Thursday, March 19, 2020

Proposing Complement C3 RNAi for Treating COVID19


Whereas my last blog considered lung-targeted RNAi for addressing COVID19, this entry will look at what a liver-directed RNAi approach could do for the disease.  It is in the liver that RNAi Therapeutics have proven to be extremely potent.  Moreover, it is amenable to subcutaneous administration and therefore appropriate for the current pandemic.

It has quickly become apparent that in a subgroup of patients COVID19 is associated with liver complications.  Managing these with gene silencing of resident liver proteins may be possible in theory and could be contemplated.  More interesting, however, would be intervening upstream of the liver in the respiratory tract.  

It is reported that it is an overactive (innate) immune system rather than cellular damage (cytopathic) by the virus itself that can cause the virus to be fatal.

And when it comes to an immune approach with RNAi at the moment, the complement pathway, many components of which are predominantly expressed by the liver and secreted into circulation comes to mind.

Interestingly, a relatively recent paper (Gralinski et al, 2018) in a mouse model of SARS-CoV-2-related SARS has shown that genetic complement C3 knockout lessened lung damage and overall health as measured by body weight.  This was associated with a reduced influx of neutrophils which are the carpet-bombers of the immune system.



The next question to be asked is that since RNAi gene silencing is not instantaneous but takes time to manifest, whether such intervention would be timely enough in a given patient.  For this, my assessment is that it should be possible based on the pharmacodynamics of a C3 RNAi in development by Silence Therapeutics (SLN500) and Mallinckrodt IF the disease can be diagnosed in time.



Accordingly, it took about 4 days for robust C3 silencing in mice which compares to the about 7-10 days it takes for SARS-CoV-2 to move from the upper respiratory tract (as manifested e.g. by throat pain) to the lower lungs where the critical battleground is.

These are extraordinary times and I believe this approach should be considered.  Besides Silence Therapeutics and Mallinckrodt, Alnylam, and Dicerna (in partnership with Alexion) are also working on RNAi for the complement system.  A monoclonal antibody approach may also be envisioned and could have advantage of a faster onset of action, but may lag in development timelines.

Sunday, March 15, 2020

RNAi Therapeutics and mRNA Vaccines for COVID19


This is a time where the biotech industry has to mobilize resources to mitigate the impact of pandemic SARS-CoV-2. 

Nucleic acid-based therapeutics are prime candidates in this battle because of the speed with which drug candidates can be designed and their specificity.  This blog provides an overview of efforts in this area with an emphasis on my two favorite (and IMO most promising) nucleic acid approaches: RNAi Therapeutics and mRNA vaccines.

RNAi Therapeutics

RNAi Therapeutics (and by extension the competing antisense, ASO approach), knocking down genes for therapy, can be used in two ways to address the current pandemic.

First, the RNAi triggers could target the virus itself in an existing infection.  The hope would be that by doing so the damage, mainly lung inflammation leading to respiratory distress, can be mitigated sufficiently for the patient’s immune system to gain time and strength to successfully overcome the infection.  The question then would be how early would be early enough.

The second approach would be to target a host factor critical for viral replication.  The cellular entry receptor ACE2 is the most promising candidate target gene here.  This strategy seems particularly promising for prophylactically protecting those at high-risk of an infection, e.g. medical personnel, as protection may last for a month or so based on the very long durations of efficacy seen in human studies targeting genes in the liver and early studies in the lungs of sheep.

Application in a prophylactic setting would probably have the added delivery advantage in that the lung would be less congested and thus more accessible.  Also, delivery may not have to reach so deep into the lung as it would need to during later stages.   

Delivery

Theory is one thing, but getting the RNAi triggers to where they are needed in the body is and has always been the main challenge for RNAi Therapeutics.  Unlike targeting genes in the liver which is now well-established, RNAi in the lung is a re-emerging area of RNAi development.

Given that COVID19 is a respiratory illness where the virus intrudes the body via the respiratory epithelium, a local, inhaled delivery approach should be adequate and also happens to be the most promising route for RNAi Therapeutics in addressing pulmonary disease.

