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@greens12
Tbh I do not think Leaps is/was primary focus of Cel SCI right now _ understatement_
This being said, I remember during the H1N1 Flu outbreak, I was given a list of biotechs with potential experimental cures and cel-sci was one of them. Funds and individual still have such list, and acted, I believe, more quickly than last time.
Just have a look at the https://edition.cnn.com/ news headlines
Last week alone, NVAX, this cash thirsty laggard, raised $100M due to the uptick alone ... and this is no pandemic yet... So everyone out there having a compound might beneficiate from it : pps for the short term and cash for the long one (whether through new dilutive public offering or by exercize of existing newly in the money warrants _ more than $40M in the case of Cel SCI if I remember well)
@lightrock
From CT :
"Primary Outcome Measures Overall Survival (OS) in LI + CIZ + SOC vs. SOC [ Time Frame: 3 year ]
OS will be assessed using Kaplan-Meier life-table and compared using a logrank test ..."
This simply means they will assess differential in the two curves through logrank test. The logrank test will say whether the whole curve (not just at a given time) are significantly different under the protocol hypothesis (Effect sized derived from their 10% superiority assumption). The "time frame" is just an estimated time frame. Log-rank test is meant for comparing overall curves.
From this document
"Comparing two Survival Curves: the Log-rank test
There are many circumstances when it is required to ascertain whether or not there are differences in the survival experiences of two groups. A naive approach would be to choose a time, e.g. 3 years, work out the proportions surviving beyond this time in the two groups and compare them.
This has two disadvantages:
- First it is difficult to define the proportions in a way that is both efficient and unbiased, largely due to the presence of censoring
- Second the choice of a time (such as 3 years) is arbitrary and it is potentially misleading to compare two survival curves at a single time
The log-rank test overcomes the problems of censoring and overcomes the problem of comparison at a single point by comparing at many time points simultaneously."
Now, how will they assess the 10% "superiority" mentioned many times by Geert but not at all in this CT site ? There is no way to calculate an "average survival superiority", only at one point in time (such as median survival). So it is not really a survival superiority that is measured, it is rather the "less death ratio" the hazard ratio with gives the effect size of the test group and is supposed to be constant at each point in time under the KM maths hypothesis.
- By sizing the sample (298 events) using the required effect size, if p<0.05 this will mean that logrank test has detected at least such overall effect size.
- They will calculate the hazard ratio which is "the commonest estimate of the difference between two survival curves", and provide a confidence interval : the more sample size is high, the more the measure of the harzard ratio will be narrowed to its true value and the effect size convincing for the FDA to approve
indeed, pure hunch / opinion
I know it is controversial, but we'll see soon enough and I hope I am wrong, I would prefer the real thing to be responsible for this run up... but ok, doesn't hurt either ...
Fosco
Hi
you guys will hear more about SARS in a few days / weeks
then you'll understand why current run up is linked to it as some smart funds are playing coronavirus fear,
then you'll have a communicate from Cel SCI who will find some interest into this,
Not sayin' it will be the only interest, but just an opportunistic one
Jmho but mark this post
Have a good WE
Fosco
PS : regarding the early termination posts : no way it can happen whatever the effect size. This is an event driven study, you need to wait for 298 as per the protocol, even if early significance is reached with limited sample size, pharma need to stick to protocol as agreed with FDA. There is no such thing as 3 year measurement of efficacy or survival. It is all about having p<0.05 with sample of 298 events, eg logrank test on survival curves which is measuring the gap between two plots of data, if you stop earlier you are breaking the protocol, reducing the sample size, increasing the standard error which gives an estimate for the efficacy etc...
Guys
Sorry for being a contrarian,
I might be wrong but I think yesterday's push was due to SARS speculation. Traders are early this time !
See this article
NVAX jumped 70%. 10 years ago NVAX had a Market cap of 7 billion due to flue speculation (now 300M)
We have now two reasons to be bullish !
Good day all
Fosco
GL
I think you have been given enough links to make you own opinion
Fosco
on investing. This focus on Aegis is secondary to fundamentals.
As for the fundamentals, I mean the real fundamentals of the company. We know this company has no earnings, so we are not talking about Boeing or GM. This is biotech.
Why is this trial lasting forever and patients that should have passed away years ago have not. This company is manufacturing a drug. Is this drug healing ? This should be the fundamentals you should focus on, but JMO
GL
Fosco
Hi There and welcome
So what's your methodology for investing Fung ?
