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I am still below the sales price i have set to my broker _ 10M$ in total tax free
But I expect it to get closer in the incoming days as shorts are being converted fast pace into true believers as the holly Truth is being revealed to them by our spreadsheet bibles.
Ahahaha, nice site, congrats Sushi !
I posted my 10M$ order.
(10M$ will be fine with me, besides its tax free for me in this part of the world)
Fosco
While its not mentioned, that's 62 sites out of 101.
I would expect 500 at least out of 928
Spidey and lightrock
I tend to agree with you as far as you agree that you are taking a conservative approach
What makes me more optimistic, in a realistic approach, are the following "keywords", if you see what I mean :
Belarus, Bosnia and Herzegovina, Croatia, Hungary, India, Malaysia,Romania, Russian federation, Serbia, Sri Lanka, Thailand, Turkey, Ukraine
Remember also the other study showing disastrous SoC from the Seeking Alpha article was from Bulgaria.
I have put some money (like 5% of my purchasing power) but I will put more in May as well, as for me May is a threshold for a conservative approach (Soc used from UK data)
Take care
Fosco
@george
Total response do not mean cured(it means the cancerous tumor is now gone and there is no evidence of disease but often the cancer comes back years later)
Total responders are not dropping out. They are being followed. Even if they die 10 years later. As long as they have followed the treatment they can be tracked in the country registers if they pass away.
@ligthrock
A drop out would be someone who does not follow full treatment including SOC. Low probability is to NOT want to follow MK treatement as it is non toxic, fast and gives hope. Not null probability is to have drop outs during SOC : such as an elderly person exhausted by chemo and who just want do stop the treatment. We can find some stats on litterature.
Agree 200 drop outs would be huge and is unrealistic. So 30% alive at Y5 is unrealistic, right ?
Agree we can't afford 200 drop outs with 55% Survival at Y5. We cannot afford much drops out with 55% survival at Y5 (less than 5% and the study better ends by end of year !) !
Now what do we do of this letter to investors ? Consider it or not ?
That's why I am sayin' : let's wait and see ! :-|
Hi,
In the mentioned study, which target the same ST III AND IVa population, Soc is SO disastrous, that ones need to take into account drop outs to keep MK efficacy into realistic figures
What this implies, is that, even with huge number of drop outs (20% or 200 people), MK should show a tremendous efficacy. At least 15% and potentially above 30% better survival than SOC. If I want to match the know events, than efficacy should be 30% for 200 people having dropped out and the 298th event reached by november.
I have updated my spreadsheet with some drop outs models. What else can I do now ? Wait and see what happens
Kind regards
Fosco
Hi
Yes, trying to factor the risk as much as possible
My realistic models says if 298 happened today we should be around 15%
I consider UK data as very optimistic and I updated the curve to match better Y5 survival. So if we can pass May, I will buy more.
Last thing I would like to leave behind are drop outs. Drop outs shouldn't be due to MK treatment but from SOC (guys giving up with the Chemo). I have put another folder. I have no idea how many would give up chemo, but I saw a study when its mostly the fact of elderly. So should be contained under 5%.
I am more confident on a bad soc : have you seen Bulgaria and Thailand studies ? Really bad. Don't forget that many sites are in "developing" countries. Furthermore, I noticed from stats that more patients have stage IV (majority being IVa) than stage III, may be in the 3/4 1/4 proportion
So probabilities ? I would say if 298 happened :now 45%, April 55%, May 65%, June 80%. But I am confident we'll go through June at least given the 208 figure we got from China. I'd love to have a confirmation back from China. May be we'll have some data in May.
Take care all
Keyword for you is log rank test
Hey, no pb at all.
But let me react a last time on " do actually negatively distort the results as prob of survival into nowadays is extremely slim for both test groups I.e MK won’t show “results”" : this is not true. You do not count survivors as of today and compare both groups. Of course, this gives an indication of efficacy of the drug if more survivors are in one arm but that's not what you do.
The survival curve says "how many % were alive 3 years after treatment". Year 0 : 100%, year 1 : 85% etc... So even if most 135 people from 2013 have passed away, some patients survived for 4 years, and others for 3 years etc...what counts is that those who made it at every point in time are more numerous (more than 10%) in the MK group than the test group.
Finli
What counts to the patient indeed is to know how long he will live more with the drug, the QOL etc...of course.
