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My take on the NY Times article is based on this quote (underline mine):
So do I.
Just wondering... Doesn't per kg in clinical trials usually mean dose per kilogram of body weight. Average 'laboratory male' weight used to be about 70 kg, nowadays more like 80 kg, if not more. Anyhow, if ABSSSI tests were reported using dosing per kg of body weight, your calculation is not correct. Using 80 kg body weight one would get for total B dose
80 kg*0.8 mg/kg = 640 mg
Average human has about 4 to 5 liters of blood. I will use 4 liters for ease of calculation.
640mg / 4000 ml = 0.16 mg/mg = 160 ug/ml
As usual, I might be terribly wrong.
Oh, I almost forgot: Hi, Loanranger.
LR, it looks to me that you are mostly right. Some nitpicker might point out that the name ulcerative colitis is often used as a common name for ulcerative proctitis (UP), proctosigmoiditis (UPS), left-sided colitis, pancolitis and acute severe ulcerative colitis.
see:
https://www.mayoclinic.org/diseases-conditions/ulcerative-colitis/symptoms-causes/syc-20353326
However, IPIX, by pointing out that foam/gel is developed for UP/UPS, limited the meaning to ulcerative colitis type of IBD other than UP/UPS.
I think this is the only one that touches on the subject
http://www.ipharminc.com/press-release/2019/1/14/innovation-pharmaceuticals-completes-gastric-fluid-testing-of-brilacidin-supporting-development-of-an-oral-dosage-form-to-treat-inflammatory-bowel-disease
I agree.
LR, mistake is mine, as usual. I managed to read 'request to have a meeting by end of December' in their December 10, 2018 press release as having a meeting by the end of December.
If what Novan says is accurate they would have gotten final minutes from FDA in about a week - I take that as an indication of uneventful and agreeable meeting. May be, also, an indication of FDA's Office of Pediatric Therapeutics work load, Molluscum Contagiosum is mostly pediatric disease so my guess is that Pediatric Office is FDA's lead in this. In any case, a good thing for Novan. A question mark, as usual, for IPIX.
There is one interestingly IPIX like thing in Novan's press releases. They never mention that 12 % solution cohorts were about half the size of other cohorts. 12 % was split in once a week and twice a week subcorhorts, others were not. But that is biopharma for you. Why to spoil otherwise splendid party?
I have some other things to pick with Novan, but all in all I currently think they have a good compound in their hands.
LR, thanks for reply. Appreciated as usual. I counted 2 persons pining after release just by my lousy memory, might have been more. Otherwise I do concede the point to you. More details in single shot a la Novan would have been better. Assuming Novan had EoP2 meeting as planned at the end of Dec. 2018 and reported receiving minutes promptly FDA is now getting minutes out in about 60 to 90 days.
Interesting reading about Novan. Especially the terms of their non-dilutive funding. One might wonder why IPIX hasn't gotten similar thing done. No need to answer, rhetorical question.
BTW: There should be a law against pharma press releases in which companies do round off percentages to nearest whole number while omitting headcounts. CoFu guys like me do get punished with extra work when trying figure out if the press release, indeed, has internal consistency. Thanks LR for that, also ;P
FDA does not publish minutes. It is up to company to do so. Can you provide an example of any company publishing detailed meeting minutes from EoP2 meeting? I honestly can't find any. But maybe you are luckier than me.
Thanks, KarinCA. I have never seen a company publish the minutes and I have looked for them. I hope MXdude will know now also.
Could happen. Creating protocol and getting it approved is not particularly costly, although it can get time consuming if IPIX decides to go after SPA.
I doubt if protocol, even with SPA, will tell us anything new about funding. First, currently pharma is not obligated to publish trial protocols - it is very unlikely we'll see protocol by IPIX. Second, IPIX can start some sort B trial without new funding partner and the amend related protocol later, if necessary. Second choice would be really, really slow going.
I haven't checked FDA/federal requirements pertaining to publishing trial protocols lately. I might be wrong - and happy about it.
Mx, you seems to know a lot. So, please show ignorant me one instance of published FDA EoP2 minutes.
