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Thanks. This helps. Learning every day.
Amateu17, it looks like Leo has a point. See dosing in head and neck cancer.
Self-education helps. You should try it. For instance, I am already feeling a bit better about the press release. All we need now is the apostle of cisplatin dosing in head and neck cancer. Any takers?
My guess: the latest Brilacidin press release was aimed at Galera's GC4419 and its fans (notice that leadership talk).
GC4419 is advertised as also protecting healthy cells against radiation damage. It may do that, but based on their P1 it probably doesn't do a thing regarding patient tolerance for higher cisplatin doses.
IPIX seems to try differentiation between B and G. Unfortunately the effort is prone to backfire as some who have done calculations what the press release means for low cisplatin dose group have pointed out. Also, IPIX does not mention if there were dose reductions in high dose group, we are left to assume: maybe none, maybe some.
A good place for a great song with insinuating title combo: Muddy Waters - I Can't be Satisfied!
TIAB, now would be a perfect time to point out small trial size.
Yes, classic in the sense of common practise. Take a look at Galera's phase I trial paper for GC4419 (sorry but reading is required, dose reductions are in the text) to take a gander at their problems with high concentration cisplatin. Doctors have their pick of sadistic ways in the name of fuzzy benefits: cisplatin around 30 to 40 mg QW or about 100 mg Q3W. The latter is known to lead to dose reductions and brusts of SOM and probably therefore favorite of some less congenial characters.
I happily eat my old underwear if that happens.
Amen! I have tried to say the same. But these youngsters, they just don't listen.
Thanks for the links Karin. I read the first one yesterday - heavy. It probably will sink in with few more reads. Coincidentally, I was being angry with myself over placebo response when I noticed your message. There has been a little fact hiding in front of my nose for a long, long time:
I don't know how much weight one should put on these observation:
1 Placebo response PASI 100 and PGA 0 are historically very low, from 0 to 1 %.
2. Prurisol PGA 0 was for 200 mg ITT: 3/28 or 10.7 % and PGA=3: 2/18 or 11.1 %.
3. Prurisol PGA 0 percentages are in the range of Otezla PASI 90 percentages, which indicates that they are roughly at least twice that of Otezla PGA 0 response- nobody has bothered to report PGA 0 or PASI 100 for Otezla, as far as I know.
DaubersUP, I love the phrase:“unexpectedly high placebo rate” as an explanation for failure. Have to figure out a way to get it in common use.
point taken. I know the malady personally and painfully.
frrol, I suspect that there is not much need. P2b has PASI75 as primary and sPGA/IGA 0/1 with ≥ 2 improvement among secondary outcome measurements.
I just wish that IPIX had gone for 16 week treatment period and then provided data 12 and 16 weeks both. But only a few among pharma are that enlightened.
But when? I have this recurring dream where I am rotting on my old age death bed and a doctor (he looks happy, probably Infinity) leans over and asks:" P, what are you last words?".
I croak:"Are prurisol phase 2b results out?"
I wake up with the doctor's hellish cackling ringing in my ears.
(I am lying, of course).
Still, no way of life, this.
Leo presented two sets of results. The ones titled as ... "with ≥ 2 -point improvement in IGA" ... are equivalent to PGA 0/1 with at least 2 point improvement.
Do I detect a plank of bias in the eye of beholder?
A little warning about those PGA 0/1 and PASI75 values people are throwing at each other.
The widely used efficacy measure PGA 0/1 response is generally defined as
PGA SCORE 0 or 1 WITH AT LEAST 2 POINT REDUCTION IN PGA SCORE.
Very often the above is reported as PGA score 0 or 1, because the trial population is composed of subjects having PGA 3 or higher ie. the 2 point drop is given if a subject scores PGA 0 or 1. It is dangerous to forget that.
