Friday, May 31, 2013

Can RXi Pharmaceuticals Spot the Difference?

The imminent announcement of phase I results for RXI109 will be a clinical highlight of RNAi Therapeutics in 2013.  RXI109 is the self-delivering RNAi trigger against dermal scarring and is developed by RXi Pharmaceuticals.  Needless to say, as the company is committing 90% of its resources to this trial and indication, the results should cause major volatility in the stock.

While the dermal anti-scarring landscape is complex, RXI109 for the present indication can safely be categorized as a cosmeceutical.  According to RXi Pharmaceuticals, already $100M are spent each year in the US on non-FDA approved ointments against dermal scarring.  The interest in RXI109 is thus for its commercial potential and the clinical results are a milestone in the development of so-called ‘self-delivering RNAi triggers’.

Self-delivering RNAi triggers are a concept coined first by Dharmacon (although one could argue that was largely a branding achievement as it essentially involved known cholesterol conjugation), but is getting more widely adopted these days.  Beyond its local indications for which they self-delivering RNAi triggers were initially developed, I expect the concept to also be applied to certain systemic delivery strategies.  I could imagine that in an effort to render GalNAc-siRNAs more potent, self-delivering chemistries will be useful.

Phase I studies

RXi has conducted two phase I studies.  In both studies, volunteers got multiple surgical incisions symmetrically on both sides of the abdomen.  For each pair of incisions, one side either received RXI109 or placebo by intradermal injection.  In the first study, RXI109 was given just once before incision, from 1mg to 10mg per 2cm incision (similar range as in the Excaliard antisense trials).  In the second study, RXI109 was given three times within two weeks from 2.5mg to 7.5mg per 2 cm incision.

In addition to safety and tolerability, the important endpoints will be a visual assessment of scarring and then, based on a biopsy obtained from a tummy tuck at Day 84, important biomarker data in the form of CTGF levels (the target gene) and a histological evaluation of the scar tissue.

Although this is a blinded study, the company has discussed blinded results in extenso.  On the safety front, there seems to be little cause for concern, and adverse events are consistent with what you would expect from an incision.  Management appears to be very bullish on the therapeutic outcomes since in many cases left and right sides look different.  So if they are different, the side that looks better should have been given RXI109, right? 

Unfortunately, you have to look very hard to spot the differences.  In one example shown, the ‘average differences’ in scar tissue area were 31%.  Since they will put their best foot forward with this example, the largest effect size that we can expect is 31%.  And this assumes that in each case, it is the drug-treated side that outperforms the placebo-treated side. 

It is thus difficult for me to be optimistic that this trial allows for a therapeutic effect to be demonstrated.  For this, the natural wound healing variability would have to be really small (I admittedly don't know what this is).  On the other hand, it is with this symmetrical, intra-patient control design that such small differences might be teased out.  Regardless, I expect enough data to be collected from the studies that it will make for a nice headline and narrative about how RXI109 had improved wound healing and the correlation with CTGF (I bet there will be a correlation, whether due to knockdown or not).

So while I think that RXI109 is a decent RNAi Therapeutics (not the best possible one given the short dsRNA length), it will be important to conduct future studies in patient populations more prone to scarring to increase signal to noise.  This could be for example in the scar-revision setting or in Asian populations.

   
Trading the event


As I expect major volatility and have some confidence in the science behind RXI109, I have taken a long position ahead of the event.  It is not clear whether the results from the two studies will be presented separately or together.  I suspect the latter given that the CEO of RXi in February/March guided the results from the first study to be forthcoming in April.  Since it is almost June already, it is likely that the company expects the biggest bang from presenting the results together.  This should happen before July.  Once again, given that there is so much potential for data-mining, I expect positive headlines- justified or not.

Wednesday, May 29, 2013

Potential Breakthrough Cure for Chronic Hepatitis B Enters Clinical Development

Arrowhead Research announced yesterday that it had filed with Australian authorities to commence clinical development for ARC520.  ARC520 is the RNAi Therapeutics candidate for chronic Hepatitis B that aims at suppressing both viral load and the immune-suppressive Hepatitis B surface antigen (HBsAg).  This is thought to be one of the most attractive ways to achieve a (functional) cure for chronic HepB infection, and I believe that ARC520 has what it takes to be a serious contender.  