In the early days of RNAi Therapeutics development, the world was facing the SARS outbreak. Seemingly attesting to the promise of speed and specificity against emerging pathogens, Sirnaomics (based in both the US and China) soon published a high-profile paper on the efficacy of RNAi in a monkey model of SARS coronavirus.  

In hindsight and with the benefit of 15 more years of RNAi Therapeutics development up-and-downs, however, these results were probably based on innate immunostimulatory artefacts given the use of unmodified Tuschl-type RNAi triggers and a nasal instillation route of administration making employing sugar water as a carrier.

Today, however, RNAi Therapeutics is much more advanced and an approach that utilizes aerosolized highly modified and thus stabilized RNAi triggers seems most appropriate. 

Arrowhead Pharmaceuticals has emerged as the front-runner in lung RNAi and is close to filing for clinical study approval for addressing cystic fibrosis.  Their approach combines the two most promising elements of today’s RNAi Therapeutics.  In addition to RNAi trigger stabilization, Arrowhead is adding targeting ligands to their agents, in this case small moieties targeting integrin on lung epithelial cells.

While Arrowhead has not announced their entry into the COVID19 race, Sirnaomics and Alnylam Pharmaceuticals (along with partnered Vir Biotechnology) have.  While it is unclear what particular approach Sirnaomics is using 15 years after their SARS work, Alnylam will be using highly modified RNAi triggers.  Whether targeting ligands will be utilized or not is unknown to me (update: the press release refers to 'conjugates of siRNA' so a targeting ligand is likely). 

Of note, Alnylam had suffered an anti-viral innate immunostimulatory fiasco with their first commercial RNAi development program around the same time that Sirnamoics was working on SARS.  That program was for the respiratory syncytial virus (RSV) and Alnylam should be able to capitalize on the the lung RNAi development experience back then.

Other RNAi-related companies with experience in inhaled lung delivery are miRNA Therapeutics company Miragen (miRNAs are structurally quite similar to RNAi triggers), Genevant/Arbutus (descendants of Tekmira which became famous for their Ebola efforts), and Arcturus Therapeutics.

mRNA vaccines

Arcturus Therapeutics and Genevant are now focused on developing messenger RNA (mRNA) therapeutics and vaccines, including for lung disease cystic fibrosis.  The most known name in this area is Moderna Therapeutics which has a high-profile, government-sponsored vaccine effort against SARS-CoV-2.  Ultimately, it is vaccines that will allow the world to fully recover from the COVID19 scare while therapeutics should be used in a much more focused manner.

The delivery challenge for vaccines is also lessened by the fact that it is a gain-of-function approach and that the immune system itself is expert at spotting foreign, in this case viral antigen expression.  The challenge here is that this is has to be achieved in the right immunological context so that a fruitful immune response is formed.  

The fact that Moderna were the first to ship mRNA for imminent trials shows how easy it is for mRNA to go from viral sequence to product candidate and drug material production.  While I used to poke fun at Moderna for building factories and installing robots without having much science behind it to fill the production halls, for emerging biothreats like SARS-CoV-2 this has proven to be prescient.

CureVac, an mRNA competitor of Moderna, has also announced their entree into COVID19.  While they may lag behind Moderna in terms of robotics and manufacturing capacity, they should be more expert in vaccine development (‘a little innate immune stimulation by the mRNA agent itself may go a long way’).

The most intriguing and differentiated entrant in the mRNA vaccine area to me, however, is Arcturus Therapeutics (disclosure: no stock position, but considering taking one) to me.  This is because they are using a self-replicating RNA ('STARR') that they claim to require ~40-fold less RNA to be intramuscularly injected. Formulation into an LNP 'LUNAR' particle may further lower the required dose.  Given that vaccinating the world will in the end also be a manufacturing challenge, being able to start with 40-times or thereabouts less material is a serious practical advantage.

COVID19 shall pass and therapeutics and vaccines will play an important role here.  Even more important, however, is that everybody does their part in minimizing and slowing the spread of the virus ('flatten the curve', #SocialDistancing), particularly to protect those most at risk without having to resort to draconian measures.