Example: Can-Fite reported 2 mg dose of CF101 scoring 23.5 % PGA 0/1 response in p2 and hurried into p3, where the PGA 0/1 response was whopping 6.2 %. Can-Fite had included PGA 2 (and 1) subjects in p2 trial. 3 out of 4 PGA 0/1 achievers were PGA 2 at baseline and went to PGA 1 by week 12. This is obvious if you study Can-Fite's generous explanation of PASI50 score for the only 4 subjects that reasched it: values 47.7, 49.9 (what were these doing in PASI50?), 73, and 90 %. Only one of those can possibly be PGA 0/1. THE REAL PGA 0/1 in p2 was 5.9 %, very consistent with p3 results and disastrous for Can-Fite.
IPIX reports that at week 12 prurisol 200 mg ITT group had PGA 0/1 response of 42.8% and PP group had response of 55 %. They did, but not PGA 0/1 with at least 2 point reduction. Both ITT and PP groups included PGA 2 subjects, some of which DID score PGA 0 or 1 at 12 weeks. THE PROPER NUMBERS for PGA 0/1 response (with 2 point reduction) are:
Prurisol PGA 0/1 response: ITT 25 %, PP 35 % at 12 weeks. PGA 0/1 response for 19 subjects with baseline PGA equal to 3: 31.6 % at 12 weeks.
BTW: that 12 weeks is important to note if you compare with Otezla. Most Otezla trials used 16 weeks treatment period and Otezla's PGA 0/1 and PASI75 scores tend to rise between 3 to 5 percentage points from week 12 to 16.
Useful examples for Otezla:
Otezla trial having only PGA 3 subjects, headcount 148, dosing 30 mg BID PGA 0/1 response at 16 weeks: 30.4 %.
If you compare this to PGA 0/1 response of 31.6 % for Prurisol 200 mg PGA=3 subjects you are giving Otezla some advantages:
1. Longer treatment period for Otezla is responsible for 3 to 5 percentage points
2. 30 mg BID is maximum approved dose for Otezla, if all goes well 200 mg for prurisol will not be. Probably 400 mg (200 mg BID).
Let's compare Otezla 20 mg BID to prurisol 200 mg (100 mg BID). There is just one Otezla trial with 20 mg BID dose and published PGA 0/1 response. Otezla p2 trial for 87 subjects with PGA at least 3 had PGA 0/1 response of 28.7 % at week 16. Remember: even here Otezla has the advantage of 16 weeks treatment time.
In 3 clinical trials with Otezla dose 20 mg BID I have found PASI75 responses are: 30 % at 12 weeks, 24.4 % at 12 weeks and 28.7 at 16 weeks. My psoriasis spreadsheet has currently about 60 trials with over 110 reported PASI75 and PGA 0/1 response pairs; 80 % have PGA 0/1 to PASI75 response ratio below 1.0. The mean value for the ratio is 0.89. Conclusion: comparing PASI75 response to PGA 0/1 response probably favors PASI75.
Perfect. Thanks JSN2000. I have been looking for this stuff.. thanks again.
Or it could be prurisol itself. Half-life seems to support that.
Well, then you understand as much as I do, maybe more :)
Can go both ways, if IPIX thinks they can handle the analysis they may want to have just raw data.
Infinity, you are right about next decade.
Nope, Nope and Nope. The sequence is:
data set full declared full --> locking = no more data accepted --> unblinding --> analysis
The PR just means that one needs have full (delared full, actually) data set before anything else happens.
Thanks Karin. About those CDA's, I suspect that good number of them have DD still on-going. Some of them may be even doing little preclinical work. For instance, it might be prudent to repeat prurisol IPIX BALB/C mouse model test if B6 mice were readily available - regardless what IPIX skin xenograft tests showed about PRINS and IL20.
Karin, is it possible that you are talking about
this trial
You should consult some lawyer you treat. If I recall correctly company blog is considered equal to company press release; stating falsehoods in either one is a legal no-no.
Greatly appreciated. Thanks Steppe.
