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I believe they are using Quest genetically altered cigarettes from Vector tobacco out of North Carolina. From a NZ article on the study:
"A groundbreaking Auckland University study has found it is possible to smoke your way to quitting by using virtually nicotine-free cigarettes.
The research found a higher quit rate among heavily addicted smokers offered nicotine replacement therapy (NRT) and the cigarettes with hardly any nicotine, than those given just NRT patches, gum or lozenges.
"It's an exciting finding," lead researcher Dr Natalie Walker, of the university's clinical trials research unit, said last night.
People in the "intervention" arm of the trial were given a six-week supply of the low-nicotine Quest brand of tobacco cigarettes and told they could smoke them if needed."
From Wikipedia:
Quest (cigarette)
Quest is a cigarette brand manufactured by Vector Tobacco, based in Mebane, North Carolina. It is manufactured using genetically altered tobacco plants.[1]
The product is available in three versions. Quest 1, Quest 2, and Quest 3.Each version of the product contained a different amount of nicotine.Quest 1 is reported to have of .6 mg of nicotine. Quest 2 is reported to have of .3 mg of nicotine. Quest 3 is reported to have only trace amounts of nicotine (.05 mg).
Importantly, the manufacturer stresses that Quest cigarettes contained all of the unhealthy carcinogens and had the same side effects of a regular cigarette with the single exception of reduced nicotine levels.
Sons - I don't think we are far away from the VLN availability. A few months? All we need is MSA according to XXII. It will not be mandated but could be made and sold by XXII. Joe even felt it could be labeled as such. A gov't. mandated nicotine reduction product is what could come out of all the scientific studies but VLN can make inroads long before that. Not sure how easy they could tout it as a way to quit prior to the completion of the studies but people know nicotine is addictive so most people can likely put 2 and 2 together. The mandate would be nice but I will settle for the MSA for now with a roll out of VLN in the U.S.
Van, loved seeing your comment at the end of the article. Every bit of PR helps to get the word out.
There is a fascinating look into smoking and nicotine addiction presented in the 900+ page report just released on the 50th anniversary of the 1964 Surgeon General's report on cigarette smoking. Much more interesting than the recent newspaper articles noting the 50th anniversary and a few cursory comments about the report. I decided to take a look at the full report and became captivated by the scientific rigor, the history and the data contained in the report. Trust me when I say I did not read the entire thing but I did read more than I intended to once I got started. I highly recommend you google the report and scan through the table of contents and pick the sections of interest to you. If you don't want to bother, here are some snippets that I found interesting:
Page 8 lists 10 major conclusions of the report you might want to look at.
Pages 31 and 32 have interesting information on the MSA.
The entire 5th chapter is devoted to nicotine alone.
Page 110 - The lag time between a puff on a cigarette and when nicotine reaches the brain is 10 to 20 seconds.
Page 112 - Nicotine itself is very toxic, it is not just the addictive ingredient in cigarettes. In fact, nicotine was widely used as a pesticide in the early 20th century. This practice contributed to several of the accidental poisonings from nicotine exposure.
Page 113 - The positive reinforcement of addiction to nicotine is primarily reinforced by the release of dopamine in the brain.(As an aside - drugs like marijuana and heroin also mimic or induce higher expression of dopamine in the brain so the mechanisms of nicotine addiction and the use of these drugs have some
similarities in the physiological response in the brain).
Page 124 - Conclusions on nicotine: acutely toxic; nicotine activates multiple biologic pathways through which smoking increases risk of disease; nicotine exposure adversely affects fetal brain development; nicotine contributes to preterm deliveries and stillbirths; nicotine exposure adversely affect brain development in adolescents; inadequate evidence that nicotine by itself causes cancer.
Page 846 - "Cold turkey" accounts for 90% of those who quit; 70% plan to quit; 50% of smokers try to quit each year; 4-6% of those who try succeed in quitting.
Page 858 - "New end game strategies have been proposed with the goal of eliminating tobacco smoking. Some of these strategies may prove useful for the United States, particlarly reduction of the nicotine content of tobacco products and greater restrictions on sales (including bans on entire categories of tobacco products)."
Lots of other good stuff I could have mentioned, but Enough Already! It is time for xxii. The FDA is under pressure and this report increases that pressure. Anything that can reduce a pesticide being put in your brain 10 seconds after a puff should not require all this foot dragging. I might just have to write my representatives in Congress to see if they might be able to give the FDA a call and see what is taking so long.