Hi 1oldprof, I appreciate your insights. I suspect that answer from SS is not forthcoming. Maybe I can pipe in. Below is the most honest comparison I can come by.
I guess some explanations are needed.
First: In general FDA (I even more) frowns upon giving ratios not based on actual ITT populations but some evaluable group. Bad practise, especially when dealing with preventive treatment where any 'evaluable' group is hard to justify. But biopharma does what it does best until time comes to file for FDA's approval. Hence, only values calculated per actual ITT population are for Soligenix and Galera's overall performance. Even that did take some undesired work: Soligenix probably did not notice that sufficient info could be found between Clinicaltrials.gov and an appendix for an article. Galera made a slip and included a slide having SOM swimlanes with actual ITT population for placebo and 90 mg groups. Rest of Galera's numbers are based on 'evaluables' which don't allow backtracking to per actual ITT values. It is easy to see that headcounts based on percentages reported by Galera (in a table touting ITT counts) for SOM subjects in subgroups do not add up to SOM counts based on swimlanes. Hmm... IPIX's numbers do add up, but are still based on 'evaluables'. Hmm... Let's put it this way: Galera is feeding us the usual press release / presentation fudge and IPIX is probably doing the same.
Some observation:
1. Both Galera and Soligenix are currently recruiting for P3 trial. Take a look at Dusquetide's performance. If that warrants P3 ...
2. Cisplatin once weekly group (Q1W) with placebo in IPIX trial seems to be anomaly. It's SOM rate is significantly different from corresponding groups in the other trials; p-values from Fisher's Exact test were below 0.05 when tested.
3. Galera's trial should be considered to involve different subject population from the others. See differences in placebo risk ratios: Somehow subjects with low weekly dose of cisplatin fare worse than those with high cisplatin dose every three weeks. Actually, risk ratios for Brilacidin and Dusquetide are not included in 95 % CI for GC4419. A bit inconclusive, but hmm...
In the table there are only two indications for statistically significant difference. One for GC4419 performance in cisplatin Q1W group. The other for Brilacidin in cisplatin Q3W group. BTW: the latter 'achievement' (zero not included in CI) is based on confidence interval for rate difference. Some dudes plenty better than me do consider significance based on confidence intervals less sensitive to small changes and therefore more reliable method when dealing with small samples. This, of course, does not mean that P3 would be a breeze, but worthwhile - yes, in my opinion.
For those who are interested methods used.
p-value : Barnard's test
Confidence intervals (CI) for single rate: Jeffrey's CI, which has nice coverage properties at 95 %.
Confidence intervals for rate difference: Miettinen-Nurminen score based CI for the same reason as Jeffrey's CI.
I guess this should take care of my posting quota for the month of May.
Your guess is as good as mine.
A bit more information was released in this January. Very little of Brilacidin got degraded in simulated gastric fluid test - a precursor test for pill formulation.
http://www.ipharminc.com/press-release/2019/1/14/innovation-pharmaceuticals-completes-gastric-fluid-testing-of-brilacidin-supporting-development-of-an-oral-dosage-form-to-treat-inflammatory-bowel-disease
No pill yet. But survival in gastric fluid test suggest that it should not be an overwhelming task.
Thanks, ffrol.
I see. The info you are using seems to be released (2016/11/16) more than a year after the meeting (July 2015). Not really what I had in mind.
Otherwise, I do agree with you that IPIX could have done (and should do) far better job of releasing and managing information.
Exactly!
LR, it is my understanding that the 'confidentiality' is usually due to details which sponsor regards commercially confidential (issues relating to manufacturing process for the drug in question, for instance) not so much what FDA wants to keep non-public.
What I really wanted to do was to instigate somebody to search complete transcripts of EOP2 meetings made public in order to show how silly I am. I haven't found single one. But my effort backfired as usual, the crowd here is minimal work crowd; you and few others excluded.
BTW: we do know these items either from press releases or by inference:
1. Agreed P3 trial population: subjects having head and neck cancer undergoing IM RT with cisplatin Q1W or Q3W chemo.
2. Endpoints: SOM incidence, time to emergence of SOM, Duration of SOM
What has not been spelled out are precifics on trial size and safety, but those things seldom are included in press releases about EOP2 meeting.