Thursday, November 28, 2019

One Pitfall to Look Out for in RNAi Therapeutics


RNAi Therapeutics have turned the corner to being a generally accepted drug modality.  Following years of ridicule and benign neglect, the industry just celebrated the FDA approval of a 2nd drug, Givlaari for the treatment of acute hepatic porphyria. This was followed in short order by the $9.7B acquisition of The Medicines Company by Novartis for its cholesterol-lowering RNAi drug candidate, Inclisiran, a harbinger for how RNAi medicines will change the game in cardiovascular risk management.

Amid all the understandable investor excitement, it is probably a good time to reflect on the potential pitfalls as we move into a world where RNAi Therapeutics dominate liver-related diseases and advance into new big areas such as the CNS and ocular disease.  Remember, investor, it takes one safety event for the most highly valued programs like HBV RNAi candidate AB-729 by Arbutus Biopharma, Arrowhead Pharmaceutical’s ARO-AAT, or the Lpa program by Silence Therapeutics to decimate your investment by half or more.

Off-targeting safety, off-targeting safety, off-targeting safety

When the discovery of RNAi was rewarded with the Nobel Prize in 2006, the Andy Fire and Craig Mello hammered home a message that would resonate for the years to come: to make RNAi Therapeutics, it’s all about the delivery!

Delivery, delivery, delivery

But as the liver has been conquered and the industry is chewing on a number of liver-related therapeutic opportunities and opening up opportunities in new areas, we still have to fully understand the odds of seeing program failures due to the difficult to predict consequences of off-targeting.

Off-targeting is the moderate knockdown of sometimes dozens of genes sharing sequence homology to the target gene.  This was shown over a decade ago and soon thereafter shown to be addressed by using simple modification strategies.

This, however, was at a time when the delivery mantra was practiced and nobody wanted to risk reducing knockdown efficacy by simultaneously considering off-targeting in their RNAi trigger designs.  I was therefore upset, as it turned out rightfully so, that Alnylam let Nastech essentially go bankrupt a decade ago when it should have acquired rights to Nastech's then industry-leading off-target-mitigation technology.


Alpha-1 Antitrypsin as testbed

Alnylam would have to pay dearly for its pride in never treating a smaller competitor well, even if it served its own interest, with off-targeting manifesting itself in markers of liver toxicity in first-generation clinical programs like chronic HBV and alpha-1 antitrypsin-related liver disease.

These two indications, unlike the now approved AHP indication for Givlaari which addresses symptoms outside of the liver, represent the most exacting off-targeting challenge as they affect liver health directly and any further exacerbation of liver stress should be avoided.  

As a result, Alnylam dug out the old off-targeting literature and in their incarnation added a GNA modification at position 7 of the guide strand while, for experimental purposes, leaving the rest of the first-generation molecule unchanged. Translational science at its best (!) and the industry can be thankful for it.

Indeed, for both the ESC+ chemistry ALN-AAT02 and ALN-HBV02 no liver enzyme elevations (above 3x ULN) were observed in 49 subjects tested, whereas 3 of 33 had such elevations with the ESC-only versions.

In Arrowhead’s case, there also were no ALT elevations >3x ULN.  However, 3 treatment-emergent grade 1 ALT elevations not exceeding 2x ULN were reported in the 28 normal healthy volunteers receiving ARO-AAT.  I am curious to see the individual time curves and the doses at which they occurred.  It is certainly an area to watch for that program as it only now moves into patients. 
Add to this considerable uncertainty about patient selection, dose and duration required to have an impact on AAT liver disease, increasingly analysts topping their price targets by the day may have to re-think how they value this program (see disclosure below).

Further behind, we have to see how Silence Therapeutics and Arbutus have addressed off-targeting with first data expected in 2020.  While Silence has avoided indications directly affecting liver health (iron overload, cardiovascular disease), Arbutus with its HBV indication will have a steeper hill to climb, although the pay-off for investors in this $80 market cap company should be considerable should it climb it come Q1 2020.


Personally, my guesstimate for non-optimized GalNAc designs would be a 50% chance of off-targeting success, also depending on preclinical vetting (after all, the very clean $9.7B Inclisiran is such a design); a 85% off-targeting success for optimized designs. 