But the trial aim is to measure efficacy of a drug and you can't wait until everybody dies to state that "those who took the drug in average, outlived 1 year those who didn't take it". To measure efficacy of the drug you need to compare survival after a reasonable number of years. With very lethal cancers, you can wait till half people die in each group and compare "median survival" (keytruda 16 months VS 12months has been declared significant). This does not mean that people will live 4 months more, just that they have a 50% likeliness of dying after 16months with the drug, and may-be a 30% of dying after 12months VS 50% in the control group.
As Cel-Sci cancer is not as lethal and metastatic you are not going to wait for half of patients to die but you can wait till "enough die" to draw two survival curves that will show significance of drug efficacy.
There are other parameters measured ("secondary outcome measures") which will be interesting the FDA, but won't be decisive to FDA approval.
George, I am longing to smoke the millionaire's club cigar with you in the near future.
I will have to fly overseas but it will be worth it
Thanks for the links Sushi,
Regarding the article :
- His column 3Y survival is erroneous as he confused 3 years survival with 3 year deaths
- The way he computes the "Current death # Multikine =no help" is a bit obscure but we can guess he extrapolated 3 Y and 5 Y survival for sakes of simplicity
SOC survival he uses is really bad. Then obviously he shows that MK is more than efficient (more than 15%)
This said... The links he provided are really good. In particular "Treatment outcome of advance staged oral cavity cancer:concurrent chemoradiotherapy compared with primary surgery" because they show how survival is in Thaïland = disastrous, unfortunately for the patients. As many sites are in such countries for the clinical trial, overall SOC shouldn't be as good as stats we have from US or UK. I am confident that if I can show that MK is efficient with 54 % at Y5 then any SOC which is worse should prove that MK is really efficient !
In summary : his article is another proof point that survival is currently much above average in this clinical trial
hehe Trusbaby
You made me laugh. Remind me to bring you over you a bottle of Lagavulin for our next millionaire meeting
I must admit then even as a an ex PwC staff when I was a young nerd I never saw any company being paid in stock ! So I must assume that CEO is approving such risky decision and will want to understand what he is stepping in. But ok, this is America and probably cultural, in Arab countries some may accept camels (or blonde girls) as a payment and I have no doubt CEOs will want to test the quality of the merchandise he's beeing given in lieu of money
My view too George,
Imagine Ergomed taking 500 00 shares and knowing the product is NOT efficient and the 298'th event getting close ... No way !
Have a good day
Thanks Sab
Advices much appreciated
Re Chinese data, indeed their publication would help predictions. I doubt we got them this time as the leak has been carefully concealed but we never know : Bets are open my take : 271 as of Feb 4 2019.
Absolutly right M. Pijoe. I was looking for the right wording actually as the decision belongs to the FDA.
Sushi
My view is that thinking that IDMC would grant earlier approval for ethical reasons _although Geert himself mentioned it his last press conf_ is still speculation.
This said and right now in March, if SOC survival Y3/Y5 is 55%/43% then the survival gap between the two arms should be about almost 60 people (+30%).
This is non negligible (as a reminder the FDA wants a gap of 25p between the two arms when 298 is reached) so would be worth earlier approval.
I was rather thinking that, as we are getting close to 298 (Around 270-280 may-be), there would be some leaks if results were good, so that the investment community would not be left in the dark and March would be good for positive speculation re the pps.
Then an IDMC decision would be an non-expected cherry on the cake
If it’s showing only 8%,then we are talking about a very narrow range of people (5 people max) who still can make the difference. If we are waiting for 10 to 20 events to happen, then those five more could be found in one arm so the trial cannot be halted for futility at this point.
We have two possibilities there:
1- I don't believe in miracles, however if IDMC could fastrack approval prior the 298 of course we will have a wild run up
2- If not then we'll need to wait for 298. When 298 will be announced, this shall make a little bit more buzz than anything we have known from now. Every serious investor on earth will start using their spreadsheets or statistical tools and this shall stimulate speculation as the spreadsheets will be telling good things. We should have a nice run up as well.
In the meantime, as we are getting closer to 1- and 2-... we should have, well at least in theory, guess what, have a nice trend up
George
That's based on 800 evaluable. Of course with more it will be better. SOC might be better as well as I suspect
Regarding Geert statement, he gave a hint in his last interview, I remember he said IDMC would find unethical to extend the study and wait till 298 if results are already showing obvious benefits in test arm.
IDMC gathered last year and what they saw based on limited number of events (208) looked encouraging.
Like I wrote on YahooMB, what they might see this year in the "spring review" with the number of increased events could be getting so statistically significant then 298 might not be required to urge FDA for an approval.