Then, Sixpence, be kind and show a simpleton me like where?
Abstract about Kevetrin was published 10 months ago. Authors imply that research is ongoing.
You get 3 points for unusual effort if you know how to use Google with this title:
KEVETRIN: PRECLINICAL STUDY OF A NEW COMPOUND IN ACUTE MYELOID LEUKEMIA
No need to thank me. Just try to be honest and open.
Infinity, let's assume that the trial had data monitoring committee. Then it probably had a stopping rule for futility. When arm sizes are around 80 to 100 subjects one will have no idea of significance at 6 weeks unless you are pumping subjects full of biologic immunosuppressants via IV . Only stop/go based on futility. Honest fact, friend.
Prurisol trial was not stopped. But that does not say that the difference will be significant at 12 weeks. Only that the trial was not guaranteed to fail at 6 weeks.
PS. The logic applies also if there was no DMC (not always required) but one sane person explaining the stuff to Leo.
In this I am with you, Infinity. Based on what competition has done the science looks to be there. Aprea has even show p53 based efficacy in ovarian cancer. What IPIX needed was to do the same and only after that go for oral formulation. But, it seems that whenever IPIX gets really close to a major triumph they just need to do one amateurish (well, at least avoidable) plunder first.
Evidence:
1. Going after oral K formulation instead of putting Kevetrin in IV with a known cancer drug to show improvement in efficacy a la APREA - doxorubicin is dirt cheap. Try with that. Aprea did. As a result they now have funding and are going ahead with Sloan Kettering. I would not call that a bad outcome for an experiment with an old drug.
2. Misreading dosing range info from prurisol safety studies and ending with wrong dosing range in p2 trial. I mean it looks like they expected 100 mg and 200 mg arms combined being about 20 percentage points or more effective than placebo in PASI75. By their design that would have produced p < 0.05. PoC - Done - Let's talk about some funding. Instead they need to run pIIb with dosing range they should have used to begin with.
3. Brilacidin is probably THE DRUG in their arsenal that would benefit big time from oral formulation so that they could go after upper intestines and UC in addition to UP (and that just for starters). Is it getting it? Dunno! But I know somebody is putting it in pouches. And those are hard to swallow - literally and figuratively. And not really needed for SOM p3.
Don't take me wrong. I think that IPIX will eventually get where it is aiming at. These crazy timings (or missteps, if you like) are just so annoying.
Let's say that the ship is on drydock for overhaul.
Thanks. Anything for you, Karin. Well, almost anything. I will not go and pummel Mr. I.
Yeah. Let me give you an example of ridiculously good.
Recently Celgene reported results from p2 trial for Otezla in ulcerative colitis. The results were considered good with 18 out of 57 subjects having a clinical remission with p < 0.05 against placebo. Brilacidin posted a clinical remission rate of 10 out 15 subjects in UP, a closely related ailment - location of inflammation being the major difference.
It looks like B has minuscule absorption thru mucosa which should take care of all those pesky (an mostly unfounded) inhibition worries on systemic level. They stay in the gut with B, so to speak.
So, IPIX needs only to find an oral formulation for 100 mg of Brilacin that delivers the stuff into intestines and they might have a ridiculously potent UC drug in their hands.
BTW. Dr. Fisher tells that probability for Brilacidin remission rate in UP being superior to Otezla's in UC is about 99.1 %. There! (my guess is that Infinity will find something to complain about that) If I were the management in IPIX I would not waste my time with psoriasis drug that, at best, will be a middle of the pack runner. I would go with B all the way to Lenox Hill or Hart Island. Which ever it turns out to be.
Agreed. Bu then the trial was not a registration trial.
Sorry. It is quite hard to figure out how to express this concisely: The idiotic design of interrupting an ongoing treatment to administer Kevetrin was suggested by a potential partner. No sane patient goes for that.
Nice! Thank S!
