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Echo20, FDA has shut down US market production at some Dr. Reddy's plant's due to GMP violations; bacterial contamination and inadequate testing. It is my belief that IPIX replaced Dr. Reddy with Evonik.
If I were IPIX I would avoid Dr. Reddy like plague carrying rat. That outfit spreads deadly shutdown-due-GMP-violations disease: "Welcome Walmart shoppers. We are happy to inform you that our Dr. Reddy Pseudomonas sp. contaminated acid reducing pills are also useful to bioremediate mustard gas-contaminated soils if need arises. Gas-Ex can't do that!".
Ahah, another in need of educational reading. Italian's put out presentation: KEVETRIN: PRECLINICAL STUDY OF A NEW COMPOUND IN ACUTE MYELOID LEUKEMIA more than a year ago and are continuing the study.
Still laughing. Thank you.
Bertolino or Harness would have understood the amount of work required from the get go. Also, all questionnaires have been in ClinicalTrials.gov filings since Oct. 2016. They were not a mid-trial change in protocol. BUT ...
You may not remember that this was discussed before: prurisol 2b trial enrollment got very back heavy. Original primary end date for the trial was June 2017, but enrollment reached only 70 % by mid-May 2017.
Heavy backend enrollment also meant delays on gathering and processing trial data. I would not be surprised if IPIX started to put pressure on CRO by Q3 2017. That may have backfired and created a mess --> CRO adds workforce on prurisol trial --> additional workforce may have been inexperienced with the type of trial --> something got omitted or mishandled --> reset data processing.
Of course this is just my opinion, but it is based on reading about problems associated with CRO:s. Most complaints are about what happens when CRO:s do reduce cost by
1. Assigning less educated plus less experienced and hence a lot cheaper persons to do tasks they are not yet qualified.
2. Compressing time allotted to process and verify data.
Disasters happen with the above recipe. BTW, big money pharma tends to keep crucial trials in house and hand "Mee-Too" stuff to CRO's. You should be now able to guess why.
If I am correct it does not necessarily follow that CRO just re-processes the data and delivers it badly late but in good condition. It all depends on at which stage of data collection the errors were made - there may or may not be a permanent data loss.
Remember to bless FDA in your evening prayers. If my memory serves me, FDA still requires that all site trial data is preserved (locally) for some years after the trial - there is hope.
Amazon has plethora of small hydrogenators under $200. I have a dear friend with Parkinson's, so I got curious also.
I think you forgot that slcimmuno was talking about $20M plus hefty milestones and royalties. The value of the deal could still be in the billions with hundreds of millions in milestones like FDA approval. Going rate (2017) for phase I/II stage drug license is about $20 to 50 M upfront. IPIX does not have the time (running out of funds) to push for the high end upfront payments.
It would do no good for CRO to participate in delaying bad results - might put them out of business. A situation analogous to familiar No Pesos - No Tequila might be a reportable material event for IPIX. That leaves problems with completing and/or analysing the trial database, and those can range from harmless but time consuming transfers between investigators and CRO to absolute disaster. My vote goes for freewheeling investigators practising delayed responses against comma hugging (not the verb of my first choice) CRO.
Thanks for the article. I assume also that Brilacidin -OM, -UP, -UC, -IBS will be the main deal target. But I suspect that IPIX may want to keep prurisol in house, if p2b is successful. IPIX has managerial talent in dermatology/psoriasis, Bertolini and Harness. Let them loose with prurisol.
MackG, I don't know that. They may have needed Evonik contract just get into negotiations - to show that there will be no problems in the supply chain.
I would argue for bit longer time from term sheet, close to 6 months if the buyer happens to be one of big pharma (corporate inertia - I have experience on that). With smaller partners it could go fast, especially if only Brilacidin is involved. Trial analysis is done, supplier is lined up. Leo probably feels that he will need new source of financing in place before the end of this year. I think he is willing to consider mostly delayed gratification - risker royalty heavy deal with around $ 20 M upfront (wild guess).
And that's about all we can say with some certainty.
Let's stretch things a bit. I came across some case studies that may explain why Leo went and made Evonik deal. The buyers prefer to have API supplier in place instead of spending time in hunting down one after the deal is done. It also saves them from some rude surprises: In one case the previous (and the only known) API supplier had discontinued the production. It took some unanticipated months to get production in place.