First you seem to be interested in investors base as I can see. Aegis is just one of them that brought limited supply of cash lately with 0 risk for cel sci. CVM could have raised much more with pps near 10$ but they have not. There should be enough cash to be able to reach endpoint without additional funding required. Btw, indeed cash is brought through dilution but with current pps it should be contained.
Are you interested in fundamentals ? Therefore you should read the links that have been provided to you. Because they reflect the most advanced DD basis you can rely upon.
As a newbie on this stock, you will discover things that will horrify you : we've been through this and survived. But if you are can overcome this, you will find that the reward/risk ratio is absolutely unequaled as, if successful, this compound may make of CVM a potential B 15$ buyout. Try to simply focus on the bottom line : the fact that patients in this trial have so far a survival expectancy of 60% at year 5 VS 37% on SEER cancer database american benchmark should be your compass
GL !
Excellent Sushi !
Must have required substantial effort to get through editorial review, but will be extremely useful for newcomers.
@exwannabe
Good remarks, but you need some updates, as obviously you have not been following the whole story !
Congrats
Thank you so much
I am impressed by your simulation. it is very thorough, drilling down to log rank test...wow...
I love the fact that you considered as well the minimal survival time as indeed it is a factor of bias VS known soc baselines.
i am happy my own median survival improvement with my simplistic xl model has shown a 28 months improvement close from your 24.5 median
This is the ultimate tool for survival analysis !!!!
Thanks for the info Static
All the best for 2020 guys !
Thank you Sab
Merry Christmas to you and your wonderful family
Confirmed today.
This is a very small dilution (606,395 shares) at a very good pps 9.07
Isn't it a Christmas message of hope and confidence ?
exactly ErlsKoffie
You can't run a startup without money
and I would add you can't play on dice the 298 might happen overnight while you have just enough funds, while at stake is the future of a hundreds millions venture !
I understand frustration as pps was on the rocket launchpad....
However this was unavoidable. Questionable could be the timing, why now, and not January ?
I wrote this on yahoo MB :
No later than 6 days ago, based on cash on hand and the fact that the 298th event has not come yet, I explained why Cel SCI would probably need to raise some cash prior the end of the phase III
This was also announced in the various seeking alpha blogs I and North Shore Research (eg Sushifishman) have written like this one back in July
“We expect a cash raise in early 2020 of about $10M and at the current high share price, it will not be too dilutive.”
Now I hear voices of 1) surprises, voices of 2) concern and also 3) bearish voices regarding today’s announcement of shelf offer.
1) Surprise : again, this was expected. The timing before Christmas while pps was going up might be a little surprise as there was still cash at least till end of Q1, but I guess Geert (and the investor) had their reasons. Some have said that manufacturing adjustment required for mass production would require more cash than usual operations.
2) Concern : a few millions shares (I expect no more than 1 or 2) more will not dilute much and should bring enough to pursue operations till end of Q3 (7 to 15 M $)
3) Bearish : We don’t have the details of the offer yet. As I expect the 298th event to happen by early Q1 2020, and end of phase III to be announced no later than end of Q2, I do expect this offer to be calibrated to cover sufficient costs till end of phase III is announced, eg a small dilution. If it is a small dilution, this will be a clear sign the management believes they will be able to raise much more capital after the announcement. Let’s see what happens and the bearish sentiment might turn into a bullish sentiment
Take care all and Merry Christmas !!
Fosco
duplicate
Interesting approach Biobonic using WHO data
I remember back in march we counted about 62 clinical trials happening in developing countries and we found a few studies (bulgaria, thaïland) showing disastrous survival curves. Survival is indeed worse there than in the US.
Now the key question remains, as those patients are not treated like the average Joe, they should have a better treatment and follow up through this CT. Therefore survival should be better than their national benchmarks. Also, when including patients, MDs will naturally discard those who have only a few weeks to survive in order to be able to complete the therapy. This should improve the early years survival score.
Should it improve so much survival as too explain sub-normal observed survival pattern in this CT ? I don't think so, but only the unblinding on the data will confirm.
apparently "till completion of the trial"
"Cel-SCI estimates it will incur additional expenses of approximately $4.5 million for the remainder of the Phase 3 clinical trial."
8.4M should be more than enough, therefore, lol
This being said, who believes in their estimate ?
I am not sure I can believe 4.5M from 1st of October till end of pHIII announced and data unblinded. That leads us to end of this year.
Now pps is going higher : is the market feeling the heat (at last) ?
