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I am adding some qualifiers to ffrol posting.
Assuming that phase 2b trial is successful and shows at least the same efficacy as phase 2a trial did. Then
1. Oral adminstration
2. More effective than most other non-biological treatments for psoriasis. Depending on the level where prurisol efficacy settles at, methotrexate (cytotoxin) or cyclosporine (IARC Group 1 carcinogen) might still be more effective.
3. With proper patient screening (some people are allergic to abacavir which is the main metabolite of prurisol) has few side-effects (definitely less than methotrexate, cyclosporine or Otezla) and, so far, no evidence of immunosuppression which is the major concern with almost all biologicals.
4. Currently no evidence of the loss of effectiveness over time.
Sure, at least I can try. First, it is my belief that PASI 75 response needs to be above 25 %. Second, if prurisol PASI 75 response is about 25 % then placebo PASI 75 response should not exceed 15 % for p value to remain below 0.05. That gives us response ratio of 25/15 or 1.67. Hence, with the headcounts IPIX has in phase 2b trial failure is very, very likely if the response ratio prurisol/placebo falls below 1.65 (approximately). It think it is neater to say it this way than playing with percentage ranges.
Yes I am. That is my best estimate, but we both know how inaccurate I can be :).
KMBJN, I agree on both points. One 'questionable' refinement though. In terms of confidence limits for sPGA 0/1 shift 2 proportion (sPGA 0/1 for short) in prurisol p2a trial. If we assume success being sPGA 0/1 score 25 %, then one can say with 72 % confidence that based on the sample used in prurisol phase 2a trial the 'true' sPGA 0/1 response proportion for subjects with baseline sPGA score 3 is above 25 %.
Using some ad hoc sensitivity analysis on confidence limits I concluded that the odds of failure of in p2b trial are from 25 % to 45% with best estimate of 30 %. Not that much different from you estimate.
Thanks for the links, untohim. Appreciated!
Looks like it. CoreRx is a commercial kilo lab specializing in clinical trial support but providing also process optimization services.
From today's pr: " for formulating Brilacidin into granular form in unit dose sachets." For now the contract probably means work on formulation. It makes sense to have that done under ANY future scenario.
First, Leo is not doing the analysis. A statistician is doing it. Probably one working for CRO. And, yes, he/she is putting data into subsets, doing a good number of exploratory analysis, evaluating effects by outliers and doing other sensitivity analysis. When all is done he/she will put all that on writing and send it over to IPIX. It is very likely that we will never see most of his/hers output.
Read this when you have time. It gives you an idea how extensive statistical reports usually are.
I agree. Statisticians were getting marinated with alcohol and well done last week.
My guess: in this case 505b2 pathway probably applies only to long term safety and does not free IPIX from doing some dose vs safety studies.
Not really. I did some buying in order to get my cost basis to more 'satisfactory' level. Even after that my current position in IPIX is nowhere near as large as some mentioned on this boards.
You should be grateful that I decided to keep some of my findings as 'tradecraft secrets' for now. I could have infuriated you to no end with central limit theorem and small sample statistics.
LR, I would not publish filing for BTD even if I were fairly certain of getting it. With FDA one never knows. Why take the risk. Most pharma companies seem to think this way.
As far as I know there is no FDA maintained lists for any kind of pending applications. Traditionally FDA does not publish details for applications (Oh, have I looked for them) only statistics. Approvals do get detailed publication, for now (my attempt for irony).
BTW: FDA is a great candidate for improved transparency. Most egregious example might be FDAs complete response letter , which FDA issues when rejecting an NDA application (Fool has a passable description without typical jargon). All publicity about it is left for the recipient. Even the existence of the letter ie. rejection of the drug application in its present form. You can guess how eager pharma Cos are to make that stuff public, especially small biopharma Cos.
Can you provide me a press release where some pharma Co announces that they have submitted BTD request? I have hard time finding one. How about a list by FDA providing the names of companies having a pending BTD request? That would do, also.
Absence of evidence is not evidence of absence.
You must be joking. See page 13.
I second slcimmuno. Typically milestones payments will cover costs up to and including commercialization.
Yes. I was aware of the abysmal history of mouse models vs clinical trials. I was hoping that there might be a clue how dose response curve behaves. No luck, as shown by BioDoc.