The first study will test how much of ARC520 can be safely given to volunteers.  While this may not sound all that exciting, safety with the unproven DPC delivery technology is probably the biggest risk factor with the program.  Based on the pre-clinical, rodent and chimpanzee, efficacy data, I would like to see at least 1mg/kg, ideally up to 3mg/kg ARC520-siRNA being safe and well tolerated.  With expected 95% and more HBsAg knockdown at these doses in many patients, it would all seem to come down to the validity of the HBsAg hypothesis.

Formal proof of knockdown potency will come soon thereafter in the form of the Hong Kong trial in which ARC520 will be given to chronic HepB carriers.  That study should get rolling in late 2013/early 2014.   

One nice thing about trials in HepB, just as in HepC, is that drug potency can be readily determined very early on by looking at viral titers in the blood.  Although this in itself is no proof of cure, in most viral infections, a rapid reduction is a good predictor of eventual outcome.  For ARC520, this should be no different. 

An advantage for Arrowhead Research in being early in aiming for a functional cure for chronic HepB is that the current treatment landscape is fairly simple (interferons and nukes).  This should greatly simplify pivotal phase III trial design and allow it to be positioned well on the market.

For biotech investors and traders, having frequent catalysts on a company’s lead candidate is obviously also very attractive.  This should keep the market entertained until 2017/8 when a potential approval could happen.

With 200-300 million chronically infected, ARC520 is definitely the popular choice in today’s drug development.   I will obviously be rooting for it, partly because I am invested in ARC520, but also for a number of other reasons.  

One of them is that I have worked for 3 post-doc years on identifying and characterizing small RNAs derived from the Hepatitis D virus, a virus that only exist in the presence of HepB.  By the way, HepD, basically HepB on steroids, is an orphan disease that I would like to see addressed with an RNAi Therapeutic.  If you are looking for potential targets, check out this paper by Dan Cao, myself and other colleagues at Stanford for potential gene targets.

And lastly, it reminds me of Professor Sir Kenneth Murray who just passed away following a quiet and productive life in which, among many other accomplishments, he was responsible for the first recombinant DNA vaccine.  The indication, of course, was for preventing HepB, and through this millions of lives were saved by his work.  Professor Murray was a co-founder of Biogen and the vaccine was eventually approved by the FDA in 1989 (licensed to GSK).  

With the money he made from his involvement with Biogen and the vaccine, he founded the Darwin Trust of Edinburgh and through this my undergrad and postgrad studies on RNA(i) molecular biology.  If you are still reading this, he shared with you enjoying both fundamental science and its industrial applications.  I also know that he liked to invest in biotech stocks. R.I.P.

Thursday, May 16, 2013

RNAi Therapeutics Ebola Candidate Achieves Critical Milestone


Yesterday at the TIDES meeting, Tekmira reported new efficacy data for its Ebola RNAi Therapeutics development program.  The non-human primate data suggest that the main remaining hurdle before regulatory approval for this biodefense agent (on which any government stockpiling contract would hinge), safety in healthy human volunteer studies, is now more realistic than ever.     

Is second time's the charm?

In 2010, Tekmira and collaborators from the Geisbert lab and the US Army reported in The Lancet of a breakthrough in the post-exposure treatment of Ebola infection.  In the gold-standard rhesus monkey model for Ebola infection, their were able to demonstrate that SNALP-RNAi could effectively rescue Ebola-infected animals from near-certain death. 

The efficacy, however, depended on doses of 2.0mg/kg is likely too high a SNALP dose to be considered safe.  Based on the SNALP human clinical trial experience to date, first dose-limiting toxicities are observed at 1.0mg/kg (note: SNALP potencies are very comparable between humans and monkeys).  Moreover, at doses higher than 0.5mg/kg, sporadic signs of immune stimulations (flu-like symptoms) can be observed.  These caused Alnylam and Tekmira to adopt precautionary transient immune suppressions with corticosteroids in some of their other SNALP-based clinical studies.   