And, yes, it's rare to see details beyond the upfront payment and the estimated total value. Royalties are usually given as "in high teens", "in high single digits" etc, if at all.
I don't deny the possibility that you are right. I am even willing to say that it is more likely than not.
Nice that you still use word 'appears'. There are few things about this sale business I can't neatly reconcile into $ 0.25 share price. However, I think that going back and starting the argument again is fruitless. We'll see what is in the next 10Q - you are free to call me bonehead then.
I think so. It's 12 month spread from 6 to 18. Ffrol says that IPIX may have been in negotiations as early as in March, maybe. Then it depends on how complex the negotiations are: B only or B+P, which indications, how development responsibilities are to be divided, payment structure etc.
if IPIX got to term sheet stage in March then it would be reasonable to except some sort of news in Q4 or later, unless they do a real 'quickie' involving Brilacidin only and with minimal contention about details.
Thanks, S. That was interesting reading. Looks like the rising deal fall thru trend will be forcing sellers to accept smaller upfront payments and hence more risk. By your document IPIX would be in $ 20 - 50 M upfront payment range with drug candidates at p1/p2 development stage. Leo may have to be content with less. I am guessing, of course.
As you know I don't share, yet, your (or LR's) certainty about the sale not being governed by the Agreement. But I would not be shocked if I am proven wrong.
And none of us should be expecting that the deal is just around the corner. I did some googling about the duration of pharma license negotiation - very little info available. Based on sample of 4 mentions I would hazard this about negotiation times:
fastest time to signed agreement - 6 months
average time to signed agreement - 9 to 12 months
longest time time to signed agreement - 18 months
Time spent seems to correlate with the complexity of the negotiations; that 6 months was for a single compound in a single 'indication'. My not so firmly founded guess is that if there is going to be a licensing deal we will hear about it well after prurisol results - but been wrong before, why not now.
Anticipated negotiation times may also explain some of the cost cutting done by IPIX, they need to be prepared for long negotiations.
I forgot to add that I do agree with you about asking clarification to April-May stock sale statement in 10Q - it is public info as is the purchase agreement (found by Karin).
Understood. And wise answer, BTW.
LR, why are you wasting your time posting about false statements in 10Q. SEC has a tip line just for this kind of stuff. Be hero and use it.
Thanks, KarinCA.
Blues, FDA has at least 20 years of history of approving drugs based on other than superiority in so-called primary measures. Do yourself a favor and read this FDA approval document from 1998 considering topotecan for treatment of small cell lung cancer. The results that clinched the approval are on page 21.
That 7B sales prediction for prurisol is not impossible. Let's consider psoriasis alone. Global market for psoriasis drugs is probably about $12 to $14 B.
If prurisol's PASI 75 response will be around 50 % it would be likely that P would become standard of care in first line psoriasis treatment. And as a standard of care capturing something like 50 to 60 % of the market is not impossible.
But there are some obvious caveats
1. Will P get to PASI 75 response 50 % is the big time ?????????
2. There is a built-in assumption in the above pricing logic: it assumes that prurisol would be priced at current price level for psoriasis drugs, including biologics. I don't know if that kind of price is attainable or even desirable. There would be all sorts of resistance.
I Agree. It looks like Brilacidin and GC4419 are about equally effective. Galera's thru 60 Gy is a brand new per protocol category invented by Galera, ignore it. GC4419 full radiation treatment numbers probably get some additional shine from
1. including subjects with slightly lower cumulative radiation dose than was the case with IPIX, 50 Gy vs 55 Gy and
2. allowing the use of certain antifungal treatments, if the trial protocol was unchanged from the one used during phase I.
For full 7 week radiation treatment
Incidence rate GC4419 : 43.4 %
Incidence rate Brilacidin: 42.9 %
Median time to onset GC4419: 61 days
Median time to onset Brilacidin: > not reached
Median SOM duration GC4419: 1.5 days
Median SOM duration Brilacidin: 0 days
Correction to my earlier statements (I ignored the possibility of censoring until now - so stupid):
It seems to me that GC4419 medians [see 1 below] involve substantial censoring before trial day 60. The reported incidence rate of 42.9 % does not allow for any sort of median time (per ITT) unless censoring is present. For comparison, Brilacidin trial had 1 censor before day 60.
