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While you wait...
Dr. Shapiro is involved in another little gem from Boston that is presenting Phase II results at the upcoming San Antonio Breast Cancer Conference and just put out a publication detailing the mechanism of action. For those that want to see the future of Kevetrin here today via the results of an advanced trial HSP90 inhibitor this is your chance. It should be pretty spectacular.
One clue, the company in question starts with an S and ends with an A.
Oh and I recently wrote an article about them. Check out their seeking alpha articles and look for a comparison to another well known cancer company. Hopefully you find it interesting and notice the similarities to Kevetrin (minus an extra HDAC inhibitor)
GLTA. This baby will turn a corner once they have a timeline on some results.
Arhdee and Orion, the trip down the rabbit hole took me further than I had ever anticipated. Keep digging. Look for another that employs the MoA. You will find some startling similarities and I venture you will also find yourselves faced with a difficult choice.
Out of respect for the board I am not going to say more on here.
Hint: There are some interesting things out there about retinal safety.
Thanks. Have traveled down the rabbit hole a bit more based on the info you provided. Some interesting notes.
Hsp90 is a longstanding target of anti-cancer drugs and it has been shown that down regulation of this protein strongly deactivates mutant p53 and upregulates normal p53.
There was actually a drug called Geldanamycin that did just that by inhibiting Hsp90, but unfortunately it had the draw back of liver toxicity. Certain analogues of the drug were being studied as late as 2010 by Bristol-Myers Squibb and studies may even be ongoing - someone contested the end of the trials on wikipedia.
"GA downregulated overexpressed mutant p53 protein (an oncogene) and upregulated wild-type (wt) p53 (a tumour suppressor). The upregulation of wt p53 by GA was independent of ATM and was accompanied by downregulation of Akt and the active form of MDM2, indicating a possible mechanism. GA also produced a p53/ATM-independent increase in the levels of p21-a potent inducer of cell-cycle arrest."
So contrary to what some on here have indicated K does not reactivate mutant p53, but actually promotes its destruction allowing it to be replaced with the functional wild type protein (which is generally ihibited by the very presence of the mutant p53).
Another interesting note is that Hsp90 has been linked to Alzheimer's disease (per the below) and down regulation has been linked to inhibiting the formation of tau (the protein responsible for Alzheimer's) so there is that implication if K can cross the blood brain barrier
"Consistent with previous research on Hsp90 clients in cancer, we provide evidence that a loss of HDAC6 activity augments the efficacy of an Hsp90 inhibitor and drives client degradation, in this case tau."
In summary, it appears that indeed the key to K's efficacy is Hsp90 inhibition via HDAC6 and HDAC2 inhibition. This is an insight that personally I did not have despite having read those posters numerous times. Thank you Orion for helping me attain this clarity.
Many thanks for the insight. I have some follow up reading to do based on those details.
Agreed. Thanks for the post.
Nice post. Agree whole heartedly with your views.
You might find good leads on there for some interesting companies, but for the love of god do not take anything you read on there remotely seriously.
Nice. Any insight into the mechanism by which K affects mutant P53? Thanks!
To be fair, the effects on dogs sound mild (though use of the words "biologically significant" is not necessarily a mild term). I mean basically the dogs had an increase in the number of red blood cells. In racing circles people take drugs like epogen to accomplish the same thing, haha.
Looking up each of the side effects listed in dogs it really does not sound like anything "toxic" happened at all.
Bucaneer, I take back what I said. Maybe we don't hit a MTD ever :)
As friendly advice I would avoid PPHM. Weren't they the ones with the mind boggling labeling mess up. Don't invest in companies that seem mismanaged. Most times they will continue to find ways to blow your mind with the important things they "overlooked".
A cancer study is hard enough to get right when it is run by extremely competent people.
Wait wait wait... I seem to recall another post form Sept Mike indicating that things might get ugly fast at 1.70 :) I remember strongly objecting as a bottom seemed to be solidly in place.
I have to say it all sounded pretty solid to me. And I am the first to be a skeptic. I continue to believe the only hold up for the financing is that they will not be sure how much they actually need for next year until they have the budget for B nailed down following the November conference (and any Partnership they are able to generate from it).
Then they will be ready to move forward with the necessary amount.
Nothing conditional about this. A Company worth 170 million does not have any issue raising $10-20M (especially a Company with such insane growth potential). All the plans announced seemed pretty damn concrete to me.
Also concur with the others that details of what has been going on in terms of in-house personnel is new and welcome and it is always reassuring to have a solid update of cash on hand.