It therefore became important to take advantage of the improvements in SNALP potencies and develop more potent Ebola SNALP-RNAi candidates.  Fortunately, Tekmira was able to get the blessing from the US Department of Defense for this, and announced in April that it would receive up to ~$7M in additional funding on top of the up to $34M initially agreed upon in order to bring such a candidate to the end of phase I clinical studies. 

Importantly, since Ebola efficacy trials cannot be conducted in humans, the regulatory approval of TKM-Ebola will be according to the Animal Rule.  The Animal Rule states that for indications where human efficacy trials are not possible due to ethical considerations, it is sufficient to show efficacy in accepted animal models and then establish drug safety at corresponding doses in healthy human volunteer studies.  

With the new formulation, 12 out of 12 monkeys treated with the magic dose of 0.5mg/kg RNAi stayed alive in a post-exposure treatment setting, compared to only 1 out of 6 treated with placebo.  This means that should the human volunteer trials show good safety at the same 0.5mg/kg dose level, Tekmira will stand a good chance at gaining regulatory approval under the Animal Rule.  Of note, the first Ebola trial were likely conducted in the absence of corticosteroid pre-treatment and it is very likely, also in light of Alnylam's recent announcement of tapering off corticosteroids in the ALN-TTR02 trial, that the future TKM-EBOLA studies will also be conducted without them.

Since 0.5mg/kg is right on the border, however, there still remains an element of risk before victory can be declared on the safety front.  It is therefore good to hear that 4 out of 6 monkeys stayed alive at the 0.2mg/kg dose. This should provide a good safety cushion despite the aggressive daily treatments that will be required in this demanding setting.

Critical human safety data, ideally from repeat-dosing studies, should be forthcoming in 2014 as Tekmira has guided that it will commence clinical studies with the new candidate by the end of 2013.

Update 16/5/2013: One issue on the efficacy side of the equation that I forgot to mention in the original post is that the DoD might ask the company to test TKM-EBOLA with longer delays after the infection in monkeys.


SNALP Shows Good Potency with Subcutaneous Dosing

Also at the TIDES meeting, Tekmira presented efficacy data for SNALP when given via the subcutaneous route of administration.  To wit, SNALP has largely been administered intravenously which may not be suitable for a number of indications, especially the lower risk, chronic diseases.  Pfizer once famously criticized the state of RNAi delivery as being limited to intravenous options.
Comments like these (which are very relevant for partnering purposes) and trends in the industry to adopt subQ dosing, most notably Arrowhead’s DPCs and Alnylam’s GalNAc-conjugates, probably motivated Tekmira to explore this route of administration with SNALP further.
 
Based on an early ApoB patent application, Tekmira had clearly had some familiarity with subQ, and I had always wondered why the company did not pursue this further.  It could be that the more potent SNALP chemistries now allow for much more potent and robust subQ RNAi gene knockdown.

The new data show a very impressive 96% knockdown of transthyretin (TTR) with a single subQ administration of 1.0mg/kg SNALP in rodents.  This compares to a much more modest ~55% knockdown with ALN-TTRsc at 1.0mg/kg given on 5 consecutive days, the subQ GalNAc-siRNA candidate by Alnylam which just entered clinical development for the FAC form of transthyretin amyloidosis.

Of course, we need to learn more about the safety of subQ SNALP to know whether it really is a clinically viable strategy and superior to the competition.  GalNAc-siRNAs in particular look quite benign, albeit not very potent.  However, since peak plasma concentrations seem limiting for SNALP in terms of safety (infusion reactions can be managed by slowing the infusion), subQ, due to its slower systemic release might actually turn out to be safer, not just more convenient.  On the other hand, my impression is that subQ SNALP could cause the type of ‘nuisance side effect’ that is frequently seen with phosphorothioate antisense.

The GalNAc comparison is obvious since Alnylam developings both a SNALP- and a GalNAc-based TTR RNAi Therapeutics in parallel.  In terms of competition for potential partnering, however, the DPCs by Arrowhead Research would be the more appropriate and challenging comparison.  I look forward to watching the race unfold as healthy competition is propelling the RNAi Therapeutics field into a highly competitive industry.