A cure for "cancer" is overly broad and unduly optimistic. There are over 100 types of human cancers and they revert to unique genetic abnormalities, which no single agent today or in the 1930's could even pretend to cure. Even today we are slow to grasp this new way of looking at cancer. For example, there are forms of breast cancer more closely related to prostate cancer than to other forms of breast cancer because of the genetic mutations involved.
Increasingly the focus is on managing the various genetic diseases, whereby people can live long and productive lives despite having been diagnosed with cancer. Repair and restoration of genetic function is the key. That is why K is so intriguing. Much more pointed and specific than turning on a machine in the 1930s and blowing up viruses, bacteria and tumor cells with a form of radiation, which is what Rife was doing.
The supposed cures of the 1930s are based on what? Not based on MRI's, not based on PET scans and surely not DNA analysis since DNA had not even been described yet by Watson and Crick. In other words, just like so many tumors that are cut out or irradiated, there was likely relapse because the fundamental genetic abnormality had not been fixed. There were likely no cures - just lack of good information. Remember the 1930s for what they were - no blood banks, no antibiotics (well there was Sulfa but no Penicillin) - and a lot of really sketchy medicine by today's standards.
I do not criticize Rife's or others efforts, in fact by all accounts he was a genius. But he lived at a time with limited knowledge of the diseases involved. Today we can be certain he was not curing cancer - a claim even he refused to make. He may have bought some people time (maybe, after all it was a form of radiation therapy, albeit very crude) but his machine did not repair DNA abnormalities caused by genetics, viruses, environmental factors. Radiation therapy today does not either.
I re-read the research report. The author did a pretty good job but was pretty conservative. One thing not mentioned at all for 2014 is the expected resale of tobacco equipment that is expected to reduce the outlay of the equipment purchase from $3.2 M to about $700k as I recall. If that happens, the benefit by my quick calculation is about $1.39/sh in 2014.
Gov, Not quite sure about all that. First it is the Wall Street Cheat Sheet, not the Journal. The WSJ would have been more thorough and clear. I say clear because I do not think the crossover trial has started yet. The author of the article is timing the one month to Leo's PR dated Dec 9th. In that PR Leo stated they were selecting a site and getting ready to submit it to the IRB. So my take is that we can expect an update on the site selection and the IRB by the 9th, or very soon. That is my take and I think the author confounded it by the way that he worded knowing something by the 9th. Actually, Leo said by "the end of the month" which I took to be the end of December but I do not recall hearing anything so far. So maybe an update soon and the pieces will be in place for the trial to start then the 30 day clock starts to tick?
Dr. J, I do not want to be unkind but a lot of people have invested considerable sums and it is important to be accurate. Both of your recent posts may give an investor pause about Kevetrin versus a competing drug.
From your first post 49893:
"ENMD 2076 appears to activate both wild type and mutant p53 in humans."
It does no such thing. None of the ENMD posters or data on their website indicates this is the case.
In your second post you say this:
"Entremed is working on developing a plan for Biomarker Driven patient selection for specific cancers and this poster clearly shows activation of p53 and have used this biomarker to guide therapy with ENMD 2076."
This is basically the gist of the ENMD effort in this poster but activation is a strong and misleading reference here too. What is really being said is that p53 will be used as a basis for developing a biomarker for what is most likely the best form of TNBC on which to use ENMD 2076, a form of breast cancer in which mut p53 causes an overexpression of p53 gene expression and protein expression. Makes sense to use p53 as the marker when it is overexpressed in a particular mutant cancerous state but that is far different than saying ENMD has anything to do with activating p53.
Entremed used Nutlin in their studies for a reason - it is the drug that activates wt p53. You will note on the poster that the more Nutlin given the better the result. The ENMD data show that knockdown of p53 mediates the effectiveness of ENMD, not the other way around. In fact, they more or less state in one cancer tested, CAL51, the absence of p53, increased the resistance to ENMD. It doesn't activate p53, it just quits working well, at least for CAL51, when p53 is not present.
I do agree and commend Georgejlls for his suggestion a while back for the combo trial for TNBC using both ENMD 2076 and Kevetrin, a combination which appears to have appeal, and which you have repeated here.
I return to Wonderland where I have yet to find a drug besides Kevetrin that tackles both wtp53 and mutp53. I will keep looking.
The clock is ticking...
