Chronic, thanks pointing this out. I totally missed it after reading the filing, maybe, only 25 or 6 to 4 times. Shame.

ffrol, I did some tinkering with Galera's GC4419 phase I results and got a group of 19 subjects with dose at least 90 mg and treatment duration at least 5 weeks. I counted only SOM cases that occured before the end of treatment period. The group should be reasonably comparable to IPIX SOM trial.

Funnily enough - comparison with brilacidin SOM trial tells that B slightly outperforms GC4419 both in incidence rate and in delaying the onset. Add to that the fact that in GC4419 trial antifungals were allowed, which is rather strange because they clearly are confounding factor. Currently I have no way of knowing if this is the case also in GALERA p2/3 trial. And, of course, I don't know if antifungals were allowed in IPIX trial. I hope not.

Awyway, not bad for an oral rinse.

Chronic, I would not get too excited over reported or not reported duration of SOM. Mean and median durations happen to be the most frivolous measures used in SOM trials.

1. For unfathomable reasons SOM trials have adopted the way median and mean are calculated in survival trials and calculate both measures over the whole ITT population. When over half of the population does never get the ailment this way of calculating tends to give medians of 0 days and means of 1.5 days (as GALERA reported before dropping it as if it never happened) i.e. not very informative numbers. GALERA reporting 1.5 day mean was especially galling when the shortest observable duration of SOM in their trial was about half a week (subjects observed twice a week).

2. Also, from patient point of view there is major difference between 4 straight weeks (28 days) with SOM and four week period consisting 1 week of SOM, 2 weeks without SOM and, finally 1 week with SOM. Currently both get reported as 4 weeks of SOM.

I would prefer to see the duration expressed in actual days or weeks suffered from the ailment and only for subjects who got SOM. Then the combination of incidence rate and median or mean duration would tell us something useful.

Good question, S. I dunno. Leo's is one perplexing dude.

infinity I do agree. Just one minor point. From legal perspective Leo's putting in company's press release P trial being still blinded is important. Lying would be a big SEC no-no.

Rdunn, I wholeheartedly agree. But at least he put that blinded thing in there. Lying in press release is prosecutable financial crime and a prime bait for civil lawsuits.

BTW: if I were in Leo's shoes and in dire need to satisfy my communicating urges I would wax poetically about Brilacidin's potential (repeat, just potential) in ulcerative colitis:

Look here people: In ulcerative proctitis (also known as C.O.F.) trial B scored above 60 % remission rate by Mayo Disease Activity Index. That We Are Bozos Co over there is salivating over 30 % remission rate in thier puny ulcerative colitis trial. Just imagine what might happen when we get our stuff in your inflamed intestines. Just imagine! Now, go and buy our shares like maniac.

Leo's is soooo mediocre.

Suvorov, I tend to agree about not communicating about meaningless stuff. But you are forgetting Leo's reputation of doing just that. That man can't stand being silent for extended periods. Just like me.

Infinity I have questions to you.

Assume for a moment that you are a CEO of a small, disparaged biotech (assuming being anything small and disparaged might be hard for you, but please try) already ridiculed for his 'non-essential' communications. You are sitting and waiting for important p2 trial results. What would you communicate about that? That you are waiting the results with enthusiasm? How would that not be ridiculed?

Well, Infinity, maybe I went a bit heavy in memory of some rather difficult persons. But the point remains: Most of the time spent between final patient visit and report goes to ensure as complete and error free trial data set as humanly possible.

If you ever happen on FDA drug review documents you probably will find a section on missing trial data. It is almost always there and never a good thing. Electronic trial management systems are significant time savers, but as long as there is humans involved vital data will go missing and somebody needs to go chasing it. Takes time.

Infinity,
Most of the time is spent pushing arrogant, bloathead doctors (I assume you know the type) to submit complete data set from their site. Often they respond by submitting partial data and an email essentially saying that the rest is coming when they feel like it.

I do agree. My thinking is: if P2b brings in PASI75 around 30 % (or better) the likelihood for PASI75 then dropping below acceptable in a larger P3 trial is very low. Provided that there are no anomalies in p2a trial population.