Thanks BioDoc. Obviously preclinical stuff is anything but my strong suit, hence absolute ignorance of mouse to human conversion formula. I am going to save your response!
This is my take from your answer:
1. There is therapeutic threshold for prurisol plasma concentration and it is somewhat higher than the concentration that can be achieved with 50 mg oral dose but below that from 100 mg oral dose.
2. Reponse saturation at 100 mg BID dose cannot be ruled out because we don't have even mouse results for equal or higher doses.
comment about tox:
600 mg daily max goes hand in hand with 8 mg/kg BID and 16 mg/kg QD dosing in pediatric use. Could it be that toxicity is no major concern with adult doses up to 600 mg BID or 1200 mg QD?
Biodoc, sorry late comment. I did not notice your post before today.
I would not call Loanranger's comments nitpicking. Detailed and meticulous- yes, but on topics that do deserve attention. And I say this as a person who has been the recipient of some biting retorts by LR. All deserved, as it turned out. I consider it a good education. Thanks, Loanranger.
Thanks for the link, slcimmuno. Interesting reading.
True. But he did not say they were late payments. A difference.
TIAB, where did Leo say that payments for CRO were delayed? Or is there any verifiable evidence that they were delayed? Your assumers are overheating - a cold drink recommended.
Baba Dane, with all due respect, the reason won't be adding the questionnaires. Those were present in the first ClinicalTrials.gov filings. My guess is that the trial just started to slip badly and had some issues with data collection (okay, could be because of questionnaires). IPIX realized that they are over their heads and dropped the managing of the whole shebang on CRO at mid-trial. And CRO did never have a chance to catch up with the original schedule.
I wholeheartedly second this KMBJN's post.
Just for clarification.
Any difference can be shown to be statistically significant with large enough trial. The difference between survival rates 67.0 % and 66.0 % at 24 months can be shown to be statistically significant with a really large trial (~ 40000 subjects). But is the difference clinically meaningful?
Conversely. Most of us would agree that 138 % difference in response rates is clinically meaningful. But it will not be statistically significant in a trial with 60 subjects. As we have seen in prurisol 2a trial.
Because I, too, have a pain in my big toe I feel entitled to answer.
In p2a trial prurisol 200 mg, sPGA =3 group recorded sPGA 0/1 shift 2 response percentage of 31.6. Historically sPGA 0/1 shift 2 percentages are about 10 % lower than PASI 75 percentages (sPGA 0/1 ~ 0.9 times PASI 75). Therefore, for phase 2b trial, one could reasonably expect PASI 75 response around 35 % if efficacy at 300 or 400 mg dose is what was recorded for 200 mg in p2a. This should be good enough for approval if placebo response stays below 14 %. Historically only about 1 out of 6 reported placebo responses have been above 10 % and 1 out 20 above 14 %. To me the chances look good.
Why one can think that p2a trial results are unlikely to be coincidences:
1. sPGA 0/1 shift 2 response was accompanied with sPGA 0 response percentage of 10.5 % which corresponds, historically, to PASI 75 and sPGA 0/1 response being in 30 to 60 % range. We have consistency of results in p2a, which is rare with placebo or chance.
2. Highest placebo sPGA 0 response ever reported is less than 2%. Highest sPGA 0/1 reponse reported for placebo is about 18 %. Either we have a record coincidence at our hands or prurisol p2a trial did show real efficacy. We can debate for ever about the REAL magnitude of the response. Did IPIX get lucky with prurisol response? If you think so, then you should also consider that 13.3 % placebo response is quite unlucky occurrence.
About small trials and p values:
As any reputable statistician knows p value scales inversely with trial size. What matters in small trials is the ratio of responses achieved, not the p value. Large trials are for showing statistical significance, small trials are for promising trend (ratio) detection. Prurisol 200 mg vs placebo response ratio reported in phase 2a is sufficient for statistical significance in a two arm trial having about 100 subjects. In prurisol p2b 300 mg dose arm and placebo arm are about 80 subjects, 400 mg arm is about 30 subjects.
This link is to very readable blog by a respected statistician. I recommend reading, at least, Statistic’s Dirty Little Secret and Why do we compute p-values?