"Should I be using the logarithmic values from the 1st tab or 2nd tab on your spreadsheet?"
Tab 2 is the survival for the exact inclusion criteria of this trial
But your question is what survival curve will be right for this CT.
That's the 12 B question.
We don't know how the patients will react in the clinical trial. Their survival should be better in this CT than from their national benchmarks because of better care and follow up than than most of the countries patients. Now the SEER data is from the US only, national should be really bad, SEER better, clinical trial better or same than SEER ? ??? How much better ???? Time will tell
Hey, thanks for mentioning the source
I agree
Furtheremore we have a hint of the dropout rate Geert has used as a bonus. It has to be around 15%
More importantly, the Success Equation Table says the first line for SOC survival implies an almost certain success
George
pleased to hear from you, it's been a while
I believe we are very close from it, but under 298 according to the actual count for sure.
Geert said they might have news from events from last year, because chasing for death certificates is not easy, that will add to the current count.
So indeed last few events to fall. Likely January will be a key month, and then they will analyse the data
I don't know how long it will take them, but count 3 months and we are there till spring.
In the meantime, god only knows what kind of communication we'll get from Cell SCI
Biobonic
Thanks for the links and in general for your research efforts !
Late to the party ? Your question is legitimate and indeed we asked it to ourselves months ago because some sources showed very strong survival. Some sources also show a pattern of improvement over the years while Cel Sci claims therapy has not improved.
These questions were addressed months ago and definitely solved
In any case no pb I will answer you with our findings :
First you need to identify staging and location of the tumor. This is well explained in
CVM CT inclusion criteria
However we needed to dig further eventually through calls with Dr Talor to conclude definitely.
So job was :
- First to understand deeply inclusion criteria
- Then find a reliable source of data from which we can have survival using those inclusion criteria (and no others)
This was done first by myself using SEER db
And then Cel SCI used a specialized team to do the same and they concluded basically the same thing (even a few % worse)
Results are in this folder of my spreadsheet
Important things to note :
1) Base of Tongue cancer is excluded. BoT cancer introduce a strong heterogeneity in the survival stats as it is much more curable because much more infected by HPV. Most figures for HNSCC found in the net include BoT cancer and are over optimistic. The unique reason HNSCC OS as improved is because it includes such zones which show a better survival through years, mainly because of the HPV resurgence (highly curable).
2) Look at "observed" and not "relative" (or "net") figures : relative survival is slightly better
3) Cancer population include the Stages III and IVa. IVa is more lethal and IVa population should be more numerous. Therefore observed OS should be a blend of both with a predominance of IVa
Now with this in mind, to you think it complements the documents you provided ? It should not contradict.
Hope it helps
Fosco
Hey
no pb
the reason I mentioned you is precisely because I would like to see how if becomes viewed from a different angle
And, its not much about disagreement, rather a difference in analysis.
Fosco
yes I agree, that was intended in the following sentence : "Did not show up during part or totality of treatment", i'll make it more clear
"Success Equation table"
I added this table in my blogpost in SA
This is the magic equation that will make us extremely wealthy or grinch for the rest of our lives.
It assumes 298th event is reached by mid January
Have a good WE
Fosco
PS 1: Please don't ask me how it was computed. This is a secret recipe, such as Multikine Formula !!
PS 2 : I am sure Mogles and Lightrock can produce a similar output
mirheydar:
May-be you saw my comment to your previous (deleted) post
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=152486148
Hope it will help
Fosco
Last visit doesn't mean that events won't be still followed otherwise the trial would not be event based !
How are events followed after "last visit" and site closes ?
Is there a "master site" or by the CRO directly (public death certificates)
I do not know
What does those figures really mean VS real dropout rates (those whose deaths can be tracked in the end) ? I suspect they are higher
Fosco
Thanks Myrheydar for the link
Indeed 22% at year five is not so terrific, there is 26% in one arm, 20% in the other (we don't know which one is the test arm)
Looks like we have a 4,5% pattern per year
As a record we are approaching year 5 in terms of weighted average year since enrollment.
Like I wrote, i believe that lost patients (by the site) can be retrieved by their death certificate for primary enpoint specifically.
Nb that dropouts are contained probably under 15% at year 3 (eg when closer follow up is required), and then we can probably stay under 20% with death-only follow up (my previous post).
Under 20%, we should be ok provided soc is staying in its not too good overall survival territories
GL and good day all
Fosco
Biobonic
That's really an interesting work your are doing, you are around 10 / 12%
Now remember, for metastatic cancer, where median survival is of a few months, there is probably a lower dropout rate. Patients just don't have materially the time to dropout.