"Each Unit consisted of one common share of the Company (a “Common Share”) and one-half of one
Common Share purchase warrant (each full warrant, a “Warrant”), each Warrant being exercisable to
acquire one Common Share at a purchase price of $4.50 for a period of 24 months following the
closing of the Offering. The Warrants are subject to an acceleration clause whereby should the
Common Shares trade at $6.00 or more for more than 10 consecutive trading days on the TSX Venture
Exchange (the “TSXV”) or other principal exchange, the Company has the right to issue notice to the
warrant holders to accelerate the expiry date of the Warrants to a period ending not less than 20
trading days from the date of notice."
I an all for clearing out the warrants as I think those who pick up shares will hold on to this and not cause any weakness.
Unbelievable finish to a great week. Had to laugh at Pete's post. My wife has suddenly become very astute at bringing up our accounts and checking balances. She was so against XXII because of the tobacco link but mysteriously has gotten over it.
This one has all the stars aligned. Can't ask for a better situation. Now if I only had a few more $ to invest....
Musings from the rabbit hole...
Last posted on this board at end of October when I went down the rabbit hole in response to some back and forth posts between TruthbyThought, Ardhee and myself. In the interim I have kept up with all the posts here but decided to stick to my probings of the science at the expense of a public mulling over of the slow decline in the PPS on the board. It was plain to me I had nothing to add to those discussions as all relevant points appeared analyzed thoroughly by others. Looks as if the decline is over and we can all hope for good times ahead. Go CTIX!
At the time of my last postings I was wrapped up in the beauty and complexity of what is involved with K and specifically the advantage of K vis a vis all the work done by Roche (nutlins) and the MDM2 and MDMX pathways. I was surprised to see today that Whoops remembered that old post so it inspired me to provide a little info on what I have been looking at since then.
As expected the rabbit hole led to Wonderland as there are amazing things being done in the battle against cancer. TruthbyThought, who has been conspicuously absent during the same period of my absence , surfaced for one cryptic post a couple weeks ago. He made an oblique reference to a drug of a competitor, which is easily identifiable and is a heat shock protein 90 inhibitor (Hsp 90). Heat shock proteins are increased in their expression by stress and by increases in temperature.
This is important to all here as K is also an Hsp 90 inhibitor and it is advantageous to know what the competition is doing. I probably have not identified all competitors of K on the Hsp 90 side of things but I have identified 15 drugs targeting this pathway. The trial of one of them was discontinued recently due to an inability to meet targeted endpoints. I have posted before that Hsp 90 is the pathway whereby mutant p53 is degraded - a mechanism of great importance as mutant p53 is the most common cause of the recurrence of cancer and eventual patient demise.
To back up for a moment - there are multiple pathways involved with K. At least two involve wild type p53 to repair cell damage or cause the cell to undergo either cell cycle arrest at the G protein receptor or apoptosis. Drug companies often target G protein receptor sites.
On this board there is always a lot of excitement surrounding whether p21 has been activated, which would indicate promising results along the p53 pathways, e.g., cell cycle arrest at G protein receptor 1. The CTIX poster presentations also note PUMA (p53 Upregulated Modulator of Apoptosis) as a pathway leading to apoptosis.
I have been poking around in the other pathway - the mutant p53 pathway involving Hsp90, which, in my view, is every bit as important as the cell cycle arrest and apoptotic pathways. I emphasize this importance for three reasons : 1) There are at least 15 drugs targeting the Hsp 90 pathway alone (Big Pharma and small biotech companies are all over this) and there are some amazing late human trial results even without any benefit of a positive effect on the wild type p53 pathway. These results are likely due to the already noted lethal nature and oncogenic potential of mutant p53 2) Dr. Menon, Leo and the poster presentations have emphasized both the wt p53 and mut p53/Hsp 90 pathways. 3) Hsp 90 is an attractive target because there are several oncologic clients of Hsp 90 (K has been shown to have potential with some of these oncologic clients such as mutant breast and pancreatic cancer cell lines). So this is an interesting part of Wonderland.
Kevetrin counts in both the Hsp 90/mutp53 and MDM2/p53 camps and, as far as I know, the targeting of both wt p53 and mut p53/Hsp 90 is unique to K. Hence, it remains my view this may prove to be the most important key to any competitive advantage of K as it winds its way through clinical trials.
Many publications make it clear that the Hsp 90 chaperone is the chief culprit when it comes to the stabilization of mutant p53. Consider this quote from a paper of a competing drug candidate:
"Mutant p53 (mutp53) cancers are surprisingly dependent on their hyperstable mutp53 protein for survival, identifying mutp53 as a potentially significant clinical target. However, exploration of effective small molecule therapies targeting mutp53 has barely begun. Mutp53 hyperstabilization, a hallmark of p53 mutation, is cancer cell-specific and due to massive upregulation of the Hsp90 chaperone machinery during malignant transformation.We recently showed that stable complex formation between Hsp90 and its mutp53 client inhibits E3 ligases MDM2 and CHIP, causing mutp53 stabilization."