Staticmirror
Thanks again
" that we haven't lost that many patients to unrelated causes.", well I don't know what "many" means but I guess that means they may have between at least 800 and at most 928 evaluable patients randomized in the 3 arms.
800 patients with a SoC survival at 55% at Y3 and 43% at Y5 would mean a 30% benefit in test arm if endpoint would be reached today.
@Sushi :
The bottom might be close those as
- shorts interest is increasing
- pps going slightly up
@Staticmirror
That is good news.2 more ticks in the checklist before take off. Thanks a lot for the feedback
As we enter the month of March, these are only 2 last risks factor that I see on why current survival would not be as good as it seems (from the quantitative analysis on XL)
1) A very large number of patients (150+) that would be lost from the overall trial (from the 928 enrolled) . Your info says that Inventiv patients are still followed so no risk from Inventiv patients side.
2) A surprising good Soc survival in those trial center sites.Surprising because we are dealing with StIII and IV patients who don't have a so good survival hopes unfortunately
...we are getting close, buddies....
Hey MPJ
I appreciate your feed back since you are an "old timer". I am not sure, were you part of the "tourers"?
Just FYI what the spreadsheet tells:
Spreadsheet assumes : SoC Benefit with a Number of eligible patients
If SOC = 55% at year 3 and eligible patients = 928 then MK group benefit over SOC group would be as of today more than 50% ...
Needless say this is not realistic therefore, if you apply logics :
-Either SOC survival is over 55% at Y3
- or eligible patients are (much) below 928
- or both
Like I said, there is a strong uncertainty on "evaluable" patients. Out of 928 how many are not counted in the end ? What about the 125 from Inventive/ Pharmanet ?
Stage III and stage IV patients were recruited. Stage IV patients did not include metastatic (m=1) patients. Therefore the SOC stats survival might be between 55 and 63 at Y3, but in any case, a wise investor will consider a more conservative SOC than 55, as obviously the survival is not matching current data.
PS : Sorry but I think I will refrain from posting from now on ...I don't fell like it's helping and I am very busy on my side running my company... At this point we just have to wait and see what happens in the incoming months. GL2A
Hey
the % method on response rates does not say "it looks good". It just says, if we replicate ph II "it should look like this" eg 25% benefit in MK arm. In this I agree it does not bring much to the predictive aspect that we are looking for
Then the XL method does discretize the events. For instance the 14 enrolled in July 2014 are randomized and "3 have survived in SOC and 4 in MK". Luckily there is not an "isolated guy" as they were enrolled by "packets" and it's easy to split 55% / 65% and round figures like in the example above. This methods says "it looks good" because today we should be worse in terms of these isolated cumulative events if MK benefit was 0% so MK should have 25% benefit. It is not based on phII results at all.
Confronting both methods is interesting because they do match and one is based on ph II results and the other on a timetable of discrete events.
This said , those wonderful findings don't seem to help the pps right now
Response rate :
===============
Basically you are stating that a fixed % of MK patients should have a response rate which allow them to survive beyond SOC at 3years.
This % should be around 15,8% based on ph II findings.
Therefore 3Y survival improvement 15,8/55 = around 29% for this 55% survival rate
If applied to a better SOC like the one I have used (63% at Y3), then benefit is 15,8/63 = ..... 25% !
That's quite interesting, although phII results should be taken with a grain of salt as based on a very low population. But still the method is interesting !!!
And in the same fashion you could set a low boundary. There were 2 Complete Responders in phII (10,5% of total) then if we consider those 10,5% as the only ones who survive better than SOC, then MK benefit should be between 16% and 20% (depending on SOC : 63% or 55%) at Year 3.
As a reminded here is how I obtained this 25% figure with the spreadsheet : I used a SOC log curve that I found realistic (63% at Y3, 54% at Y5) and applied it to the recruitment table. Then I adjusted the MK benefit to be able to fit with known 208 events Feb 2018. 25 % improvement in MK arm matched the 208 figure. Then I set a date to get number of calculated events by XL in Feb 2017 and I got a good matching as the XL showed me 131 events VS the 133 known events. That comforted me with the method. Finally I set the dates until I got 298 events and, to my big surprise, this date was mid October 2019 while cel sci was still announcing "early 2019"
800 patients:
=============
928 patients have been enrolled. That means then many where screened to match the inclusion criteria and that 928 where selected as eligible. Among those 928, 1/7 where randomized in third arm, and 3/7 (397 so almost 800 in total) in both arms that interest us.