Also, it makes sense for a potential buyer/partner to see if there is a base for nice dermatological franchise, P + B, before committing. Currently prurisols value is up in the air. Neither Leo nor the buyer can say what it is. That will change with p2b results.

Not really. Headcount needs to be over 5000 (like with Xeljanz) before some of us get that comfortable robusta feeling down there and over 10000 for arabica.
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I am speaking about THE GUT like in "My gut feeling is that the trial results are robusta, but not quite arabica." That's the only way I can explain the logic sometimes employed around here.

And THAT, being slightly dyslexic, I consider a blessing.

Sorry, but I am piping in to add some unneeded detail.

As Karin said phase 2 trial is done (mostly, purposes for phases 1 and 2 tend to overlap) for efficacy and side effects based on dosing found in phase 1. Numerous phase 2 trial for the same compound may be by design: a company wants to identify the best combination of dose efficacy vs side effects using a few trials with different dosing. Sometimes additional trials follow dosing related benign or not so benign 'surprise' findings in the first phase 2 trial. Possible examples for the world of psoriasis:

A. Both prurisol's and Otezla's first phase 2 trial employed too low highest dose which needed to be addressed in subsequent phase 2 trials. I am not the person to say if either company did this by design or not.

B. Xeljanz 15 mg BID dose showed great efficacy (PASI75 response close to 70 %) in a phase 2 trial, but it also showed worrisome number of side effects. Obviously 15 mg dose was in there by design. The company did proceed with 10 mg BID max dose.

'Market is not sure about pipeline.'

I dunno. To me it's more like the market does not know/understand the pipeline. IPIX may be in a pickle because only prurisol has comparable drugs from companies covered by analysts and commentators. With Brilacidin and Kevetrin the main competition is either in private sector (Galera) or foreign (Aprea) or both --> little or no knowledgeable coverage beyond occasional press releases.

Likeliest reason for silence: nothing to report

1. As I have pointed out before a company with much better resources than IPIX spent 100 days before reporting results from a psoriasis trial comparable in size to prurisol phase IIb (That would be Celgene with Otezla). We have yet to hit day 90 with prurisol. Nothing to report, unless you yearn Leo to publish day counters in an effort to earn biotech's dunce of the year cap.

2. Partnership negotiations take time and negotiations have this strange feature: there is nothing to report before an agreement is signed. Speculation in guise of 'known facts' or 'experience' is generally reserved for professional speculators and rumor mongers also known as biotech press and true believers. Unless, of course, you expect Leo to handicap going-ons in an effort to earn biotech's deal spoiler of the year award in addition to dunce cap.

True believer
definition: a person who is so set on his/hers beliefs that no fact to contrary penetrates his/hers abnormally thick skull. Hence, in colloquial vernacular a synonym to numbskull.

And probably larger clinical trial resources. Drop 'probably' - Celgene was already raking in Revlimid money.

And Look at that, still Q1 as promised.

Celgene Phase II (later renamed to IIa) trial for Otezla (apremilast), CC-10004-PSOR-003
Subjects: 260
Objective: evaluate doses 20 mg QD vs 20 mg BID vs placebo
PASI75 Response
placebo: 10.3 %
Otezla 20 mg QD : 10.3 %
Otezla 20 mg BID: 24.4 %
Conclusion: 20 mg QD crapped, 20 mg BID obviously warranted phase IIb with added dose of 30 mg BID.

But the really interesting stuff:
First Subject Enrolled: Apr 23 2006
Last Visit Completed: Feb 07 2007
Topline Announced: May 22, 2007 or about 100 days after the last patient visit. If this (IPIX) board can provide any insight then PSOR-003 trial must have failed around mid April, partially resurrected about May 1st (Labor day) just to fail again by mid May until the Lazarus day: May 22.

Were you failure whiners Celgene’s shareholders circa 2006/2007?

Thanks for this, cabel. I have a favor to ask. With you connection to Leo can you ask him if antifungal medications were allowed in Brilacidin OM trial?

It is funny how the belief that big pharma is aware of everything medicinal on the planet is so wide spread. I used to work there and I have news to you:

Relative to typical education and training levels in big pharma the density of 'lazy bastards' and 'sheer idiots' may be higher there than in general population> The density of narrowly focused minds and over inflated egos certainly is. A lot good to great science slips by because of that.