The ASCO poster from June 2013 states that K "induced degradation of mutant p53 mediated by reactivation of MDM2 E3 ligase". This is a key mechanism as one can deduce from the quote of the competing drug candidate noted above. In other words, K, like the competing drug, is able to overcome mutant p53 stabilization and it does so by overcoming the inhibition of MDM2. The weakness of the other drug and its ilk is the lack of any effect on wt p53.
I think one reason we hear more about the MDM2/p53 pathway is the p21 marker was identified as a marker for the study. There are several reasons I suspect it is not as clear cut on the Hsp90 side of things: the Hsp 90/mutant p53 pathway is quite involved and I sense markers are not well understood as of yet; as if it is not enough for p53 to mutate there is also a propensity for Hsp 90 itself to mutate and become resistant to particular drugs; the tendency for Hsp 90 inhibition to activate other cancer survival mechanisms through Hsp 70 and Hsp 27 and possibly HSF-1 transcription factor, which is a key regulator of both Hsp 90 and Hsp 70 (all of these proteins are attractive cancer drug targets); and the fact that some of the drugs do not access the Hsp 90 of the mitochondria.
All this really leaves one in awe of how determined a foe cancer is and of the really amazing front line work being done to try to overcome cancer's incredible adaptability. As I encouraged the board some time ago - read Mukherjee's pulitzer prize winning book "The Emperor of all Maladies" and I think you will gain a new appreciation for what the Menons' of this world are up against.
I am trying to find out the ability of K to cope with these Hsp90 issues but I suspect a few more CTIX posters and presentations will be required before we know for sure. Many of these mechanisms are poorly understood as I have noted a full understanding of the pharmacokinetics of Hsp 90 seems to be lacking with many of the drugs targeting this pathway. It is complicated. About now in Wonderland the Red Queen has approached and -oops - is off with my head!
So for now that is about all I have discovered about the Hsp 90 side of things but I am still running into strange creatures in this part of Wonderland. There are a bunch of them here. I haven't even started to look at the angiogenesis pathway of K via alpha-tubulin. And there are creatures like HDAC6 , HDAC2, Akt, HAT etc. that I have only brushed up against a little bit.
So for now I am going back down the rabbit hole but I must confess I like the look of the terrain better than the last time I was up here. Things are looking up and I can't wait for the JPM conference and update. I will leave you with this:
One pill makes you larger
And one pill makes you small
And the ones Dr. Menon develops
Does wonderful things for all
Go ask Leo
Gov says he knows
And if you go
Chasing share price
You know you're going to fall
Just tell them a genius
Veterinarian
Has given you the call
Go ask Leo
He's feeling 10 feet tall
All the men on the IR Board
Get up and tell us where we'll go
And we just had a PR update
And the posters are in an uproar
Go ask Leo
Gov says he knows
When manipulation
And deception
Have fallen
We'll be millionaires
And the shorts will be buying backwards
And the red ink
Will no longer be here
Remember
What Kahuna said
Be in or dread
In or dread
Gov and BK-hope you don't mind. I did not say anything you haven't said yourselves. And I agree with both of you on those points.
If you are like me you will prefer this version...
I think big market players do know the value of xxii but are unable to invest because of constraints, namely that xxii is an OTC stock. Van has stated this and so has Big Puff. The key is to uplist.
Relying on the DD of individual investors to unlock the value of xxii so it can uplist is asking a lot. First it is small and unknown by most. Also, there is a stigma factor that must be overcome and some folks won't take the time to do it. It is easy to give it a cursory glance and assume it is a "tobacco stock" rather than a plant genetics company with some socially desirable goals. It took me awhile to get serious about it even as a HTSBS subscriber because I was turned off when I saw the link to tobacco. I went straight to SPIHF, which turned out fine. I picked this one up last of the 3 and had to convince the wife too as she was adamant we were not going to invest in tobacco. I had to explain the VLN concept and the research studies but she still doesn't like the investment here. Such are the whims of individual investors. I do not think the big players have any such qualms but even in that space there may be social responsibility mutual funds that may be reluctant to take a bite of this one.