I would like people asking for transcript (which IPIX did not promise to deliver to us) to name what additional things we might reasonable learn from EOP2 transcript made public by IPIX. Potential partner present in the meeting would surely be redacted among other tidbits.
I am saying that making the transcript public may not simple matter. It may need FDA's permission due to confidentiality and might end up being redacted (what would say then?). I can be wrong about this - would not be the first time. I am fairly confident that Loanranger is willing to educate me.
On related note: have you seen any company making public EOP2 meeting transcript? Highlights as in: "FDA gave go ahead for P3 with these endpoints (plus possibly some safety related requirements)", but whole transcript? BTW: we already happen to know what endpoints for brilacidin in SOM are going to be, don't we.
This may provide some helpful info (underlines mine):
"Type B—Confidential between sponsor and the FDA. These include
pre-IND meetings, certain EOP1 meetings, EOP2, and pre-BLA
meetings. Type B meetings should be scheduled to occur within 60
days of receipt of the sponsor’s complete written request. Generally,
only one of each of the type B meetings for each potential
application will be granted."
There is plenty other good stuff about communications between FDA and sponsor in the article where the above came from. I recommend reading it:
https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.5966/sctm.2012-0104
And in today's PR:
"The meeting with IPIX Pharma has been scheduled by EMA for mid-April 2019 and will serve to complement the regulatory feedback and advice obtained by the Company from the already completed End-of-Phase 2 Meeting held with the U.S. Food and Drug Administration (FDA). At this meeting, an acceptable Phase 3 development pathway was agreed upon by the FDA and the Company to advance Brilacidin for the prevention of SOM in HNC."
The following has been said before, but please masticate it one more time.
Only one drug has been approved for oral mucositis and that approval is for very different indication (in patients with hematologic malignancies receiving myelotoxic therapy) than targeted by Brilacidin, GC4419 and Dusquetide.
In this kind of situation, where there is no previous regulatory specifications available it makes sense to go and ask those agencies what would satisfy them. And EMA may be crucial if, as it seems, there will be some 'competition' of USA subjects for trials - both Galera and Soligenix are in phase 3. Next comer may need to cast its net also outside USA a.k.a. Europe. If my memory serves me right running even a part of a trial in Europe requires EMA's approval.
BTW No 1: Dusquetide P3 trial is registered with EMA under Soligenix UK Limited. Probably just an end run around FDA regulations. What else? [IRONY, in case ...]
EMA:
https://www.clinicaltrialsregister.eu/ctr-search/search?query=Soligenix
Soligenix UK Limited
https://suite.endole.co.uk/insight/company/06560847-soligenix-uk-limited
The last one looks familiar, somehow.
BTW No 2: I guess Soligenix Inc is a bit miffed with Brexit. Subsidiary taking off from British Isles might be on the books. I wonder if current UK director plus obligatory executive assistant will make it.
"but retest that dubious arm". And that there might be the reason why IPIX is after EMA advice now - they hope to reconcile FDA and EMA takes of the matter into one marketable trial design. Makes sense - that's all.
It is common parlance to refer a drug accepted by FDA into phase 3 as phase 3 drug. Tell me what else it could be? It seems that you equate expressions phase 3 and phase 3 clinical trial.
On the other hands, I see your point about of making too much out of acceptance into phase 3. What, by the way, means potential gamble? only only sometimes a gamble?
LR, you might want to check what these people at some sort of authority say about completion of phase 2 trial(s). Where does the drug move?
https://www.fda.gov/forpatients/approvals/drugs/ucm405622.htm
So, It seems to me that IPIX does have one phase 3 drug, Brilacidin, in two indication: ABSSSI and SOM. But, you are correct in saying that there is no phase 3 trial on-going or even started. And, that is the thing that matters currently.
Just wanted to point out that GC4419's activity against tumors is so far not proven. Otherwise I totally agree that Galera is doing far better than IPIX. I actually think that GC4419 will be the first effective SOM treatment to be approved.