Disclosures: long Silence Therapeutics, Arbutus Biopharma; short Arrowhead Pharmaceuticals; no position in Alnylam.

Monday, October 7, 2019

Open Letter to Arbutus Biopharma Board and Management

HBV RNAi or Nothing

It is now 4 years that Wunderkind Vivek Ramaswamy handed you a bag of worthless small molecules for half of what was then one of the premier nucleic acid therapeutics companies with a strategically valuable position in RNAi Therapeutics and bright prospects in mRNA Therapeutics and genome editing.

To this day, I wonder what he put into your drinks that you would agree to such a deal.


Today, your actions have destroyed almost all of that value as close to a dozen clinical candidates, one after the other, have failed in development revealing shocking deficiencies in evaluating preclinical safety.  Meanwhile, shareholders have lost almost everything as the share price has been decimated from around $15 to less than a dollar as I type.

But instead of dwelling on the past, I want to look to the future and make it very clear to you that with your in-house capsid inhibitor having been abandoned last week, you have no choice, but to now try and extract as much value as possible from your HBV RNAi candidate ABUS-729 with the goal of selling the company. $5 per share (~$400M) for a compound backed by phase I clinical data showing it to be safe, potent, and fairly long-lasting in knocking down its targets would seem reasonable given the interest in the space for RNAi assets and achievable before 2021.

Waiting for in-house candidates to mature enough to combine them with 729 would leave you too far behind the competition and cause you to waste your other main current asset: the $100M in cash balance (don't even think of in-licensing yet another poorly validated small molecule!).  $100M meanwhile would allow you to comfortably develop 729 to clinical validation.  This, of course, also means that you need to cut your functions to what is strictly necessary to achieve that goal, including eliminating all of pre-clinical research.

Further cash could be raised by monetizing your stake in Genevant.

The time to act decisively is now. 

Tuesday, October 30, 2018

RNAi is the Future of Cardiovascular Disease


At least, this is what Big Pharma and Biotech is saying right now following deals between pure-play RNAi companies Arrowhead Pharmaceuticals and Dicerna with Amgen and Eli Lilly, respectively, and the sale of The Medicines Company with its lead PCSK9 RNAi asset really being only a matter of timing.  Besides its new relationship with Eli Lilly announced yesterday, Dicerna has an ongoin CVD-related NASH/NAFLD collaboration with Boehringer-Ingelheim.  In addition, Wave Life Sciences and Akcea, the commercial Ionis spin-out, have been pursuing cardiovascular targets along with Pfizer and Novartis, respectively, using the competitive RNaseH antisense gene knockdown technology.

Drugging the undruggable

Part of the attraction of RNAi for CVD for the pharmaceutical industry is because the targets that come from large genetic studies (e.g. ApoCIII, Apo(a), ANGPTL3) based on chance alone are not readily druggable.  To make matters worse, amorphous lipid macromolecular aggregates are particularly difficult to target with either small molecules or antibodies.

Infrequent dosing

What a difference 10 years can make.  When Protiva (now Arbutus) was one of the first to enter a systemically administered RNAi therapeutic against LDLc-related ApoB into the clinic a decade ago, it often found itself ridiculed for using RNAi in such an indication.  Systemic RNAi back then required relatively frequent (1-3 weeks) intravenous administration which would make it an unlikely modality for widespread diseases that ideally require decade-long preventive treatment strategies.

Fast-forward to the present and now we have subcutaneously delivered RNAi with potential dosing frequencies of up to once-a-year as evidenced by the lead candidate of this crop, phase III asset Inclisiran by The Medicines Company.  If the remarkable safety profile holds up following about 2000 patient years of clinical experience, such a drug should be very widely prescribed, not least because it should enjoy great adherence, one of the major impediments of treatment success in cardiovascular disease.   

Undoubtedly, it has been the Inclisiran performance so far that has attracted the attention of players like Eli Lilly and Amgen, the latter of which, of course, should know particularly well about the competitive threat from RNAi having an antibody-based PCSK9 agent on the market (Repatha).  Beyond the upcoming slew of phase III read-outs with Inclisiran, it will equally be interesting to see the types of new targets being pursued and the clinical validation of targets like Apo(a) by the antisense competition.