400 took MK+SOC and 400 SOC only. What I don't know is what Cel Sci initially meant by "evaluable". Does is mean pre-screening or patients attrition (drop downs) during trial ? As they gave a big number of non evaluable, this could change our survival analysis by some significant % if this number is big. So in my opinion it is the main uncertainty in all this survival analysis (The other being SOC survival but I believe SOC is as bad as we figured out due to the characteristic of the population)
Question to you
===============
Just curiously You seemed to have followed thoroughly our findings and asked very relevant questions. Are you a shareholder ? Are you a would be shareholder ? Are you writing a PhD thesis ?? (lol)
What is your goal with all these questions ?
Sushi
Indeed 298 mean 63% survival. It's the "static" figure. The dynamics is the time arrow. The more we wait, the better it is. Right now this time arrow is approx. 4 years and it's moving (and we are aging also lol)
This said I read Cel SCI presentation and there is indeed new stuff which clarify things :
-p12 : confirmation of Stage III and IV cancer in patients population (this is important as there is a significant discrepancy of survival between stIII and IV SOC survival)
- p20 : confirmation on study arm : 800p and implicitely that 298 observed deaths had not happened yet
-p21/22 : Keytruda and Opdivo
- p28 : written confirmation that the trial is blinded to Cel SCI (I was doubting this since it had been written nowhere)
So it's all looking good from my point of view
@Stab. All good. Thanks for bringing your art and hope
@stockpicker. I do appreciate your enthusiasm. If I have time I will review your calculation.
Hi
I have a feeling to have addressed all your concerns, if I missed, sorry it is simply that I didn't understand the question
"Then the Phase 3 must have a lot more Stage 3 patients than Stage 4. Correct? " : that's another question, which I think the answer is NO because if you look at literature you will see that there are more patients going to the oncologist with a stage IV than a stage III
Sorry, I am not a PR from Cel SCi and don't have time to address all the questions , just trying to share my findings, so personal DD is welcome here,
So to finalize on this topic, if all patients where stage III, trial would last longer (stronger survival) for sure but benefit of MK would be around 10% if we got the 298 by now.
Knowing that there is a mixture of Stage III and IV is a hint, in my opinion, that MK effect is much better than 10%
Take care and place your bets
Fosco
SAB
last friday was an extraodinary day.
I have no science on TA, and not clue at all what has happened but it looks as if we had reached a kind of turning point where some desperate longs sold and some shorts started recovering OR that simply the longs exceeded the short.
That's just an impression as I have absolutely no clue of what is happening. Pps could very well continue to go down , or up...???
Therefore please understand that I do appreciate when guys like you bring a you knowledge and science in a field I am just a nerd. But I can't comment. For me why things go down as they should go up is a mystery. I understand the long picture but not the short one that's why I refrain from commenting, having nothing to say but observe. But again, thanks for bringing your science
Fosco
Stockpicker
I have run the XL with better SOC figures, for instance, this one extrapolated (log) from UK cancer data :
Year Survival%
1 78,0
2 68,2
3 62,5
4 58,4
5 55,3
6 52,7
7 50,5
8 48,6
9 47,0
10 45,5
62,5% survival at year 3, 55.3 at year 5
this one shows that a 10% improvement will be reached by mid March 2019 if 298 from 800 are not dead yet.
Why I don't believe that survival curve applies for cel sci trial :
1- Inclusion criteria for the trial include Stage IV patients (in addition to stage III) for which the prognosis is really worse : T4 and N2)
2- it is based on UK data, and most sites of the clinical trial are in countries which don't have an efficient system as the UK one. Even German survival data is worse than UK data.
And no : the FDA will consider the 10% improvement between the two arms. Patients are screened to the inclusion criteria and randomized in both arms. There is no reason for some patients to be in better shape in one arm rather than on another. That's the rule of the game.
Agreed, nothing "material" to celebrate or worry about. Very likely a stupid form that requires an date entry set in the future when a clinical trial is updated and still active.
I am absolutely positive this trial will finish before the end of the year. My take was October, it could be a bit before or a bit after but definetely not Dec 2020 !
Fosco
ah ah, "non-zero probability " doesn't sound too good either ! But I'll take it as a positive reversal of probability.
Btw, are you sure something proved in a QBM can apply in our ST ?
500 million is may be the value of the company based on current manufacturing capacity and current target cancer population in the US alone
5 to 10 B is the potential of expansion of a proven successful compound
my friend,
Geert is like us, getting a bit older and tired about this.
