KarinCA, the first quote seems to confirm what LR has been saying and what I have been observing with certain companies (Novartis, for instance).

In case somebody wants have a personal copy of the linked document do the following: Save the rtf version. A link to original .rtf version was on the top of my google chrome rendered html page. RTF stand for Rich Text Format which is readable by MS Word, for instance.

Thanks LR. You confirmed what I thought might be case with Aspire and IPIX's strange aversion of generating reasonable cash buffer in early 2018 - all on IPIX.

About material events
I did read your previous post about clinical trial results and material events and agreed. But does making them transaction triggering milestones in financial agreement have any bearing on materiality?

Those footnotes:
table is from an old post of mine. If I remember correctly you did criticize the footnotes being incomprensible or plain wrong then. I just can't find cover... :)

Interesting take, I say. I think most of us here are like me: keep forgetting the 'one shot' nature of the milestone payments. As you said: that has implications.

While we both linger in "fantasyland" and I have your attention let me take you down the memory lane to the column for Cash at the end of quarter in the below table. Yes, the table regurgitates old stuff. Still, if IPIX had held their cash reserves at the level of Q4 2017 then the June 28 agreement (date, not necessary the content of the agreement) would probably have been the first time when a new agreement with Aspire would have generated these WTFIGO discussions.

Did IPIX suddenly start (and might still be) suffering from astounding lack of foresight and financial caution or were they dead certain that some positive event for share price was to emerge during Q2, but was delayed to their utter surprise. The worse alternative - positive catalyst(s) disappearing looks unlikely in light of the language in the latest Aspire agreement. As I see it THAT agreement makes named milestones material events, if they weren't before ((yeah, it's me --> might not hold legal water). Or did Aspire put limits on the 'normal' share selling during Q1 2018 and knowingly forced (too strong expression?) IPIX into future scrambles? And if Aspire did, how?

I know this: during Q1 2018 IPIX share price stayed above $0.60 until March and was still above $0.50 at the end of that month. Looks to me like there was room to sell some millions of shares to get that cash buffer back above $3M. Otherwise I have absolutely no clear clue. I don't expect any answers - just wondering and agitating - and still having my shares.

Or we are talking about re-filing, which is permitted by FDA.

Not ignored. Assumed that I had an answer. I still may.

Timelines on this bother me. IPIX knew that efficacy with weekly dose of cisplatin does not look 'convincing ' in May the latest.
Scenario Quess 1: If IPIX filed for BTD in February/March then the knowledge about efficacy with cisplatin weekly dose might have come as a result of FDA inquiry. But that would mean IPIX potentially lied in 8K filing unless
Scenario Quess 2: It is possible that IPIX worked on responses to FDA and re-filed later, say in July.
Scenario Quess 3: Otherwise IPIX DID SIT on Brilacidin OM data for about 3 to 5 months depending from where you start your count AND then filed for the first time.

We can't be certain of the BTD status. Not funny however you look at it.

Loanranger, a helluva good questions. Made me think long and hard. that produced a headache, not much else.

Honestly, I did ignore Aspire's side. I thought IPIX might have been the originator of the milestone based agreement as an additional deal to existing $30M purchase agreement, because then the new deal manages to makes some, if not much, sense as a quick source of carry over cash.

If Aspire would have agreed to longer period the cost/risk for Aspire would have been ... what? Maybe about $4M instead of $2M and upto 16M shares for Aspire to sell over 6 months instead about 8 over 3 months? I could well be that Aspire did think that only 3 month variant was acceptable.

What puzzles me now is this: If IPIX had a choice between the old $30M purchase agreement and this milestone based agreement, why enter into the latter? To prop-up the share price? Repeated need for a pile of cash?

I agree - the BTD application was probably rejected on the grounds you stated.

Pete, thanks for your thoughts. Mine follow:

I think that IPIX is way past multiple suitors stage, and probably was at the beginning of July. The termination dates in the purchase agreement with Aspire makes sense to me (others will disagree, see below) only if the detailed negotiations were already ongoing.

So: in June 2018 IPIX thought that there is a very good change of inking the deal they were already negotiating before the end of September, but monies might not to be in the bank for some additional time - the exact schedule of payments is usually not the first item to agree upon.

BTW: for those who think that the purchase agreement is just a smokescreen then why give oneself only 3 months of time before armageddon? I would have used something like 6 or 9 months and still been able to explain the time frame, convincingly.

"October at earliest". And might appear on IPIX bank account as late as December. This is a situation where the buyer has the power.