I agree. 400 mg is there mainly for dose response purposes.

Yooper, PASI75 data is from Celegene 'core study' PSOR-005 for apremilast doses 10 mg, 20 mg and 30 mg BID vs placebo. You find PASI75 scores also here and publication here.

IPIX has about 80 subjects both in 300 mg and placebo arms and about 30 subjects in 400 mg arm. Assuming that the placebo arm behaves and has a PASI75 response around 10 % then 25 % or better PASI response rate in 300 mg arm would be success in statistical sense (p < 0.05). 400 mg arm would require PASI75 response rate at about 27 % or better. Both very doable in my opinion.

Hello Frrol plus Infinity. Just for your info: the best Otezla phase 2b PASI 75 score at week 16 is 40.9 %. Happens to be the only time it has cracked 40 %. Happy betting.

I agree. Both Bertolino and Harness have excellent dermatology background and experience of running clinical trials plus dealing with FDA. Should bode well for Brilacidin and prurisol.

But who is running K development? Menon?

K, it's not quarteed that prurisol behaves the same way as Otezla or Xeljanz. It is still somewhat possible that the PASI 75 response at 300 mg turns out to be less than the response at 200 mg. That would make the current value at 200 mg to be an outlier in linear (straight line) response model. I don't expect that to happen, but ... well, nightmares are made of unexpected.

Giovanni, there were 19 subjects with PGA/IGA = 3 in prurisol trial. That does not figure in conversion factors. But it does give granularity to prurisol results - one reponder more or less counts roughly as 5 points more or less in responder percentage. And that is the reason why I have occasional nightmares. Thou, Otezla P2a (Celgene PSOR-004) was done with 30 subjects and scored about 30 % PASI 75 response. Not much better setup and slightly worse outcome.

Linear, yes. My only scary thought is if that darn 200 mg response for prurisol turns out to be an outlier! That did not happen with Otezla. It graduated from 30 subjects trial with PASI 75 response to 40 mg around 30 % to 90 subject trial with practically the same response.

This we do know about prurisol as of now.
While waiting prurisol P2b results I got illustrative, again. I took a look at some dose ranging and other trials for Otezla and Xeljanz. Results for that peek are below. Correlations (R-squared values) with trend lines are so nice that it looks borderline educational. Then I plucked in what we currently know about prurisol. Draw your own conclusions. This time I stick to illustrating data, also known as facts.



Don’t get excited about what I call normalization. It is just a trick making it possible to display all values on the same chart. The base values for normalization are the smallest doses for which I could find some clinical data.

Also, don’t get excited about Xeljanz dose 15 mg/day (normalized value 7.5) docs will not give that to you. The approved dose cap is 10 mg/day. After that things got too risky for FDA. The same goes for Otezla beyond 60 mg/day dose (normalized value 6).

Obviously there have not been 3 separate trials with prurisol 200 mg/day dose. Those 3 green marker rings at prurisol normalized dose = 4 are PGA/IGA = 0/1 response percentage for 200 mg dose by PGA/IGA = 3 subjects in prurisol P2a trial converted to a corresponding PASI 75 response range. Where did I get the conversion values? They are from 14 clinical trial arms for Otezla and Xeljanz totaling 3130 subjects. I did the conversion by multiplying prurisol PGA/IGA = 0/1 response percentage with mean + standard deviation (high value), mean and mean – standard deviation (low value) for the PASI 75 to PGA/IGA = 0/1 ratios in those trials. BTW, the values are: mean = 1.06, stddev = 0.19, range: [0.90, 1.52].

Greyish placebo response range [5 %, 12 %] is also from the trials for Otezla and Xeljanz.

Argh, on the level throw me off. But, anyway in a profession where openness and kept promises are greatly appreciated. Not in pharma, secrecy and misdirection rules there. It sort of has to be that way if you think that 'me too' science probably originates from there. One tends to find being carted to poor house for being too open.

I am making a guess here, govorchin. I get a feeling that your background is in engineering or similar discipline, not in pharma.