There is a toxicity and only time will tell where that toxicity turns to MTD. One thing to remember is that for the mice who received chemo as a control in the preclinical trials, the dose of the chemo chosen was "equitoxic" (meaning it had equivalent toxicity in the mouse to 200mg/kg of K)
Also note that the dogs did seem to hit a MTD (depending on how severe the biologically significant changes were) at 60mg/kg, per the below from the posters
"biologically significant decrease in MCHC and increases in RBC, hematocrit, and sodium (high dose)"
I am done converting that to a human dose because we seem to be dealing with an unknown scale, but it means there is a limit. We will just have to see where that is.
Nice. Important not to forget that D is a wildcard drug that is also ready for Ph2 studies as soon as they can wrap their heads around what the source of the AE blood pressure drop was. It seems ripe for alternate dosing mechanics as a possible solution.
Interestingly the only competitor for D (a drug called protamine) has similar hypotension blood pressure effects if given too rapidly per the below.
"Too-rapid administration of protamine sulfate (protamine (protamines) s) can cause severe hypotensive and anaphylactoid-like reactions (see DOSAGE AND ADMINISTRATION). Facilities to treat shock should be available."
I think another possibility is we hit cohort 9 without a MTD (still think this is a reasonable outcome especially given the statement at the conference early this year that we may not hit MTD during the Ph1). We will have a 1b escalation study starting at some point - cohort 8 sounds reasonable though could wait until Cohort 9 starts and confirmation that it is not showing adverse reactions.
If we do not hit MTD in our Ph1 I think the prudent course would be waiting for the 1b trial to establish the MTD and then proceeding with Ph2 based on the maximum dosing knowledge provided by the 1b.
This seems like the most efficient path - avoiding dosing patients at lower than ideal doses (which for a drug like this that is so highly concentration dependent will always be the maximum tolerated dose).
A quick google search reveals that it is common to have a Ph2 with multiple solid tumor types examined. A study by Puma biotech for example had 6 cohorts each with a different type of cancer.
None of that makes Sierra any less of a joke. They are literally a joke.
If you are talking over 80 then yea many cancers slow down and become less life threatening. I'm sure some are sill more serious than others and some might slow more than others but the general rule is that their tumors are going to grow more slowly.
From a quick google search:
"Many cancers in the elderly are slower growing and may not contribute to morbidity and mortality"
Sierra is not worth listening to. It is a sham with a steady stream of made up BS. Just ignore anything from Sierra and keep walking. A complete joke.
To be fair, when people get that old their metabolism slows down a lot and with it so does the cancer. So much so that there is often a preference not to treat when a person gets that old because likely something other than the cancer will be what kills them because the tumors grow so slowly.
Just something to keep in mind.
It's not super necessary to have a shelf, just convenient so you don't need to do a full registration every time you do an offering. Serrated registrations each time accomplish the same thing.
Separately, I agree with the approach of delaying financing as long as possible on the assumption that time will likely afford you a higher share price as things continue to progress. However in this case I would wager the delay is likely a tesult of waiting until after the November conference to figure out if we have a partner and on what terms so they know how much money they actually need to advance all three drugs through 2014.
We will likely have our financing announcement only after that conference.
A shelf registration is exactly for the purpose of the mood striking. Generally companies put them in place with no intention of issuing shares in the foreseeable future but just as a matter of good corporate house keeping for a public company. Many big players in stocks will similarly require as a matter of contract that the shares they purchase be registered. It creates the option to sell without the obligation. Who in their right mind wouldn't want that. But that by no means indicates they are actually selling. The only way you would know that would be if they have to publicly disclose changes in their position on a quarterly basis.
Still as a matter of stock manipulation they may be inclined to temporarily force down the share price through sales if they know the Company is going to need additional funds in the short term. But there is no reason to suspect they have any interest in dumping their core position. If anything they are accumulating like the rest of us in all likelihood. This is a good small cap biotech play and they are likely in it for the same reasons as the rest of us.
B seems solid to get through a Ph3 given it has completed Ph2 with limited side effects. Slight risk that they can't subdue those hypertension reactions, but that in itself would not kill the drug. Its not like it was causing anaphylaxis. Likely would just be approved with a warning to watch out for hypertension during treatment and discontinue use if it occurs (in the worst case). I would say 50/50 that they successfully tame the reaction in Ph2b with the dosing changes, but this is a drug that will make it to market barring the 1 in a million problem that we can't foresee.
P is actually where I think there is the most risk of failure/sub par results given the role of the human immune system in psoraisis and the difficulty of replicating its involvement in a mouse study. Nevertheless, we know that the drug impacts Prins which is a known factor in psoriasis and the fact that the other treatment didn't cure where ours did in the mouse study is encouraging. Overall, I am still highly optimistic that we will have a similar result. Still who knows what can go wrong in terms of determining an effective dose, unforeseen reactions etc. Without the PoC we are flying dark here and its a gamble. These will be the results that will make me sweat.