Not commenting about Menon credentials, but Tom Frye seems to be only half wrong:
Emil Frei III, familiarly known as Tom, was born in St. Louis on Feb. 21, 1924.
Is that better than totally wrong? Dunno.
Oh, look, another falling for AF's selective truths. AF rightfully criticizes Leo for comparing Brilacidin enema to oral medication. Then he goes and compares Brilacidin enema to budesonide foam instead of budesonide enema for which clinical results are also available. One wonders why? Could it be that the best remission rate budesonide enema managed was 27 % . And don't bring up this study. It uses very lax (and specifically not approved by FDA) definition of clinical remission in UP/UPS.
And about that subject baseline not provided by Leo. AF's budesonide foam trial had subjects with mild to moderate UP/UPS. Next step down in severity is healthy.
There is a rule to be followed when reading AF's articles. If AF gets "personal" with management - check what he may be omitting and/or distorting. An Example of AF's reality distortion field in action (Sorry, S.J): AF once called doxorubicin an old and marginal treatment for STS. Old: true. Marginal, with < 20 % response rate: true. At the time of AF's article still the Standard of Care in first line for STS: true and omitted by AF. That omission sort of changed the whole thing. Don't you think?
Baba Dane is dispensing some serious wisdom. Grand collection of these will eventually be found in:
Collected Utterances by Baba Dane, The Founder of Viking Way Investing Ashram.
Of course only with permission by The Honorable Utterer Himself.
Yes. A fact in my books.
LR, and you thought that I am the thick headed one. LoL. I have been converted, probably friendly New Yorker will be also, in time.
I did not know that the moderator position was equivalent for guidance counselor. Somehow I thought it had something to do with keeping conversation here civil and at least moderately factual. Learning everyday.
Your assumptions and feelings have served you well. Fine, then keep trusting them. However, that does not make your claim a fact. Neither does reading between lines. Try that approach in court of law and see what comes your way. There they use this kind of definition: a fact is something that is verifiable with evidence.
"as management kept the fact hidden that the CRO wasn't paid"
How come this is now a fact? As far I know this has been freeform speculation on this board, but never an established fact. Leo writing that $2M from the sale of shares went for "clinical trials and production of Brilacidin does not imply that CRO was not paid. It does not even imply that CRO was paid late.
Thanks, slcimmuno. I was not aware of AntibioticDB.
If this closes above $0.40 I have no choice (in light of your previous prophetic post) but start calling you Baba Dane.
Baba (from Wikipedia):
means "Father", and denotes very great respect, usually also indicating the bearer's spiritual mastery.
LR, "top line" usually refers to primary outcome measures as stated in the study protocol (which we don't have, but importantly, FDA does) and usually also in ClinicalTrials.gov filing. In prurisol trial case, PASI 75 response and adverse effects.
Nice reminder that p2a trial press release. I expect IPIX will waste no time between data lock and releasing 'top line' results, but one week might be pushing it with this particular trial.
P.S. Next time when some financial conclusions pop into my hard head, I promise to ask you first if they make any sense. It clearly is better that way.
"Because I'm built for comfort, I ain't built for speed
But I got everything all the good girls need"
Should we then start calling him Howlin' Leo?
Maybe confusion is a product of several companies not bothering with press releases about data lock. Big pharma sometimes ignores even to announce last enrollee or last required observation/event. Then they sit on data until a suitable conference comes along (like Novartis did last year). Several drugs on market make stuff from a single trial very non-material.
This, of course, won't apply to small struggling biotechs like our IPIX. I expect Leo to rush topline data out while documenting every step on the way with press releases.
That would be the time of last observation(s). Then comes possible transfer of data from local storage to final storage, double check for errors, outliers and hunting for missing data. All with some time needed to poke investigators to submit/check their data. Only when it is reasonably certain that all available info has been curated to a T and entered into database comes database freeze ie. data lock.
In case of IPIX prurisol trial it is even possible that CRO polished data from later part of the trial first and then went to curate and enter data from the early part of the trial. It looks like CRO gained full control of the trial only after half of it was already done.
Loanranger straightened me out, as usual. Ofcourse he was right (and don't you dare to larf, ffrol); intentionally omitted is used in amended contracts to indicate a section not any more applicable. I should have known that. It is not so long ago when I was reading filed license agreement with most dollar values REDACTED.