My experience is that there is no such thing as 'on the level' in pharma industry as a whole. Famous 'Neutron Jack' Welch is a choirboy compared with the carnage an average pharma CEO is capable of. And that includes lying to your underlings on their face. I guess it would be called presidential nowadays.

Lemme give you an example. Once I was listening our widely admired (means in professional press) CEO telling us that our division stays where it is, only metabolic diseases will recocate. "We will have a strong presence here for years to come!"

For god's' shakes, I had once nursed an elephantine hangover with that guy, a good, straight shooting chap! So, I went, put my signature on the mortgage papers, bought a big and costly house ... and less than 2 months after our division was packing.

Based on what I have seen I regard IPIX being as on the level as any management ever will in pharma.

Well. From my pharmaceutical experience it usually goes like this:

Big Guy: "I am not so convinced with this, nor with that. We would have done it...". At which point the Little Guy starts to scramble.

Nothing promised.

Govorchin, I think you are reading her with unwarranted bias of fear.

In my less than illustrious first career I saw a company division vanish around me practically overnight, a project going down with the Berlin wall, found a job offer disappearing to jail with the potential boss (don't mess with government contracts, boys and girls) at which point I felt that considering events so far a change of career even in the middle of dissertation writing is prudent. Since then I have walked off from few jobs and been thrown out once. Every time I had a feeling of sadness due to unfinished business and lost friendships.

"all 3 outcomes were very different" hardy means two flops out of three. Lemme see: one takeover (a jackpot), one bankruptcy (a financial flop), one Brilacidin staff reduction. Does that fit?

frrol, don't take me wrong. I am with you on this, but want to add some reddish pepper flavor.

Correct me if I am wrong. Wasn't K trial design by a possible partner? If so, would you think that the possible partner was consulted before stopping the trial?

Furthermore, it would be enlightening to know (for eternal short the hell out of idiots purposes) which Co was behind the moronic trial design: interrupt ongoing treatment of desperately ill subjects to squirt in Kevetrin for 3 weeks. Sure you have people clamoring to be your subjects. They just were in such a rush that got stuck in the door frame. What a shame - Small door messing up a well designed trial.

If I happen to recall wrong the above tirade still applies. I guess.

Agreed. Over 100k shares in a minute at 0.65 is not bad news panic - it's agreed sale.

Daubers, I did some additional harebrained analysis on apremilast trial data, which is the only data set one can even try any analysis without being totally anal (bad pun, if even that, sorry. It is this latent analcyst is me). Apremilast has whopping 4 trials with enough data.

Apremilast PASI 75 has weak positive correlations with the size of PGA/IGA > 3 proportion and mean BSA value. That makes intuitive sense because high values for both indicate wider spread of psoriasis. One can't really say that this means that prurisol scores in P2b will be better than those achieved in P2a, but one can say that there is no evidence of the opposite.

I made an another observation, which means I finally bothered to read UNVEIL trial report thru. Hello! Apremilast UNVEIL trial is a BSA outlier for a reason. That study went after low BSA, IGA = 3 subjects! And what that has to do with prurisol? In my predictions for prurisol 2b I used PASI 75 to IGA 0/1 ratio from UNVEIL. If I include tofacitinib and methotrexate trials we have 6 trials with the ratio over 0.9 (three over 1.1), 1 trial with the ratio at 0.7 and that trial is UNVEIL, a trial skewed on purpose. Looks like I was too cautious with my predictions.

That's all.

I think you both may have a point (and being overtly pointed with your points). Yes, prurisol trial would add to IPIX's knowledge of prurisol's value. That is very meaningful for license negotiations. But it would be 'present' value, based on present knowledge. RG seems to be speaking about how one can or cannot account for possible other indication.

There is a way. It's called a clause in licensing agreement. Made public usually like this: "... and high single digit royalty for any additional indication ..."

Thanks Daubers. I have a hunch that you are right. It so much depends on which part of the curve 200 mg lands, on accelerating or on decelerating (I assume saturation curve, may not be even that). But, as I said I made conservative assumptions in order not be tarred and feathered immediately. I prefer slow roasting.

In any case, over long run, I will take the 60/40 odds anytime. One ends up making money that way ;)