K will attain a theraputic dose and will be approved. Its toxicity profile is just too favorable to be an issue and the concept of this drug has been proven by the Nutlin Phase 1B study completed in 2012 which also successfully fought leukemia by activating p53 - meaning you can activate p53 to a level that destroys tumors in humans without generating systemic toxicity. Its a golden child that just needs time to grow up. Risk of failure is extremely extremely low.
Lol ihub is definitely having a lot of issues today
If you believe the 100 as a key marker and efficacy story then getting out now would be a mistake. If that is true we may start to see some reportable responses sooner than expected. No reason to believe that DF would prevent updates on tumor markers or tumor shrinkage if it was observed. There will still be plenty of additional follow up data and final results to report at ASCO for DF to bathe in glory even if they let out progress reports. Lack of updates has simply been due to a lack of material news (as much as some have hyped the updates to date there has been nothing solid reported even at R&R - even P21 was qualified in its entirety). Add to that at these levels we are undervalued again given progression. It's a bargain at these prices. No point selling at bargain prices.
That is what puts a bottom in.
Where was 200 mg/m2 stated in a PR? I looked and only saw that as an email response to someone on the board. If it was stated please provide a link.
The reason why restaging to stable disease followed by progression did not impress is conveniently summed up in this abstract from 2009:
"With a high percentage of new oncologic agents failing in phase III studies, the confidence one has in predicting later success in randomized studies when stable disease alone is observed is understandably low. Continued uncertainty of the value of stable disease is based on the lack of precision in defining this as a meaningful outcome. With the term stable disease encompassing a broad range from <20% enlargement to <30% reduction using standard response criteria response evaluation criteria in solid tumors, what one refers to as stable disease is open to diverse interpretation."
There is nothing that has nailed them down to efficacy meaning tumor reduction. Further, we have no idea how efficacy dosing actually converts according to their model. We just have a MB post that range is 100-200 for efficacy and that 100 was always an important marker. No explanation of why or how provided.
Nevertheless, hoping you are right. If 200 gets us there I will be ecstatic. If it doesn't well what is another 6 months, haha.
I am glad there is hope in this range though I still wish I knew what Leo meant when he said they expect efficacy in the 100-200 range. To me the word efficacy has a wide range of meanings. On a technical level it could mean as little as p21 activation if the definition is pushed to its outer limits. Like all ambiguous terms used in the world of biotech it's usually best not to assume there is something more positive implied than what is plainly stated without ambiguity.
Still no response from Leo on what he meant by efficacy. But hopefully we will be in for a happy Christmas surprise after all. Heck at this point a March or April surprise work just fine for me as well.
Wow. So basically lots of room for error when figuring out how dosing converts. Lots and lots and lots of room for error in every direction. Allometric scaling may work or it may be thrown off considerably by a million and one factors. Basically seems like everyone puts their head down and hopes for the best in a Phase 1.
Our effective dose may be 100, 500 or something higher. This will be an interesting year. Nobody can know when this thing will start to really work. How exciting :)
For those who are interested in a more in depth discussion of dosing. Just started reading myself but sounds interesting.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737649/
Yep thanks. Figured that out taking a closer look at the article you posted. Thanks for that. The fact that nobody is publishing ways to figure out mouse to human efficacy and seem to only be using it to calculate safe starting dosage does lend credence to the "it's complicated" model. Will try to see if there is anything that discusses the complexity more formally.
So you were thinking about this over a year ago and resolved that efficacy was too complicated for us to calculate off of the animal model without complex algorithms. Good to hear, but as you know I love to see for myself if I can. Any useful references that taught you about the complexity that goes into modeling efficacy?
Thanks.
Are you saying DLT was observed in some species at 100 mg/m2 human dose equivalent?????
You said starting dose is often DLT of lowest scoring species divided by 10. We started at 10mg/m2. That would mean they saw DLT at 100mg/m2 in a species not specified in the posters.
Please tell me I am misreading what you are saying.
If the Company would say that it would be great. Would gladly hear that the model based on HED is wrong. That they are basing it off of some ultra complex model that yields dosing numbers that are 3x lower than the basic HED model. But instead hearing crickets. Still anxiously checking my email.
Sorry I had missed your post. It was a concern of mine as soon as we found out the initial dosing was 10mg/m2. Good to see we came to the same numbers independently. Polkadot did the same at some point so i know we are not making this stuff up. Still no response from Leo. Very disappointing.
I would have emailed him sooner, but the last time i thought about this we were expecting increases that would take us to 600 by Cohort 8. The 50 percent increases from Cohort 2 I think took everyone by surprise. And by the time the new increases were announced I had forgotten that my calc had shown such a high number was needed. So many on here talking about 200 as an effective dose for so long it's easy to forgive the error.
I am a bit frustrated to not have received any response yay or nay or a "can't answer you". Maybe I am asking too much, but something... Hate to bring this to the fore, but for those who are interested here was my email to Leo.