My rare turn in public service: I guess at least some of you are already familiar with these sources.
This is what I consider the bare minimum set of sources to check in any drug related DD. From these you usually find links to additional relevant professional publications - some of which are unfortunately behind paywall (more about that later).
ClinicalTrials.gov Change history alone is worth gold!
FDA approved drugs. Dreadful to read, but FDA approval documents usually have some details not found elsewhere. Check at least clinical review docs.
EurdaCT EU counterpart to ClinicalTrials.
EMA approved drugs EU counterpart to FDA approved drugs.
PubMed NIH's publication database.
Sometimes you find yourself in situation when that absolutely crucial (often only in your febrile mind, as it turns out later) bit of info happens to be behind paywall. Before digging out your credit card try these two tricks:
1. Paste the title for the article of interest from pubmed to Google and see what happens. Check any link to ResearchGate. Authors may have made the article available there. Check any link that looks like a link to pdf. You never know.
2. Try this combo at google.
Systematic name for the drug or company's ID for it +
company's name +
pdf.
I have found wonders this way. Once I found GSK admitting in internal documentation that Votrient's median PFS in soft tissue sarcoma was more like 3.7 months instead the 4.6 months reported. They did not include that data in FDA application.
Thanks for adding "color" to Validive story. I checked it via european trial registry, which does not provide change history but sometimes has additional info to ClinicalTrials.
In case somebody will find EudraCT useful: link.
Okay students of the shorty arts. Here we have a prime example of subtly misleading presentation. Let's begin.
1. 12 patient UP trial at some unknown location. The claim is misleading by 20 %. UP trial was with 15 subjects. Note: A shorty would have added "whopping" before 20 % to add weight on otherwise measly percentage.
2. 2 patient K trial that couldn't recruit. Omission of 5 words for added smell of incompetence. More accurately: 2 patient K trial suggested by a potential partner that couldn't recruit.
3. Leo's 420K salary survival... Not providing comparison context. For instance, average US physician salary in 2017 was 297000. 420 000 USD for below average failure rate does not look so bad.
Correct. I interpreted Galera's swimlanes. I am, as you seem to be, waiting some kind of publication of their p2 results. Nothing, so far, at ClinicalTrials.gov. But the filing has one interesting tidbit:
Galera likes to publish it's trial minimum cumulative radiation requirement as 60 Gy. At first glance that looks like higher requirement than IPIX's 55 Gy. But IPIX's minimum is for ORAL CAVITY (ie. the target environment) while GALERA ALWAYS publishes numbers for TUMOR (ie. the target only). In the filing at ClinicalTrials GALERA lists the minimum for oral cavity as 50 Gy.
"Planned radiation treatment fields must include at least two oral sites (buccal mucosa, floor of mouth, tongue, soft palate) that are each planned to receive a total of > 50 Gy"
Right! IPIX better meet with FDA about B.
IPIX would benefit of getting at least SPA out FDA before starting p3. One thing a small biotech does not need is FDA saying after commercialization filing: "Sorry, we don't agree with your targets and methodology. You need to do this over."
I would try to get FDA committed for Kaplan-Meier style efficacy evaluation for incidence rate and onset combined plus mean count of days with SOM. That would put some needed intellectual rigor in SOM clinical trial business and probably would benefit B also. I bet they could get support for it from health insurance industry; they like to get their hands on better measures for cost estimation.
One can always dream.
Yup. Leo said "advance to discussions". Quite different from "advance to and immediately complete discussions" in my books. But maybe I assume too much.
kfcyahoo, I am interested in what kind of english dictionary you are using? I might want one.
The dictionary I have now does not list the meaning "completed" for expression "advancing to". Mine is just old paperback Webster's I 'borrowed' from my college lab. You must have some fancy and expensive one. Or is the proper word here "expansive".
On the other hand: I have heard that in military use expression "advancing to battle" assumes a complete victory, otherwise there would not be much advancing.