So he will have the opportunity to bring it himself to marketing rights, manufacture and sell using and expanding the cold fill facility which will bring him a few tenths of millions yearly & recurring $ and deal with the hurdle of execution or....
sell the stuff (patent + cold fill) to a Big Pharma which will value cvm a lump sum (5 to 10B) to do all this stuff he would have done plus much more and expand R&D to multitude of cancers....
He won't hesitate a minute and his next problem will be to get a good counsel for his tax calculations and chose the color of his yacht.
Disappointed to have no news from Stockpicker as I diligently answered his questions
Anyway I have more calculations"nuggets" relative to survival.
It might not be ultra-precise science but gives the flavor of what we should expect from this trial.
We know 4 points for the observed survival curve of 794 patients treated in the two arms.
Point 1 100 % survival at year O
Point 2 83% survival (133 events) as of feb 2017
Point 3 74% survivors (208 events) as of Feb 2018
Point 4 63% survivors (298 events) somewhere between now, eg March 2019 and the near future (less than 1 year)
We have the Y (survival), we are lacking the X (time). For the X we could use the patient dosing time table that we have precisely to calculate an average time since treatment taken by the group of 800 patients. Doing this we can now draw the survival curve of the trial:
Point 1 100 % survival at year O
Point 2 83% survival at year 2
Point 3 74% survivors at year 3
Point 4 63% survivors at least at year 4 (could be anywhere from 4 to 4,5)
well well, as a matter of fact that's a pretty good survival curve ! Just compare it to fig. 7 (ST III and IV) :
https://www.ahns.info/resources/oral-cavity-cancer/4/
JMHO, repeating myself but there must be happening something in one of the two arms of the study !
hi stockpicker
Where you got wrong is that you are using phase 2 results as a benchmark. Phase II is based on 19 patients.
You have to compare SOC to actual survival on 794 patients, the two arms of IT MATTERS clinical trial
Actual survival is based on :
- date where patients got dosed
- # of deaths as we know them
We know for sure that 298 death did not occur yet, hence we can compare this survival to 1. and 2. 298 is 37% of initial pool, eg 63% have survived.
How does it compare to SOC knowing that some patients were does in 2011 ?
That's the essence of the spreadsheet. Do your DD and you will find out that there is a significant discrepancy between SOC and actual observed survival
Fosco
Sushi, I am so glad we share the same view and timing, I was expecting the "spring review" of IDMC
The key question is about what will the IDMC have "for their eyes only"this time.
We know what they saw in 2014 : nothing much of interest and significant by the statistics as very few events had happened to be able to draw any conclusion on survival
We also know what they saw in 2016 : nothing significant as well
We don't know what they saw in 2018 but it was looking good enough to remove all the holds
Based on several simulations, whether 5Y observed SOC survival would be 43% (as stated by Cel SCI), 50% or even 54% (as per my survival model), what should the IDMC see now is a huge difference in deaths between the two arms. For ethical reasons they should urge FDA to grant its approval for this drug
JMH of course
Fosco
PS : I would be happy to keep the good quality of this board and it would be great if we could avoid any "yahooization"
----duplicate----
well I hope so ! Thanks alexander-johannes !
Btw, other thing (from the spreadsheets) : each months that passes without news means 0,75% better survival for the group, eg potentially 1,5% better survival on MK test group than on SOC arm.
From my models, 10% better survival in MK arm would have meant 298 reached in January. 298 reached in October would mean 25% better survival.
Hi
These are very good questions and I have no authority to answer you, only can make assumptions
One thing is absolutely clear : the 298th event has not been reached so far by any count and that comes from the word of the president of Cel SCI in all his latest interviews. He may have not the obligation to declare it as a material event (8K) _this I am not sure_ but if he states that he is waiting for it, then this means that it has not been counted by Cel SCI.
lol... or we'll end up still waiting for end of phIII in the grave
For Yank, I promise not to brandish my spreadsheet again... unless new excitings developments & news from Cel SCI or strong sollicitation from a rich billionaire Qatari friend of mine (both events eventually linked 8)
Frankly speaking
It would help a lot that they would communicate :
- approx number of observed events to date (we know that the do monitor this number)
- a confirmation of the initial pool of evaluable patients (is it 794 ?) in both arms
This would allow lots of people, and not only on MB, to compute the figures and confirm that current pace of events is a really good sign.
- I would like eventually to understand as well why they are blinded. There is no reason, the criteria for success being patients survival, there cannot be subjective bias to the study caused by the investigator
With Cel Sci past history, every thing that seems to be concealed looks suspicious unfortunately and a bit of full transparency could be salutary for a change !