Dear Mr. Ehrlich,
Although this is my first time writing to you I have been an investor in Cellceutix since March of 2013 and currently hold approximately 100,000 shares, which is a substantial position for me. On a personal note I am a great admirer of both you and Dr. Menon. However, there has always been one question on my mind that has been a source of uncertainty and that is the expected dosage of Kevetrin for efficacy in humans. Specifically, I would like to understand better if possible the basis for the statement in your October 2nd press release that 100mg/m2 has always been an important dose.
My confusion stems from my review of your past poster presentations (including ASCO 2013) containing your mouse response data that showed no clinical response at 50mg/kg in mice (specifically the yellow treatment line lines up almost exactly with the control in the A549 lung carcinoma mouse study) and some signs of efficacy beginning at 100mg/kg. Although I unfortunately do not have a clinical background there does appear to be an established conversion matrix for mouse to human mg/kg dosing and from mg/kg to mg/m2 dosing in humans (per this link to ACUC tables http://ncifrederick.cancer.gov/Lasp/Acuc/Frederick/Media/Documents/ACUC42.pdf).
Following the metrics in that table, 50mg/kg in a mouse is equal to 4.16mg/kg in a human which is equal to approximately 154mg/m2 in a human (50 divided by 12 and then multiplied by 37 per the table and its examples). Therefore according to the mouse model even at 150mg/m2 dosing one would not expect to observe a meaningful clinical response. According to this same calculation the first signs of efficacy in the mouse studies that are graphed were at 100mg/kg in a mouse which is equal to 8.3mg/kg in a human which is equal to approximately 308mg/m2 in a human (100 divided by 12 and then multiplied by 37).
This discrepancy has caused me some sleepless nights and therefore I would greatly appreciate any clarity you may be able to offer. Is the Company's expectations regarding expected signs of efficacy based on something other than the mouse studies and if so what is the basis? Are my calculations above inaccurate in some way (though the converstion factor from mg/kg to mg/m2 in a human may vary it seems any variance would be to a factor higher than 37)?
Does the Company believe that the range of efficacy is expected to be between 100mg/m2 and 200mg/m2 and if so what is the basis for the Company's conclusion? What type of efficacy would you expect to observe at these levels?
Any answers you may be able to provide are very much appreciated.
Many thanks for your efforts to improve the lives of all.
Sincerely,
I have asked for both clarity on what signs of efficacy they are expecting between 100 and 200 and what the basis is for their figures.
They must be getting it from somewhere, but nothing that has been publicly disclosed as far as I can tell.
I would urge caution as to what to expect in terms of "efficacy". They may only be talking about p21 activation. Don't be expecting definitive signs of tumor delay until we are much higher. Possibly not until the Phase 1b escalation gets underway. We had assumed (as late as June) that our cohorts would be at least at 200 by now. At this point unfortunately we will be lucky to be finishing Cohort 9 at 300.
However, I continue to believe this stuff can be dosed at well above 500 safely and the 1b trial will prove that. We should be able to get close to 1000 based on the dog safety data.
"Efficacy" has an extremely ambiguous meaning. Hopefully Leo responds to some of my questions. Anyone know how long he normally takes to respond? I sent him the email Saturday.
Could you clarify why you think 100 is the important dose? This goes back to a debate that happened a long time ago now. So long ago that I had forgotten the original predictions. I have an email into the Company to try to figure out why 100 is so important. My numbers (and I have reworked them many many times at this point and run them by others) indicate a much higher dosage is required (based solely on the mouse study numbers). I will not repeat the logic here since last time the topic was raised it appeared many on here were not very good at math. But lets just say it led me to believe that based on mouse tumor response data we had to be at a minimum above 150mg/m2 to see effects on tumors.
To put what to expect further into perspective - from what I can tell the mouse model showed slowed growth at 300mg/m2 administered 3 times a week and much more significant delay at 550mg/m2 administered 3 times a week. Add a second round at 550mg/m2 and you get the best of the predicted results.
I will concede that extended treatment at something above 150mg/m2 may also yield delay, but the drug we are dreaming of exists closer to 500mg/m2 dosing in humans.
Happy to be wrong, but so far no response from Leo.
How long did Leo take to get back to you? Just curious.
Seems like a reasonable explanation to me. I always thought the stalking horse position put CTIX at a considerable diligence advantage. And everything is definitely sleepier in the summer. Hard to get anything done in August unless it has been teed up well in advance.
LoL, they do a deal in 10 min, but pretty sure its not binding until they have signed an agreement. You at least need a term sheet and an agreement to bargain off of it based on good faith to have any sort of binding agreement.
Have to move from talks to documentation with a couple of turns each way. Minimum of 3-4 weeks to closing and announcement from time they figure out who they are doing a deal with and general terms.