The company understands the value of uplisting to unlock value by attracting investment from the big boys. The warrant exchange is the last real impediment from a balance sheet perspective. All indications are the warrant exchange is going to be successful. Assuming there are no BOD or other governance issues, all that remains for uplisting is to increase the share price. The warrants will help with that and we will see if it is enough. If not, there are other catalysts , i.e., the start of production, increasing profitability, MSA news etc. but it is unclear how long it will take to cross the threshold for uplisting. I am optimistic all will be in place by mid to late Q1.
You may go to the retail investor presentation website and read the slides for today's presentation. I have looked them over but will defer saying anything more at this time as it is important to hear the additional info the speaker provides.
Hi Pete, You should be able to tell the difference. If you made the same mistake I did you will not. I was running my HD TV through a receiver that did not support HD. Had to get a new receiver then I saw a big difference.
It doesn't get much better than this:
" As of October 31, 2013, 22nd Century Group had total assets of approximately $9.4 million, including approximately $6.5 million in cash and only $700 thousand in current liabilities. The company's only long-term liability is its derivative warrant liability, which the company expects will be significantly reduced through this warrant exchange."
The desire of funds and brokers to get in is going to push this stock after uplisting. Early 2014 is looking good for this one.
Thanks. I went down the rabbit hole on my last post at the other place. Haven't resurfaced yet but I have been looking at a lot of interesting stuff. May stick my head out of the hole soon. Hey, by the way didn't you set the record or something for those $50 payments to Fidelity for SPIHF?
As I accumulated I made 4 buys. Even though I didn't like it I have now forgiven Fidelity for charging $50 each time. I guess that was the price of admission to get a good seat to see this Saturn V liftoff.
Thanks JFM, That is helpful. I am amazed the warrants could be called that soon after the financing deal. I am not too worried even if the shares have to be absorbed given the technology and likely continued demand for the stock. The dilution is still going to result in a company that has relatively few shares. Still, I like your scenario and it seems quite plausible once the word is out as to what this technology can do.
At this rate the SPIHF warrants from the recent financing may be eliminated soon:
"The Warrants are subject to an acceleration clause whereby should the Common Shares trade at $6.00 or more for more than 10 consecutive trading days on the TSX Venture Exchange (the "TSXV") or other principal exchange, the Company has the right to issue notice to the warrant holders to accelerate the expiry date of the Warrants to a period ending not less than 20 trading days from the date of notice."
If they are eliminated say a month from now that will be the shortest time that I will have ever seen a warrant overhang for a company.
But I am not sure if that can happen that quick because of this:
"The securities issued in connection with the Offering are subject to a four-month hold period from the issuance date in accordance with the policies of the TSXV and applicable securities laws."
So my question is whether the four month hold prevents the start of the 10 consecutive days with a price over $6. My bet is it does not but does prevent the securities from being sold. Anyone have any insight on this?
Yes the warrants are still a drag on the company. But the notes payable and the convertible notes have all been paid in full from what I can see. That eliminates an obligation of about $3 million.
Yes I see that. I did not properly connect what I quoted as being applicable just to the registration rights agreement. Also, the purchase agreement is much more detailed on the termination provisions for the purchase of shares and delineates several ways to terminate. I think it is likely Aspire has been selling, but the proof is lacking.
Yes that is possible. In light of your comments I think it is likely they have some shares. But I still see them in a different light. That is, they have many options to dispose of shares and certainly may have exercised some of those options. The ability to turn over funds is of some advantage to them for on-going opportunities. I do not think they are lined up to put $30 million in this company and just hold all of the shares they acquire. I may be wrong. But they start with a competitive advantage vis a vis the small time investor and start with a profit via the "commitment shares". No doubt there has been pressure on the price so Aspire, with their large holdings are a possible source.
That aside, I hope the selling is over and we settle down for some appreciation. How else will I end up being your neighbor when you are living in that Hawaiian 10 room mountain top home you'll be getting?
So from the info in my prior post I now have a better idea of the role of Aspire. They are not a long term hold but have sold off all their shares. Likely they are now using the profit to at least partially fund the second round of $20 million. It is good for us and good for them.
This approach makes sense as they do not have to commit as much money to any particular company, which reduces risk, and they have the ability to roll the funds over to the same company (as in this case) or to a different company that has caught their eye.
The good news is they have sold all shares so the drag on the share price from that is over. Also, it is unlikely Leo will tap into the $20 million right away so they will not be flipping any shares from that for awhile. So as I see it, we are now in a position where normal market forces are at play rather than absorbing the sales from the prior financing arrangement. It will be interesting to see how that plays out in the next few weeks.