For trials that last for years the dropouts rate is probably higher. If you count a 4% dropout rate per year, CVM trial is currently at weighted -at 4.6 year of treatment so that should make it above the 15% mark. It is not hard to imagine 4% of patients dropping out each year. I wonder how long the trials that you mentioned lasted. Now that's the CONS of CVM trial : too long. The PROS is that like I mentioned, once they have followed patients for 3 years, the only thing to follow is life or death. This can be done even if you don't have to call or be called by their relatives, through, for instance, the countries death registries.
TBC by Cel SCi : how do they track deaths once : 1) Sites have closed (and in this case who is tracking) or 2) Patients are not showing up or both
Indeed a key variable Sushi
In the sense that IDMC won't complain if the number of dropouts do not jeopardise the power of the study (but it would be needed huge to jeopardise the power of the study, like 60%)
BUT
a high number of dropouts could explain (in addition to a better SOC than expected) why study is taking so much time
We can't know well at this point but speculate
This a text I wrote a few days ago :
I would add, how they assess ultimately an event is a question mark. Many sites have closed, (1/3rd if I remember well), which means that patients events are not followed anymore by the site but still followed, probably by one of the 2 CROs.
Some of those site did use to report (either internally either through a public available report) how many patients were followed or lost for follow up. Still within those "lost for follow up by the site" or "site closed" the CRO could still follow the event.
Interesting to note that there is room for interpretation to what is a dropout : a patients who has been lost for follow up by the CT site (which we don't care much after 3 years because all secondary endpoint data has been gathered) or a patient whose outcome is totally unknown by the CRO. Patients might be unknown to the CRO until they die. Therefore we can tell with certainty that he was well alive before we knew of his death (through the country registries etc...) . But what about the others ? Those who we don't know if alive or dead ? They are a "potential dropout" if they are never reported dead, but as soon as their death date is known no more a dropout.
That's why I think real dropouts should be contained, because finally, appart from the Inventiv mess which we don't know exactly the impact (and is not to be forgotten in our dropouts assumptions), the data from most of patients should have been gathered in the required critical timing (3years) it was required for secondary endpoint, and few in the end should escape to be noticed for the ultimate data point, the primary endpoint.
ahaha !
Thanks
Thanks for this good recap Sushi,
Institution are emotionless, unlike the average investor nervously looking at the time passing, and fact is that the more time passes the more they are buying.
They waited till the very end of the phase III, index effect impact sure, but not only I suspect.
That's a good sign to add to others : IDMC, Strong management optimism and $$$ commitment, patients not willing to die and not dying.
I hope we won't be disappointed and got, at present and till D-DAY, 26K reasons to hope this, adding to the joyful prospect of meeting my friends at the millionaires club.
Good day to all and bless you
Fosco
Sab
all credits to Sushi
No Fosco involvement in here
Take care
ha ha ha good one M. Pijoe !
Have a nice WE
Fosco
and yes I do believe as well that we have there a combined effect of a better soc survival (than the standard SEER STIII+IVa), some dropouts and MK efficacy that make all together patients living longer.
There can be no other explanation for this observed survival duration where median survival is supposed to be much shorter.
Dropouts do not really change efficacy, and as you say they prolong the trial
but a better SOC than expected could prolong the trial
and a better efficacy in the test arm could prolong the trial as well
As you know, the trial is being prolonged as the expected end date was in the past.
So which effect had the most impact on the patients population of prolonging the trial up to the point that we reach 298 only in January 2020 (or 290 only in October) : soc, efficacy or dropouts ? The more one effect, the less the others are likely to be the effect that prolonged the trial up to where we are now.
Is it more clear now ?
There are various factors there playing plus and minuses
1) I have used a very conservative SOC survival as I have not considered stage IVa (like Cel SCI has) so in theory efficacy should be better as there is a 10% gap between my SOC survival and the one that should be used in reality. But may-be the dropouts should be higher so one should counterbalance the other (but not up to 10%). Consider as well a "clinical trial bias" which should add a few % of survival to the SOC as probably survival is better in CTs than in real life
2) Indeed other countries are worse except may be countries like Taïwan and UK
Can't say more, we are reaching the limits of the models.
Bottom line, IDMC said CT should continue and management is buying.
Fosco
Hi
This sheet is always accessible
Under its assumptions, we should be 172 (SOC) / 121 (Test)
Fosco