Friday, October 12, 2018

AASLD Abstract Continues to Support Promise of ARO-HBV, but with a Twist


Yesterday, Arrowhead revealed the abstract for data on its new HBV RNAi drug candidate to be presented at the big annual Liver Meeting in November (AASLD).  The data continue to support highly potent knockdown of not only the surface antigen (HBsAg), but also other HBV components.

Dose response issues

When Arrowhead announced initial first-in-patient knockdown data from its 3rd generation HBV RNAi candidate ARO-HBV, I found it suspicious for them to only reveal data for the 100mg and 200mg cohorts although more data was available at the time.  Curiously, the new data seem to suggest that there was no apparent benefit from going higher than 100mg in dose, at least when dosed with the current monthly frequency. 

Whether there is significantly worsening safety with increasing dose remains to be seen.

HBeAg positive/negative dichotomy

Similarly (but not as earth-shattering for sure) to the history of a prior HBV RNAi candidate by the company before, ARC-520, however, Arrowhead was able to learn more about its drug candidate as they went along in the study.  In particular, the first dose escalation cohorts (100, 200, 300, and 400mg monthly x3) encompassed a mix of HBeAg positive and negative patients, with 13 out of 16 being HBeAg negative.    

When Arrowhead then decided the last 2 cohorts to be just HBeAg positive, a remarkable increase in drug response was observed: whereas it took the predominantly HBeAg-negative patients 70-90 days to achieve 1.5log reductions in HBsAg, it looks like the pure HBeAg-positive patients only take 30-40 days to achieve the same.

Ergo, the reason why no clean dose response had been seen in the first cohorts is best explained by the fact that they were mixed and at that small cohorts.

Trigger choice likely explanation

ARO-HBV comprises 2 RNAi triggers: one that targets all (intact) HBV mRNA (X trigger) and one that makes sure the surface antigen is hit (S trigger) even in those patients with integrated HBV.  These typically lose the corresponding DNA element targeted by the X trigger during integration.

In the early days of RNAi, there was some controversy about the usefulness of using 2 or more triggers against the same target in terms of knockdown potency and specificity.  When I first started to practice RNAi in the lab in 2003, it was my experience that when you combined a very potent trigger with a less potent one, the knockdown was less than with the highly potent one alone.  As a result, I am a firm believer in the concept of RNAi trigger competition.

In the case of ARO-HBV it means that in HBeAg negative patients that have lost the X-trigger DNA, there will be one sterile/inactive trigger somewhat blunting the potency of the active one.

HBV biology is certainly complex and downstream events could also account for final knockdown differences.  Accordingly, in the HBeAg-only cohorts  it appears from the early observations that the nuc-experienced patients that in previous studies corresponded to patients that had lost the X-trigger-targeted elements by study enrollment not only responded as well, but in fact slightly better than the nuc-na├»ve patients.  It will therefore be important to learn more about their HBV integration status at AASLD to confirm or disprove the competition theory.

Wednesday, October 10, 2018

Review of Recent RNAi-Related Developments


The last 2 weeks have been busy ones in the lands of RNAi Therapeutics.  Here, I would therefore like to offer my take on the most important developments.

Alnylam’s Primary Hyperoxaluria Drug Breezes Through Clinic

With 20 subjects on Lumasiran, a GalNAc-RNAi targeting glycolate oxidase, for a median of 7 months, the investigational treatment for type I primary hyperoxaluria (PH1) ismore and more looking like a solid drug.  If the data presented last week at a Paediatric meeting in Turkey hold up in another 30 patients, it should fly through approval onto the market by the end of 2019.

While the relatively small numbers in each cohort has caused a bit statistical noise, it seemed like 3mg/kg monthly gives you an advantage over 1mg/kg monthly or 3mg/kg monthly in terms of the key biomarker urinary oxalate.  Interestingly, the company has chosen 3 times 3mg/kg monthly as the loading dose regimen in the now ongoing pivotal ILLUMINATE-A trial to be followed by dosing every 3 months. , the initiation of which the company has just announced.    