Another great job by Leo. He was able to get a better deal from Aspire than the last time too. When you look at the detail of the 8k from last time and the 8k this time there are some differences. First, the last time Leo had to pony up 336,625 shares as a commitment fee, a freebie for Aspire. This time there is a commitment fee of 210,523 shares for twice the amount of capital. Last time, Leo also had to sell 112,208 shares right off the bat to Aspire for $100,000. I do not see any such provision in the 8k for the new agreement. See below -
...dated as of October 25,2013 (the “Purchase Agreement” ), entered into by and between the Company and Aspire Capital Fund, LLC (the“Buyer” ) pursuant to which the Company has agreed to issue to the Buyer shares of the Company’s Class A Common
Stock, par value $0.0001 per share (the “Common Stock” ), in an amount up to Twenty Million Dollars ($20,000,000)
(the “Purchase Shares” ), in accordance with the terms of the Purchase Agreement. In connection with the
transactions contemplated by the Purchase Agreement, the Company has registered with the U.S. Securities and
Exchange Commission (the “ SEC ”) the sale by the Buyer of following shares of Common Stock:
(2) 210,523 shares of Common Stock which have been issued to the Buyer as a commitment fee (the“Commitment Shares” ).
It would seem that maximum dilution under the new agreement is about 13.8 million shares per the following excerpt from the new 8k:
(1) up to 13,789,477 shares of Common Stock with an aggregate value of up to $20,000,000 to be issued upon
purchase from the Company by the Buyer from time to time (the “Purchase Shares.” ).
Also, there has been a lot of speculation about who has been selling. The language from the first agreement says the agreement is terminated when Aspire has sold all of their shares by a variety of means enumerated below:
· ordinary brokers’ transactions;
· transactions involving cross or block trades;
· through brokers, dealers, or underwriters who may act solely as agents;
· “at the market” into an existing market for the common stock;
· in other ways not involving market makers or established business markets, including direct sales to
purchasers or sales effected through agents;
· in privately negotiated transactions; or
· any combination of the foregoing.
The real key to who has been selling is in the following quote from schedule B accompanying the first 8K:
This offering as it relates to Aspire Capital will terminate on the date that all shares offered by this prospectus have
been sold by Aspire Capital.
In today's PR Leo specifically states that the prior agreement with Aspire was terminated per the terms of the agreement. Which would seem to indicate Aspire has now sold all of the shares from the first agreement to brokers, underwriters etc. I think this is the smoking gun as to who has been selling.
By the way the current agreement contains the exact same language.
Thanks Truth. That information on Hsp 90 is very interesting. If you look back at post 39739 I was speculating about AD and some other conditions that all come back to some of the cellular processes manifested through use of K. But I did not get into enough to see it was linked to Hsp90. Since K is a novel compound with many iterations covered in the patent it is hard to say where it may all lead. When I get the time I may poke around a bit more, maybe you will do the same. If so, please share.
Truthbythought - Sorry for the late reply. After posting yesterday I took a long hike and was pretty tired when I got home.
Excellent and difficult question. Journal articles note the complexity of the pro-apoptotic and anti-apoptotic pathways. There are multiple molecular players involved.
Mutant p53 relies on a tumor specific activation of a p53 stabilizing pathway. To quote:
"The identity of this pathway seems to be linked to the Hsp90 chaperone machinery, which is highly and ubiquitously upregulated
specifically in cancer cells... In fact, in tumor cells mutp53 forms stable complexes with Hsp90."
Kevetrin disrupts the stability of the Hsp90 complex. HDAC6 is the positive regulator of the Hsp90 chaperone activity. Kevetrin modulates the expression of HDA6. Inhibition of HDAC6 leads to mutp53 ubiquination("the kiss of death" for a protein) leading to degradation.
There may be other pathways involved too. But this one is shown on the poster presentation on the CTIX site.
It is quite amazing to me that Dr. M was able to pack so much wallop into this small molecule called Kevetrin. He must be driving Roche crazy after all the time and effort they put into this.
More about Roche - Roche is an interesting competitor because they have invested so much into p53 which yielded the Nutlins , which in turn, provided much of the insight into the science needed to continue the efforts to reactivate p53 in a more efficacious manner. Now Roche seems to be placing it's bet on Aileron, a company that is touting "stapled peptides" as the way to reactivate p53. Roche has provided millions and perhaps could reach $1 billion with Aileron and Lilly, Glaxo Smith Kline and Novartis are also participating via venture funds.
