well for IONIS-HTTRx, but for the entire neurological disease franchise of Ionis Pharmaceuticals. 

The human safety and tolerability results are consistent with a range of small and large animal models (including dogs, pigs, non-human primates), some of which were a year or longer in duration.

Robust huntingtin lowering

It is widely thought that mutant huntingtin protein is harmful to the cell expressing it, ultimately resulting in neuronal death throughout the brain.  This can be visualized by considerable, 30%-level atrophy of the brain over the course of the disease.

Although it is not possible to assess huntingtin levels directly in brain tissue in humans from biopsies, the experience in the preclinical animal models and human data from spinal muscular atrophy drug SPINRAZA allows one to model the correlation between ASO-dependent protein changes in the cerebrospinal fluid (CSF) and the various areas of the CNS quite well.

Since SPINRAZA is based on chemistry that is highly similar to that of IONIS-HTTRx, they behave identically in terms of biodistribution for all intents and purposes.

In the two highest cohorts, 90mg and 120mg, mean 40% mutant huntingtin reductions in the CSF were observed shortly after the last dose with further reductions (50%+) seen thereafter.  Such levels are predicted to reflect 55 to up to 85% reductions in the cortex and 20-50% in the caudate.

This degree of knockdown exceeds that necessary to see changes in HD animal models, some of which with manifest disease symptoms at treatment onset.

The future is bright

The study results therefore raise hopes that  IONIS-HTTRx may halt or even reverse disease in manifest HD patients.  As exciting and medically likely with the biggest bang for the buck is the prospect that the drug candidate may prevent disease symptoms to emerge in the first place when given early to those at risk of developing the disease (~1 in 2 with a parent having HD, 200,000 in the US alone). 

The companies and clinical investigators are now busy designing a pivotal outcomes study which I would guess will ultimately involve 150-250 early-stage patients over a period of 16-24 months.  The size and extent of the trial will depend on which endpoints are chosen.  A pre-planned interim look at ~12 months may also make sense to look at brain size as a potential way to obtain accelerated approval.  Accelerated approval under the new FDA may also be possible based on functional analyses the investigators are currently conducting using data from the present study and the open-label extension with dosing well beyond 3 months..

In drug development, sometimes you can tell early on whether a drug candidate is destined to breeze through to approval. In this regard, IONIS-HTTRx certainly feels like Spinraza.

Friday, February 23, 2018

Recognizing and Addressing Critical RNAi Off-targeting Issue

In late 2016, Alnylam discontinued its alpha-1-antitrypsin program due to observed increases in liver transaminases. A year later, its HBV program was also terminated with the goal of advancing a new compound with increased targeting specificity.  

Apparently, close to half of RNAi triggers largely picked based on potency cause hepatotoxicity in rodent studies.  It's been clearer than ever that Alnylam, if not the industry as a whole needed to pay more attention to minimizing off-targeting and not just focus on potency in candidate selection.

Formal presentation of their findings of the causes underlying the toxicity  have now been published in a paper titled ‘Selection of GalNAc-conjugated siRNAs withlimited off-target-driven rat hepatotoxicity’.  

In an elegant series of experiments, the authors first sought to disprove that other steps in the delivery pathway that were possible candidates for the observed toxicity were responsible.  They then went on to show that it was indeed microRNA-type off-targeting that were at the root.  

Endolysosomal Constipation

GalNAc-conjugated RNAi triggers need to be highly stabilized to be active.  As a result, they reach high, antisense-type tissue accumulation, largely through sequestration in the endolysosomal compartment.  This has led to the concern that toxicities may arise from interfering with endolysosomal functions in the liver.

Strongly arguing against this possibility, when a toxic GalNAc-conjugated RNAi trigger with standard 2’-O-methyl and 2’-F-chemistry and partial phosphorothioation was rendered incapable of being taken up by the RISC RNAi effector complex, liver toxicity was abrogated without much change in the tissue accumulations of the respective oligos in rodents. 

Still, it will be important to further follow this risk in humans, especially when there is long-term, chronic exposure given that the present studies lasted for ‘only’ 5-9 weeks.  Also, patients with pre-existing morbidity in the liver may be particularly susceptible to adversely reacting to the accumulation of RNAi triggers in the endolysosomal compartment. 

Modification Chemistry

One concern with the high degree of chemical modification of the RNAi triggers which are employed to stabilize them in the absence of nanoparticle delivery formulations is that the modification chemistry could be toxic.  Rival Ionis Pharmaceuticals e.g. had previously claimed that 2’-F-modified antisense and RNAi constructs are genotoxic- at least in cell culture system.  Alnylam, however, had already disputed this claim and now argues that this is only the case with single-stranded, phosphorothioated formats Ionis is using.

The fact that preventing RISC uptake abrogated toxicity already exonerated chemistry and degradation intermediates as culprits since such abrogation in itself does not change overall RNAi trigger metabolism (note that RISC-incorporated RNAi trigger represents only a very minor fraction of overall tissue RNAi triggers).