The core double-blind portion of the trial runs for only 6 months, so I am a bit puzzled how much the trial can inform on the value of the loading dose regimen and whether quarterly maintenance doses are sufficiently effective.   In any case, the trial design apparently was blessed by the FDA (incl. the urinary oxalate lowering primary endpoint), so surely they will know (e.g. based on preclinical animal data).

Regarding the competition with the primary hyperoxaluria drug candidate from Dicerna, the approximately 2/3 lowering of urinary oxalate and essentially all patients getting into a range considered safe and an unremarkable safety profile sets a high hurdle for the upcoming data presentation of DCR-PHXC at ASN later this month.

Arbutus HBV-RNAi Drug About to Die   

Yesterday, Arbutus provided an update on its LNP-enabled RNAi drug candidate for the treatment of chronic HBV (ARB-1467) and it does not bode well.  Similar to most other drug candidates attempted and barely tried, ARB-1467 should be canned in the not-too-distant future. 

In a combination study testing ARB-1467 in chronic HBV patients on nucleoside reverse transcriptase inhibitor tenofovir, probably only 1 in 6 patients hit a pre-defined criteria in terms of HBsAg lowering that would allow the patient to then receive immune booster PEG-Interferon.  The not very forthcoming revelation and the fact that the data was mentioned even after dropping another shoe that its small molecule HBV RNA destabilizer is also biting the dust makes it clear that not even the company sees much value in ARB-1467.

What an utter disaster this company has been since its inception as a HBV solutions entity.

Arrowhead Early HBV Deal Further Validates

Last week, shareholders in Arrowhead Pharmaceuticals got a lesson in biotech investing as it shares have given up ~1/3 of its value following a nice deal with Johnson&Johnson for the leading HBV knockdown asset in the space, ARO-HBV.

The deal gives Arrowhead a solid $250M in financing, including a $175M upfront fee and a $75M investment in company stock at a premium of ~50% to current trading.  While this avoids an imminent dilutive secondary share issuance- the company had been running low of cash- the ‘up to 15%’ in royalties from future sales of early phase II-stage ARO-HBV is clearly disappointing.  The relatively low royalty despite of it having confirmed strong HBsAg knockdown in patients can be explained with the fact that Arrowhead has avoided bearing the full risk of having to show proof-of-concept of HBV control.  This despite of having earlier paraded results obtained with an earlier DPC-based RNAi candidate (ARC-520) as strong evidence that RNAi can achieve such immune control.

While Arrowhead got punished for playing it safely, it can now focus on commercial home-run indications with highly validated targets and transition to being a broad platform company with a wholly owned attractive lead candidate in ARO-AAT.  Indeed, Arrowhead may emerge as the leading RNAi company as Alnylam, with a market cap ~8x that of Arrowhead, is still burdened by late-stage RNAi drugs with suboptimal specificity.

While humiliating, this serves Alnylam as a good reminder to also value innovation by the direct competition (note: specificity-enhancing technology now adopted by Alnylam has been available for a decade and could have been had for peanuts, e.g. from now defunct RNAi play mdRNA/Nastech).  Fittingly, today long-time archrival Silence Therapeutics issued a press release indicating that Alnylam is playing hard-ball with regard to Silence-owned IP purportedly covering ONPATTRO.

My guess is that Alnylam would rather risk an injunction and deprive patients of a very good medicine than to submit to what appear to me legitimate demands of a competitor.


Akcea’s antisense drug for TTR amyloidosis gets FDA nod

Last Friday, Akcea’s TTR drug TEGSEDI (licensed from Ionis) finally got FDA marketing approval for patients suffering from TTR-related polyneuropathy.  As expected from the delay in the approval process, TEGSEDI’s approval is accompanied by hefty black box warnings highlighting thrombocytopenia and renal risks of the (non-GalNAc) phosphorothioate oligonucleotide.  

Furthermore, the REMS program calls for frequent blood monitoring, essentially negating the claimed at-your-home convenience advantage over competing RNAi drug ONPATTRO.  Add to the poor safety profile clear efficacy disadvantages and pricing at parity with ONPATTRO, ONPATTRO should clearly win out in the marketplace.

Having said that, the TTR community is relatively small and key opinion leaders with relationships to a given drug company tend to support the drugs from the same company.

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.