When you look at the Aileron PRs they claim a superior approach because the stapled peptides allow them to modulate both MDM2 and MDMX which are the "big two" protein regulators of p53. MDM2 is regarded as the primary inhibitory pathway because it acts on p53 in more ways than MDMX. MDM2 inhibits through 2 mechanisms (inhibition and degradation) while MDMX inhibits p53 but does not degrade it.
Kevetrin does not directly modulate MDMX so this would appear to give the stapled peptide approach an advantage over K, which only modulates MDM2. To quote: " The inability of MDM2 inhibitors to target MDMX-p53 interaction or induce MDMX degradation prevents full activation of P53, imparting resistance to MDM2 inhibitors." It also is important to note that MDM2 and MDMX interact with each other and those interactions allow MDM2 to in turn degrade MDMX. But if Kevetrin has downregulated MDM2 that is not going to happen.
So score a point for Roche/Aileron.
But before we dismay too much there are two important points to consider: First, Kevetrin is in human trials while Roche/Aileron is claiming they will start a human trial in 2014. The transition from preclinical to human trials is tricky and who knows if they can pull it off with a candidate that is both efficacious and non-toxic.
The second point is a huge advantage for Kevetrin as it does something which the Aileron drug candidate does not. Kevetrin affects both wild type and mutated p53. The Roche/Aileron drug affects only wild type P53. This is quite significant as mutant p53 may promote tumor progression and resistance to therapy. Consider these quotes:
"p53 mutants that promote tumor progression and resistance to therapy become the most common prognostic indicator for both cancer recurrence and death."
or this:
"Introduction of wild type P53 by gene therapy can correct loss of function in tumor suppression, but cannot diminish the oncogenic effects of mutant p53 on tumors. "
So the fact that K is in human trials and addresses the type of P53 mutants that harbor "the most common prognostic indicator for both cancer recurrence and death" garners Kevetrin a couple of points. And there is this too - the following quote hints that Kevetrin may still have some effect on MDMX because CTIX data indicates K activates Bax.
"Thus, the combination of MDM2 inhibitors with chemotherapeutic agents such as doxorubicin, which induces MDMX degradation, or with a BH3 mimetic ABT-737, WHICH ACTIVATES Bax AND OVERCOMES MDMX-MEDIATED SUPPRESSION OF p53 FUNCTION, MIGHT HAVE THERAPEUTIC VALUE.
If that bolded section is indicative that Bax activated by Kevetrin would provide an indirect means to degrade MDMX then any advantage of the stapled peptide approach of Roche/ Aileron disappears. And that might occur without the combo therapy described in the quote but by the use of K by itself if the Bax expression CTIX has noted is significant enough to do the job. But this is speculative on my part as there is no direct quote from CTIX regarding any effect on MDMX.
To me it is obvious which approach holds more promise and that is where I have put my money. It would seem even a less robust activation of P53 partially inhibited by the lack of downregulation of MDMX is better than no defense against an oncogenic mutated P53 which will only buy some time before resistance and recurrence. So CTIX is the most advanced candidate and, in my opinion, has an important advantage that outweighs the MDMX issue.
For what it is worth. My degree in biology is 40 years old - a time I refer to as the "pre-genetic era" LOL. Still, I like this stuff and my conclusion favoring K is what I take from delving into the science of the two different approaches. But you can draw your own conclusions.
About Roche - Many will recall Roche is the rumored company behind the Univ. of Bologna K trial. It would not be surprising they would be interested in K as Roche developed the Nutlins and are now deeply involved in a stapled peptide approach to p53. If they really have interest in B and K then somewhere down the line things could get interesting between Roche and Pfizer as try to figure out what they might want to do about this little company called Cellceutix.
Here is a link that explains "adaptive trial design" that Leo listed for the Prurisol trial in the PR. Sounds like a great way to go as you can change the study as you move forward based on information the trial has shown so far or even based on information from outside the trial. Saves time and dollars. Leo is always thinking of ways that will get us to the finish line in the most expeditious manner and with a reduced monetary outlay for the trials.
http://www.pharmafocusasia.com/clinical_trials/adaptive_trial_design.htm
BK, I'm sure your calculations did not account for this new information:
" Cellceutix’s biologists believe that there could be a ‘treasure chest’ of drugs waiting to be developed for several disease indications that may never have been thought of by PolyMedix."
Who knows what that might mean. But 'treasure chest' sure has a nice ring to it.
It takes both science and management to win at this game. We are all aware of the fall of PolyM and yet when I look at B the science seems solid. Posters who have followed the science are now over here confirming that management was not up to par.