To further rule out this possibility, the Alnylam scientists varied the degree of relative 2’-O-methylation and 2-F-modification to see whether this impacted toxicity in the rodent models.  There was no correlation between the type of modification and toxicity.

So at least for acute treatments, 2'-F modification does not appear to be a relevant tox issue for RNAi Therapeutics.  Based on the recent demonstration that 2'-F metabolites can be incorporated into endogenous RNA and DNA, there still remains a need to be vigilant about this modification regarding its potential to be genotoxic, i.e. promote cancer.

Competition with endogenous microRNAs

Years ago when I joined as a post-doc in the Kay lab in Stanford, colleagues of mine had found that high levels of RNAi trigger small hairpin precursors expressed from DNA templates could trigger severe toxicity in mice and that this could be traced back to these precursors interfering with normal microRNA function. Subsequently, studies to investigate the same were performed using synthetic RNAi triggers and modest competition with endogenous microRNA function was sometimes seen.

In contrast to the elegant investigations above, Janas and colleagues from Alnylam offered only circumstantial evidence to rule out competition.  In particular, they found no correlation between the degree of RISC occupation of the exogenous RNAi trigger and toxicity. 

It would have been interesting to study e.g. whether delivery of the RNAi triggers resulted in the de-repression of known targets of endogenous microRNAs to get insights into whether further investigation of this issue had merit.

MicroRNA-type Off-targeting

By contrast, the authors found strong evidence that it is microRNA-type off-targeting that is the culprit for the toxicity of many RNAi triggers in vivo.

To wit, in addition to directing the cleavage of mRNAs with near complete sequence complementarity (~20 base pairs), RNAi triggers may also participate in microRNA-type mRNA interactions based on limited sequence complementarity (mainly ~7 nucleotide seed) with more subdued silencing impact and without the canonical RNAi cleavage.   

Importantly, a reversir molecule with the function to soak up RNAi trigger-loaded RISC and consequently interfere with its silencing activity, reversed the toxicity.  Parenthetically, if competition with microRNAs were the problem, this ‘freezing’ of the RISC complexes would not have been expected to relieve the toxicity since it would not have freed RISC for loading the endogenous microRNAs.  

Supporting evidence came from seed swapping experiments where it was the seed from the toxic RNAi trigger that dictated toxicity. 

Practical solution

Since microRNA-type off-targeting does not translate well- if at all- between species (it doesn’t take much to change a microRNA target into a microRNA-refractory sequence), simply screening RNAi triggers in rats to weed out the toxic ones does not help much.

Fortunately, following a decade of studying microRNA off-targeting in RNAi, one chemical strategy in particular has risen to the top to minimize microRNA-type off-targeting.  Based on the hypothesis that the limited sequence interaction in microRNA target recognition renders it more susceptible to weakening the binding energy compared to a fully, or almost fully complementary RNAi target, incorporating energetically less favorable nucleotide residues were found to greatly minimize microRNA-type interactions while leaving RNAi on-target recognition intact.  

I  consider studies by Jackson et al. (2006) and Vaish et al (2011) to have been seminal, and long underappreciated, if not downplayed by RNAi industry leaders in this regard.

Similar to such prior efforts, Alnylam incorporated an ‘empty’ placeholder residue (glycol nucleic acid, GNA) which cannot base pair.  This indeed greatly reduced off-targeting as assessed by transcriptomics and, importantly, abrogated liver toxicity.  

In the end, the risk of clinical failure due to microRNA-type off-targeting can never be fully excluded before studying the RNAi trigger in humans.  Still, reducing clinical attrition due to this from 30-40% to more like on the order of 5% is well worth the effort.

Clinical studies with the new candidate for AAT by Alnylam will be the first direct test of this hypothesis.

Tuesday, February 20, 2018

Wave Rides Coattails of Ionis, Strikes CNS Deal with Takeda

Today, Wave announced the licensing of their (stereopure) antisense technology to Japanese Big Pharma Takeda for their application in the central nervous system (CNS).  In return for $110M in upfront cash, a $60M equity investment and other biobuck goodies, Takeda receives an option to co-develop/commercialize ASO candidates for the treatment of Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and type III Spinocerebellar Ataxia (SCA3).  Takeda also receives opt-in right to additional preclinical programs.

This deal has clearly been driven by the outstanding data gathered by rival Ionis and its corporate partner Biogen in applying phosphorothioate antisense chemistry for diseases of the CNS.  This not only includes the remarkable efficacy and commercial success seen with splice-skipping oligo Spinraza for spinal muscular atrophy (SMA), but also preclinical knockdown and biodistribution data from many other CNS programs. 

Also of note, Ionis and Roche disclosed last December statistically significant knockdown of huntingtin in people with HD, the same indication as Wave’s lead neurology program which has entered clinical development.  Important additional color for the Ionis HD candidate, especially relating to the actual depth of target knockdown is to be presented  at the upcoming CHDI conference at the end of this month.

To wit, the efficacy of exon skipper Spinraza relied on gain-of-function where minor (say 20%) target engagement may already translate into significant clinical benefit.  Most other programs, however, aim at inhibiting a disease-causing molecule from being made.  Here, you may want more like something of the order of 50%+ target engagement. 