Monday, May 13, 2013

Poor Stock Offering by ISIS A Homemade Problem


Last week, shares of ISIS Pharmaceuticals came off multi-year highs of $23/share to close to $18/share when the $2B market cap company raised $170M in a public secondary offering.  The poor reaction to the stock offering is in stark contrast to other fund raisings in the industry lately and includes the impressive $170M offering by Alnylam in January, a $125M offering by Sarepta in December, and most recently the $36M offering by Arrowhead Research.  In all these cases, the offerings hardly registered on the stock chart and if, it was to the upside.

What happened?  Given that ISIS Pharmaceuticals is regarded as a bellwether of the industry, has the frenzy surrounding RNA Therapeutics and orphan drug development died down?

I don’t believe so (and expect the stock to bounce back in the coming days and weeks for the same reasons that it had tripled in the few months before).  The more likely explanation is that the management of ISIS Pharmaceuticals has never understood the money-making aspect of drug development and the sensitivities of the financial markets. 

The business strategy of seeking to out-license all its drugs before commercialization (supposedly, the new money is to hold onto drug candidates longer), may betray nothing more than its lack of confidence in the safety and efficacy of its own compounds.  We will likely see evidence of the cleverness behind this and the deal with Genzyme/Sanofi, when sales of recently approved mipomersen, once heralded by the CEO as a replacement of statins, but now relegated to the ultra-orphan homozygous FH population in the US only, will be made public.  

And at one point, the low-hanging targets will have been licensed and new technologies such as RNAi Therapeutics firmly replaced RNase H.  At that point, the company could have repeated the strategic mistake of PDL Biopharma in the monoclonal antibody space which has now degenerated into an IP management and royalty company.

The fallacy of that business model is also supported by the fact that cash flow break-even from licensing revenues alone was supposed to be just around the corner forever it seems.  Instead, we recently had a debt offering and this secondary.

I was recently asked on Twitter why I am always so negative on ISIS Pharmaceuticals.   In addition to my fundamental bias towards RNAi as the far more compelling mechanism for gene knockdown compared to brute-force RNaseH antisense with the phosphorothioate backbone, it comes down to credibility.
 
I have no doubt that the scientists at ISIS Pharmaceuticals are leading in many aspects of oligonucleotide chemistry, but it makes me wonder whether vasculitis is really only a peculiarity of non-human primates, gross morphological changes of proximal tubule cells really of no functional significance, injection site reactions and flu-like symptoms just ‘nuisance’ side effects as Dr. Crook recently called them (even better is the 'vanity' comment in explaining why the homoFH teenagers discontinued on the trial), and low-level inflammation in multiple tissues due to the persistent high concentrations of innate immunostimulatory oligonucleotides really not predisposing to diseases such as liver, lung, and kidney fibrosis.

But fortunately for the ISIS executives, the fact that their personal financial management skills are better than their investor relations savvy will help them sleep despite of these concerns.  According to Yahoo! Finance, Dr. Crooke and his team cashed in several million dollars through option exercises and stock sales in the month before the offering, and a few more since the beginning of the year:

Apr 30, 2013
29,945
Direct
Automatic Sale at $22.26 per share.
666,575
Apr 30, 2013
29,945
Direct
Option Exercise at $6.81 - $11.12 per share.
N/A
Apr 29, 2013
30,000
Direct
Option Exercise at $11.12 per share.
333,600
Apr 29, 2013
30,000
Direct
Automatic Sale at $22.51 per share.
675,300
Apr 24, 2013
25,854
Direct
Option Exercise at $6.81 - $11.12 per share.
N/A
Apr 24, 2013
25,854
Direct
Automatic Sale at $22.50 per share.
581,715
Apr 23, 2013
30,000
Direct
Automatic Sale at $22.12 per share.
663,600
Apr 23, 2013
10,417
Direct
Option Exercise at $15.38 per share.
160,213
Apr 23, 2013
10,000
Indirect
Automatic Sale at $22.12 per share.
221,200
Apr 23, 2013
10,417
Direct
Automatic Sale at $22.38 per share.
233,132
Apr 23, 2013
30,000
Direct
Option Exercise at $11.12 per share.
333,600
Apr 22, 2013
20,000
Indirect
Option Exercise at $6.81 per share.
136,200
Apr 22, 2013
10,000
Direct
Option Exercise at $11.12 per share.
111,200
Apr 22, 2013
27,320
Direct
Automatic Sale at $22.13 per share.
604,591
Apr 22, 2013
27,320
Direct
Option Exercise at $8 - $15.38 per share.
N/A
Apr 22, 2013
10,000
Direct
Sale at $22.10 per share.
221,000
Apr 22, 2013
20,000
Indirect
Sale at $22.10 per share.
442,000
Apr 22, 2013
30,000
Indirect
Sale at $22.10 per share.
663,000
Apr 21, 2013
20,000
Direct
Option Exercise at $7.26 per share.
145,200
Apr 21, 2013
17,656
Direct
Automatic Sale at $21.40 - $21.49 per share.
379,0002
Apr 21, 2013
10,000
Indirect
Automatic Sale at $20.99 per share.
209,900
Apr 21, 2013
20,000
Direct
Automatic Sale at $20.99 per share.
419,800
Apr 21, 2013
17,000
Direct
Option Exercise at $11.12 per share.
189,040
Apr 21, 2013
17,000
Direct
Automatic Sale at $21.26 per share.
361,420
Apr 21, 2013
30,000
Direct
Option Exercise at $11.12 per share.
333,600
Apr 21, 2013
30,000
Direct
Automatic Sale at $20.99 per share.
629,700
Apr 21, 2013
17,656
Direct
Option Exercise at $14.47 - $15.38 per share.
264,0002
Apr 18, 2013
2,042
Direct
Option Exercise at $11.12 per share.
22,707
Apr 18, 2013
2,500
Direct
Automatic Sale at $21.25 per share.
53,125
Apr 18, 2013
30,000
Direct
Option Exercise at $7.26 per share.
217,800
Apr 18, 2013
30,000
Direct
Option Exercise at $7.26 per share.
217,800
Apr 18, 2013
2,500
Direct
Option Exercise at $11.12 per share.
27,800
Apr 18, 2013
30,000
Direct
Automatic Sale at $20.01 per share.
600,300
Apr 18, 2013
2,042
Direct
Automatic Sale at $20.80 per share.
42,473
Apr 18, 2013
30,000
Direct
Automatic Sale at $20.01 per share.
600,300
Apr 18, 2013
15,000
Direct
Option Exercise at $14.18 - $15.38 per share.
222,0002
Apr 18, 2013
15,000
Direct
Automatic Sale at $19.60 - $21.01 per share.
305,0002
Apr 11, 2013
5,460
Direct
Automatic Sale at $19.60 - $19.62 per share.
107,0002
Apr 11, 2013
5,460
Direct
Option Exercise at $14.18 - $14.47 per share.
78,0002
Apr 10, 2013
7,000
Direct
Automatic Sale at $19.52 per share.
136,640
Apr 10, 2013
7,000
Direct
Option Exercise at $11.12 per share.
77,840
Mar 20, 2013
9,000
Direct
Option Exercise at $14.18 per share.
127,620
Mar 20, 2013
1,000
Direct
Automatic Sale at $19.50 per share.
19,500
Mar 20, 2013
1,000
Direct
Option Exercise at $11.12 per share.
11,120
Mar 20, 2013
9,000
Direct
Automatic Sale at $19.26 per share.
173,340
Mar 19, 2013
3,924
Indirect
Automatic Sale at $18 per share.
70,632
Mar 19, 2013
14,376
Direct
Option Exercise at $11.12 per share.
159,861
Mar 19, 2013
3,924
Indirect