[1] GALERA insist that they are reporting medians. I have my doubts about the duration of 1.5 days. But that is minor. As a whole reporting of SOM trials is an art form I have not encountered before.
That said, the major difference between GC4419 and Brilacidin is the method of administration where Brilacidin has a clear advantage. Issue of tolerability may be another where Brilacidin has distinct upper hand - censoring hints into that direction. But, things can change, if GALERA can show, as it is aiming to do, that GC4419 will also reduce cancer recurrence rates. GC4419 converts radiation created superoxide to hydrogen oxide which is, supposedly, not well tolerated by cancer cells. So far no evidence of rate reduction based on phase I trial. It is too early to say if p2 is showing anything.
Pete,sorry about that U. I should have written "inverted U shape" response to dose increase: low - high - low. So rare in psoriasis trials (even the one reported is mostly due to bad analysis) that I would not worry about it.
U shape dose vs PASI 75 response curves are rare. I know exactly one: Can-Fite's piclidenoson managed that with doses 1mg-2mg-4mg BID, the best and only good PASI 75 response was with 2 mg dose. More common is saturation; after certain point PASI 75 response stops growing with increased dose. Taltz is a good example of that - no benefits from going over 80 mg Q2W.
The above in mind a conservative estimate for prurisol doses 300 and 400 mg is PASI 75 response around 30 %, or the same as for 200 mg. That is good enough.
Additional things working in prurisol's favor:
1. Prurisol's phase 2a response percentage ( ~32 %) was for sPGA 0/1 with at least 2 point shift. Historically PASI 75 response is about 10 % higher than sPGA 0/1 response.
2. PASI 75 and sPGA 0/1 responses for subjects with moderate to severe psoriasis are usually higher than corresponding responses for subjects having mild to moderate psoriasis. This has to do with how both these measures are constructed.
And the thing making me a bit jumpy: we have only one good data point so far, at 200 mg dose in a small trial. One point does no trend make - could have been a fluke, although I have some good reasons to believe that a fluke is not in the cards. We'll see. Soon. Hopefully.
Whoa!!!!, Kim Papp. A HUGE (sorry, I am stealing your style, Mr. Current Resident of White House) name in psoriasis research.
TIAB, what I have found about the time from inking a CDA to signing a deal varies from 6 or 7 months to 18 months. The quickest deal I came across was for what looks to me like one freaking food additive and even then the negotiations took about 6-7 months, from mid May to December. And it is not clear if the article about that deal considered time under CDA as a part of negotiations. Your source could be right, as far as I can tell.
As to P results, I can't fathom any reason why the announcement of P results would be tied on B deal. The other way around, yes - no deal before P results are known, especially if P is included in the deal. It would make sense to IPIX to wait P results even if P is not included in the deal. If P results are crap (as you assume) then, for IPIX, there would be fewer immediate money burn targets. If the results are good then IPIX might want to see bigger upfront payment and try trade that to reduced royalty or milestone payments. Big royalties are nice, but one never knows if or when they start flowing.
Mark this warning: I am but one of those SS's uninformed schmucks with tattered shoes. But boy, am I glad that The Superior Soul is not yet in the Y's with his dictionary research, I resent being called a yokel.
I thought it might be beneficial to our communal mental health to have some diversion from constant bickering over the fate of prurisol trial, the degree of criminality in Leo's acts (or should I say Acts of Leo) etc. So, here is what I currently know about drug candidates for treatment of severe oral mucositis.
Some comments.
SOM Incidence Rate:
1.The inclusion threshold for cumulative radiation dose into oral cavity varies between trials: For Brilacidin and Dusquetide it was 55 Gy, For GC4419 it seems to be 50 Gy, and no reported threshold for the rest.
2. In case of GC4419 the comparative values to others are reported as last RT, or thru last radiation treatment – thru 60 Gy is Galera's invention for per protocol analysis.