Another wrinkle is that the target cells in the CNS will differ from indication to indication whilst antisense efficacy is not homogeneous throughout the CNS, so the SMA and HD program data will not have de-risked all the indications.   

Nevertheless, it is crystal clear that phoshorothioate oligos hold tremendous value for the many diseases of the CNS of high unmet medical need for which the industry is more and more relying on gene-targeted approaches after years of failures with small molecules.  And kudos to Wave for retaining substantial commercial value to the licensed programs.  

So thank you, Ionis, for making it exceptionally easy for them!

Tuesday, February 6, 2018

Happy Gene Therapy Talk Presaged Market Correction

In January, many biotech stocks went parabolic shattering all-time-highs.  Now they have started crashing back down to earth.

The run-up was partly driven by real fundamentals.  These include corporate tax reform in the US, a new FDA commissioner (Scott Gottlieb) who makes all the right decisions (speeding access to innovative medicines, fostering generic competition, amenable to rational discussion etc), and a voracious appetite for innovative pipelines in the pharmaceutical industry which has manifested itself in a number of chunky, multibillion dollar acquisitions. 

At the same time, ever-increasing valuations in a deceptively low-volatility stock market environment has emboldened analysts, investors, and managements alike to proclaim that the golden era of curative medicines is upon us.  Gene therapy and genome editing in particular got hyped beyond reason as if all of a sudden critical bottlenecks in tech development had been solved.  CRISPR companies Editas Medicines and CRISPR Therapeutics, without a single drug candidate in the clinic, were bid up to $2B valuations although access to genome editing tools have become a commodity and cannot be considered gate-keeping tech any more.

Not much changed technology-wise

I understand that gene therapies have made tremendous inroads into the pharmaceutical marketplace with the first 3 gene therapy approvals in the US over the last year, one for an eye disease by Spark Therapeutics and two CAR-T cell cancer therapies going after the same target.

While I acknowledge these successes, what is really surprising here is that it took that long to get there given that the related delivery and genetic technologies (AAV, gene insertion, immune cell transfer) have been in existence for a decade or two already.  In that light, the recent Happy Talk around gene therapy seemed overdone.

The CEO of one genome editing company, Sangamo Therapeutics, is a great example of this divergence between scientific progress and clinical reality.  

Having come on board only a year ago, the good Dr. Macrae looks as if he is having a steep learning curve ahead of himself.  The reason I got the impression is that he likes to grandiosely talk about how the company's AAV capsid shuffling will enable them to cure all these CNS disorders while making great progress with LNPs to address the rest of humanity's afflictions.

Well, LNPs have gotten 10x more potent every year for the last 15 years so we must have reached homeopathic doses by now; and looking at the literature, AAV shuffling hasn't changed all that much since I completed my post-doc in an AAV lab in Stanford.  Or maybe Jim Wilson has grown exceedingly gun-shy when he resigns from his well-paying function at AAV company Solid Biosciences over concerns of toxicity from high systemic AAV doses and possibly also his finding that delivery to a certain tissue in the mouse does not predict same delivery in humans.

Certainly, there are also tailwinds supporting gene therapy that had not been around a decade ago.  As alluded to above, society and regulators have finally warmed up to a very sensible approach to medicines in the genomic era.  Moreover, there are established paths now to effectively develop such therapies and the challenge of producing large quantities of viral vectors is gradually being addressed.

Still, amid the hype and stock market giddiness, valuations in many of these companies have run ahead of themselves and were ripe for a pull-back.

Next time you hear so much Happy Talk around a biotech subsector leader as has been the case for gene therapy, watch out for a correction.   

What about RNAi stocks?

RNAi stocks have also benefited from the overall bullishness in the biotech sector with ARWR and DRNA having run up by 300% or so in a matter of months.  While I still hold shares in these companies, I have written calls (largely in-the-money) on essentially all of them meaning that I am fairly insulated should they fall another 10% or so.   

Since I still like ARWR and DRNA ahead of their first clinical GalNAc knockdown data, and in the case of Dicerna the potential removal of the overhang from the Alnylam litigation, I am eyeing (and have been) selling out-of-the money puts on these for 10+% premiums or so.

If the market turns back up, you pocket the premium. 10% or so in a matter of 2 months is not bad in my mind.  If, however, the stocks decline and the puts are in-the-money at expiration, you get handed a stock that you like anyway.  Say Arrowhead for a price of $4.5 instead of $5.45 yesterday.  

But before you place any such options bets, consult with your investment advisor first to familiarize you with the risks of writing options!

On the simple, naked long side, I like Ionis Pharmaceuticals which, as a biotech stock that has essentially missed out on the post-Trump rally and with the upcoming Huntington’s data catalyst, has the potential to become a new biotech bellwether following subsector rotations that usually occur following corrections (remember the 2015 correction following which oligonucleotide stocks turned from sector leaders to laggards?).  Alnylam, meanwhile, looks tired here with a lot of the upside priced in, at least regarding the TTR story.

Happy trading and be mindful.
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.