A new case in point is a company I have followed for some time but never invested in: SNTI. I like their science but the management of the company has kept me from pulling the trigger. Now trading for .03 and yesterday announced a 100 to 1 RS. Good luck with that. Company has 300 million plus shares outstanding and a market cap of under 10 million. SP 52 week change is -85%. Makes our approx. 100 million shares at $1.70 look like nirvana.
Bottom line is that it is hard to do what CTIX has done to get even this far. Bright people fail at this all the time even with good science. There are a million ways to get it wrong and only a few ways to get it right. I think CTIX has done it right so far.
This PR just upset the apple cart for some timeline projections. An antibiotic study is much shorter than anything else in the CTIX pipeline so this will pave the way for good things, e.g., a partner. Just great news!
And your hopes come true Incubus.
Pete I agree it is way under the radar. It costs less than when I made my first purchase so I just keep adding. I will probably add more this upcoming week. I keep saying to my wife that it is a good time to buy. I think she is tired of it as I say that is a good time to buy pretty much every week. But you know what? It is a good time to buy!
Thanks for posting this. What I take from it is there is a long way to go before anything will come from this, if ever. If the effort is successful, it looks like it would have to be from a derivative of mithramycin as mithramycin itself is too toxic to the liver and has a small therapeutic range.
No doubt in my mind that the 3 scientists awarded the Nobel prize in Chemistry on Wednesday have had a great impact on the PolyM drug pipeline and perhaps on much of the work of Dr. Menon as well. They are US based but all 3 have multi national status. Their work was done in the 1970s and provided a new way to do chemistry on a computer. It was a tremendous breakthrough as they had to blend the great dilemma of Physics - the reconciliation of the very large (Newtonian Physics) with the very small (quantum physics). The computational system they developed allows scientists a way to understand interactions between thousands to millions of atoms according to the press release. The article I read has the following quote..."There are thousands of laboratories around the world using these methodologies both for basic biochemistry and for things like drug design."
I remember someone posting a short bio on the lead scientist for Poly and he extolled the virtue of the use of a supercomputer model for identifying the best drug candidates. Said it would not have been possible without it. It all goes to show the seemingly logarithmic advances that are occurring. The work of Martin Karplus, Michael Levitt and Arieh Warshel pushed drug development into a new era.
I have never been a take the basis off investor. But looking at that Ariad chart gives me pause about that strategy.
Great news! K jumps to 110 mg/m2 for cohort 6 and starts up in a week or week and a half. IND for Prurisol shortly after the end of this month. Two more INDs for Brilicidin in January. Presentation at conference and likely meetings with interested parties in November.
Bottom line is these guys are all over it. The market doesn't get it yet but it will in time. GO CTIX!
If you say so. Your reply shows you understand the complexity very well.
I was in Hospital Admin for 35 years until I retired last year. Many people have asked me what I think of the ACA and my answer is always the same. Something had to be done. Is it perfect? No. Can it be modified to make a better system than we have today? Probably. Richard Nixon made the first major overhauls to Medicare and Medicaid that were needed. And it got better. Speaking of Nixon, that old Republican was the first to propose national health insurance. Might have gotten it too if not for Watergate.
The ACA is complex. There are many good provisions. One that my hospital benefitted from was the rapid adoption of a sophisticated electronic medical record. We received millions in government payments for being an early adopter. It cost our hospital over $100 million to put in place so the millions (I think it was $7 million in incentive payments) did not come close to paying for it. But the government got it all back in improved care and the elimination of duplicative care. For instance our lab tests went way down because one MD would order a test another had already ordered and there was not a good way to prevent that. The lab test reduction was $50 million alone.
I suspect there are bad practices that can be fixed like Nixon did with Medicare. But anybody who doesn't think something had to be done better look at the rate of health care inflation over the years. Just abysmal. They are now going down - not health care costs but the rate of health care inflation. And please don't look at infant mortality if you think the existing system is great.
Remember too that anyone without health insurance goes to the ER -where costs are the highest. Mandated by law that they must be seen. So my hope is when the dust settles and those who now go to the ER are seen by a primary care MD and the savings from that switch will offset some of the cost of insuring the uninsured.
One last point - my hospital was 70% Medicare and Medicaid. A lot of so called socialized medicine has been in place for half a century. But under these "socialized" programs you do not get cancelled for a pre-existing condition. There are people on this board who have gone public with their health conditions and under the existing system they better be loaded when there policy comes due. I have seen many people cancelled with the kinds of conditions discussed on this board.
Not easy stuff. But simplistic rationales based on half the story don't get us to the kind of health care outcomes we need to see in this country.