SOM Duration:
1. In general duration numbers as they are currently reported fall well short of useful. This is amply demonstrated by values for Brilacidin and GC4419. When incidence rate is below 50 % then median duration per ITT is bound to be ZERO - effective reduction of incidence masks what is happening with duration. It would be far better if durations (median and mean) were reported per number of subjects experiencing SOM.
And that brings up the question: What the hell Galera is reporting? It can’t be median duration per ITT because: A. Incidence rate is below 50 % B. Non-zero median below 3 days is highly questionable, because the typical minimum number of days between SOM evaluations is 3 days. I suspect Galera is reporting average duration of SOM per ITT. In that case average per subject experiencing SOM would be 4 days – and that makes sense.
It Would have been nice to see Galera report onset and duration also thru last radiation treatment. But one can apply ‘TIAB’s principle’ here – delayed or omitted values mean bad or at least worse than reported.
2. That stupefying 3 days median duration of SOM with placebo reported for Brilacidin trial is a reflection of low incidence rate (60 % which is bested only by Galera’s thru 60 Gy group) and low number of subjects – the subject with 3rd lowest duration of SOM happens to be the median subject in prurisol trial's placebo group and he/she shares the duration value with the subjects having 1st and 2nd lowest durations, at least.
Feel free to draw your own conclusions.
I would say Aspire is holding a substantial portion of those 8 million shares. according to Yahoo finance total volume of shares sold since April 1st is about 9.85 million shares.
My guess is that Aspire may be responsible for 3 million shares sold, at best, during that period.
Can't leave that business solely on your shoulders! Besides, I am free to speculate - Leo is less so. I understand Leo's silence about the delay even if CRO has communicated something about its nature to him. What would it help to announce that:
"We are waiting for the final responses to our FDA mandated questionnaire about changes in libido during the treatment."
If 'Chicken Littles' of the investing crowd start immediately running around and screaming:
"Told you so! I DID Tell you so! Didn't I tell you so! Sure I did! DO you HEAR ME...ME... MEEE! IPIX's prurisol is so totally screwed by lack of libido!"
I agree with about there being issues. I am not as sure as you about the seriousness of them.
We should keep in mind that prurisols phase 2b trial is different.
505.b2 approval pathway makes is it far more important to get all protocol details right than would ever be the case with normal phase 2 trial. Why? There is a distinct possibility that the trial is enough for approval even with mediocre (~ Otezla) results for efficacy. Phase 2b reportables were selected this possibility in mind. They are covering all possible bases when it comes to approval, including quality of life.
My guess is that CRO's marching orders were to aim for perfect data collection. Perfect will never happen, but even getting close will take time. So, the delay is not necessarily because of inconsistencies in data (thou that is possible - some inconsistencies are always present), it may be also because CRO is insisting on getting all possible data in plus as many inconsistencies resolved as possible while the investigators are already into other things and slow to respond.
This is the first board where I have been learning several new expressions to describe my dumber trades. And I though 'ripped the seat of my pants on that one' was clever. Forever grateful.
Well, we can't say for sure, but it fits. One thing that comes across from the article is that CROs risk a lot if they start jockeying with FDA rules like adding data to unblinded clinical database. And that means to me: at the end of March the prurisol database was blinded unless and unlikely Leo turns out to be SEC certified liar.
And that could lead to CRO pestering investigators about finally answering to sent queries. It seems like, in general, the relations between CROs and site investigators are getting.. well... strained .
Pre-emptive statement so that TIAB can rest his typing fingers (I hear patients are starting to complain about Good Doctor's finger calluses): "But, of course, nothing like this could ever happen in IPIX trials. Leo is too crooked to let something like this to spoil his smoothly rolling fraud"
And a question in general: How do CRO bill their victims... er ... clients on this stuff. Probably the same way as lawyers do:
Billable hours for the month of April 2018.
1. Pestering clinical investigators: 400 hours @ $ 200 /hour
2. Thinking of asking a secretary to think of pestering clinical investigators: 50 hours @ 100 $/hour
To whom it may concern. Before you incite a bad lawsuit read this obviously absurd academic paper:
Competitive Algorithms for VWAP and Limit Order Trading
Actually, reading the introduction will suffice. Then check the text in September 2017 prospectus again. Do you conclusions if you are able. Have a nice day.