Option Exercise at $5.93 - $16.32 per share.
N/A
Mar 19, 2013
14,376
Direct
Automatic Sale at $18.13 per share.
260,636
Mar 19, 2013
31,597
Indirect
Automatic Sale at $18 per share.
568,746
Mar 19, 2013
31,597
Indirect
Option Exercise at $5.93 - $16.32 per share.
N/A
Mar 18, 2013
11,179
Indirect
Automatic Sale at $18 per share.
201,222
Mar 18, 2013
11,179
Indirect
Option Exercise at $5.93 per share.
66,291
Mar 12, 2013
20,800
Indirect
Automatic Sale at $18.01 per share.
374,608
Mar 12, 2013
20,800
Indirect
Option Exercise at $5.17 - $5.93 per share.
115,0002
Mar 4, 2013
18,240
Direct
Option Exercise at $6.81 per share.
124,214
Mar 4, 2013
18,240
Direct
Automatic Sale at $16.86 per share.
307,526
Mar 4, 2013
5,040
Direct
Automatic Sale at $16.86 per share.
84,974
Mar 4, 2013
5,040
Direct
Option Exercise at $6.81 per share.
34,322
Mar 3, 2013
11,700
Direct
Option Exercise at $11.12 - $11.27 per share.
131,0002
Mar 3, 2013
11,700
Direct
Automatic Sale at $15.82 per share.
185,094
Feb 20, 2013
10,000
Direct
Option Exercise at $5.17 per share.
51,700
Feb 18, 2013
1,600
Direct
Automatic Sale at $14.80 per share.
23,680
Feb 18, 2013
1,600
Direct
Option Exercise at $10.29 per share.
16,464
Feb 14, 2013
350
Direct
Automatic Sale at $14.80 - $14.82 per share.
5,1832
Feb 14, 2013
350
Direct
Option Exercise at $10.29 per share.
3,601
Feb 12, 2013
6,100
Direct
Option Exercise at $7.25 - $8 per share.
47,0002
Feb 12, 2013
6,239
Direct
Automatic Sale at $14.17 per share.
88,406
Jan 29, 2013
2,000
Direct
Automatic Sale at $14.82 per share.
29,640
Jan 29, 2013
2,000
Direct
Option Exercise at $10.29 per share.
20,580
Jan 28, 2013
300
Direct
Automatic Sale at $13.40 per share.
4,020
Jan 16, 2013
242
Direct
Sale at $14.16 per share.
3,426
Jan 15, 2013
309
Direct
Sale at $14 per share.
4,326
Jan 15, 2013
330
Direct
Sale at $14 per share.
4,620
Jan 15, 2013
345
Direct
Sale at $14 per share.
4,830
Jan 15, 2013
143
Indirect
Sale at $14 per share.
2,002
Jan 15, 2013
759
Direct
Sale at $14 per share.
10,626
Jan 15, 2013
242
Direct
Sale at $14 per share.
3,388
Jan 15, 2013
1,317
Direct
Sale at $14 per share.
18,438
Jan 14, 2013
695
Direct
Option Exercise at $0 per share.
N/A
Jan 14, 2013
542
Direct
Option Exercise at $0 per share.
N/A
Jan 14, 2013
1,715
Direct
Option Exercise at $0 per share.
N/A
Jan 14, 2013
317
Indirect
Option Exercise at $0 per share.
N/A
Jan 14, 2013
776
Direct
Option Exercise at $0 per share.
N/A
Jan 14, 2013
737
Direct
Option Exercise at $0 per share.
N/A
Jan 14, 2013
542
Direct
Option Exercise at $0 per share.
N/A
Jan 14, 2013
2,978
Direct
Option Exercise at $0 per share.
N/A
Jan 3, 2013
1,296
Direct
Automatic Sale at $10.76 per share.
13,944
Jan 2, 2013
265
Direct
Automatic Sale at $10.84 per share.
2,872
Jan 2, 2013
311
Direct
Automatic Sale at $10.84 per share.
3,371
Dec 31, 2012
447
Direct
Acquisition (Non Open Market) at $8.87 per share.
3,964
Dec 31, 2012
431
Direct
Acquisition (Non Open Market) at $8.87 per share.
3,822
Dec 31, 2012
2,328
Direct
Statement of Ownership
N/A
Dec 31, 2012
898
Direct
Acquisition (Non Open Market) at $8.87 per share.
7,965
Dec 31, 2012
215
Direct
Acquisition (Non Open Market) at $8.87 per share.
1,907
Dec 31, 2012
N/A
Direct
Statement of Ownership
N/A
Dec 12, 2012
6,000
Direct
Automatic Sale at $9.63 per share.
57,780
Dec 12, 2012
6,000
Direct
Option Exercise at $5.25 per share.
31,500

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.