Unfortunately (for me) I do also believe that Galera will go public overpriced and only after FDA approval is at hand - That 'named team of investors' will want to maximize the return from this particular investment.
Yes, fewer dropouts should have an effect. But, Galera is specifically looking at tumor response at 1 year mark after completion of RT. Their thinking is: GC-GC4419 converts superoxide to hydrogen peroxide -> hydrogen peroxide has been shown to have tumor suppressing effect (sort of) -> GC4419 might show that also. So far results is: Nope.
I would use word presumed. As in "it is presumed that GC4419 has anti-tumor effect". So far no evidence of this has surfaced from either phase I trial or from still ongoing phase II.
I agree. Infinity did predict Prurisol P2b outcome correctly. No bones about it.
No, It does not. I intentionally avoided estimating it.
When I was still working for big pharma at least these companies had the week between Xmas and new year paid vacation time (year end closure):
1. Traditionally most European companies: AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Novo Nordisk, Roche, Sanofi, ...
2. And quite of few of US companies also: Amgen, Lilly, Merck, Pfizer, Vertex,...
In practise this vacation break resulted in two week period when nothing important got done. I know, it is hard to think that some people might be putting their feet up and be with their families. During Christmas, of all times! And it's probably harder, for some of us, to think that Leo might say something remotely related to truth.
It is my understanding that Japan's 2015 PMD Act put Japan's drug approval process on par with EU and USA. Before that it was notoriously slow. Maybe I am wrong.
A Little comment here on that linked message.
1. Easiness of approval, if defined as more lax rules, is questionable. There is not much difference in regulations between US, EU, Australia, Canada and Japan - countries where pharma makes most of its profits.
2. That NJ company may have registered their innovation first in another country for several reasons. One being that their trials were non-IND, were done outside US and did not satisfy FDA's conditions for approvability in US. For instance: A company can forget US registration if either of below conditions are not met:
A. Study was conducted in accordance with Good Clinical Practice (GCP)
B. FDA is able to validate the data from the study through an onsite inspection
sources:
https://www.fda.gov/downloads/drugs/newsevents/ucm441250.pdf
https://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm124939.pdf
LR, it is in the study protocol, page S3. Patient's were keeping a diary.
protocol:
https://clinicaltrials.gov/ProvidedDocs/35/NCT02324335/Prot_SAP_000.pdf
Thanks again. I try to keep that in mind.
Why not? Every uncertainty if not addressed drives price down. And the fix is not done with their dime.
Thanks, LR. Obviously I was looking in the wrong place or with typo.
Come to think of it: this IPIX new patent business is somewhat hard to match with negotiation timelines. Getting a patent approved takes time, current average is about 2 years. This new patent is derivative ie. it builds on existing patent(s) and as such might have gotten thru USPTO faster than brand new one...
So, if somebody interested pointed out to IPIX that they had things to do patent wise my guess is that it could have happened during late summer or fall of 2017 or about time IPIX started fishing for CDO:s.
BTW: Try to search US patent no: 10166232 (IPIX's projected patent number). It looks like the new patent is not yet officially issued, which complicates (but of course) figuring times out even further.
Karin, you may be right. Last few PR:s (while being 'minor') have had the feel of responses to concerns raised by negotiation partner.
- IPIX has extended brilacidin patent protection with new 'method' patents.
- According to recent studies RT plus cisplatin every 3 weeks will stay the de facto standard of care in HNC.
- Stability of Brilacidin in simulated gastric environment shows that formulation of Brilacidin for oral treatment of IBD will not be a major obstacle.
At the very least IPIX seems to be addressing an audience beyond plain investors like us. As ffrol has often pointed out revelations like brilacidin is stable in gastric acid is nice to know but at this stage it will not move share price. However, it probably is important for a potential partner. Hopefully the effort will yield results.
I agree with you that reporting only median is very uninformative in this case. But it is the traditional pharma way how 'time to event' measures are reported. As far as I know all clinical trial reports concerning oral mucositis give median duration for SOM and not much more.