KarinCA and Loanranger, good that you settled your 'differences'. My first post was based on a very hasty read of the review article, so your little tussle made me nervous. Now I have read the review again and intend to wade back into dangerous waters.

I am getting a feeling that the review is more an attention getter for RRx-001 than a serious review - short treatment of each drug with references to some significant articles and letters not to be found. For instance: the report of GC4419 phase 1 trial in OM, criticism for both palifermin HNC trials. The article does touch the criticism of palifermin trials, but without references for their mildly strange conclusions.

It will be interesting to see how well RRx-001 protection of bone marrow will extend into protection of oral mucosa. Based on the information the authors of the review provide and with my extremely limited knowledge of biology involved, RRx-001 modified red blood cells probably will accumulate in the environment of some (dense) tumors. Bumpkin explanation: they can't get in due to collapsed tumor blood vessels so they bleed into tumor environment. But to what extent? Accumulation will probably be in much lesser numbers than in bone marrow. My opinion, not a fact, which usually makes the opposite more likely fact.

I do agree with the authors of the review that future treatment of SOM will be a combination of drugs where one will work, using Sonis model, in early initiation/oxidation stage of cell damage, the other will act on cytokines and/or other inflammatory agents and may even promote healing process. It is helluva hard to design a single, tolerable compound that would be active in all 5 stages.

Maybe the emphasis on radioprotection has something to do with the scope of the article.

Amifostine and RRx-001 both originate from military radioprotective research. GC4419, a superoxide dismutase, has direct radioprotective properties by snubbing (not a scientific term, yet. I am working on it) superoxide radicals produced by radiation. Palifermin is not an actual radioprotective, but it is the only FDA approved drug for oral mucositis and probably serves as reference for the others. Excluded drugs, Dusquetide, Brilacidin, Validive, Epicatechin (EC-18) and AGO13 are more active in damage repair than in direct radioprotection.

Detonate,

1. Your first link is about reporting rules for NIH funded clinical trials only.

2. From LR's link (underline mine):
Typically, a duty to disclose arises out of one of two scenarios. In the first, there is a statute or regulation that mandates disclosure such as the line items in a current report on Form 8-K or under Regulation FD. In the second, disclosure is required to avoid rendering existing statements misleading such as in connection with an offering and sale of securities. As a general principle, absent one of these scenario or under other limited circumstances, there is no affirmative duty to disclose material information simply because it exists.

3. Things don't seem to be different even when communications with FDA are considered. For instance, this study found that 18 % of FDA's CRLs (Complete Responses Letter, weird name for FDA's decision to reject drug application) did not get any press release out of the receiving company (silence), 21 % of press releases did not match anything in the CRL (creative interpretation... ahem... lying) ...

Good to know.

Loanranger pointed out that no shorting clause is omitted in the latest agreement, as it is. But LR, being an honest man (I presume, meaning the man part), also said this:

You are maybe remembering Bertolino's presentation a year or two ago. If I remember correctly (no guarantee) he mentioned some surprising indications based on prurisol trial data at that point. I have feeling that he did not mean treatment for constipation or cancer.

TIAB, but of course FDA will request an efficacy analysis covering certain subsets. I guarantee that at least this subset analysis will be required:

Efficacy with different cisplatin schedules: There is some evidence that most toxicities, including oral mucositis, are more severe with weekly cisplatin and there is compelling evidence that cisplatin every 3 weeks is more effective in treating HNC. Differences in treatment effectiveness of SOM in these groups is of great interest to FDA and, for god shakes TIAB, to ANY treating doctor.

Applicant also needs to address efficacy in subjects with HPV induced HNC vs subjects without HPV. HPV induced HNC is considered easier to treat and that may alter efficacy results in treatment of SOM.

No they did not. There is better, more informative, Galera GC4419 data set here.

Galera's CG4419 is one of those funny compounds that looks worse every time when additional data is provided. Don't take me wrong, GC4419 is still far better than anything currently available for everyday use, but the latest data does not live up to Galera's early press releases.

The rest follows SS's and the Carrot Chomper's way of informing people (ie. giving away nuttin')

As a game I recommend gazing intently - as if thinking (TIAB: 'the diagnosis stare') - above linked slides titled:
- GC4419 Phase 2b Enrollment & Assignment
- Primary Endpoint – Duration of SOM (Grade 3+4)
- Secondary Endpoint – Incidence of SOM (Grade 3+4), Thru 60 Gy
- Secondary Endpoint – Incidence of SOM (Grade 3+4), Thru all IRMT
and prettiest of the them all (mirror, mirror...)
- Individual Patient “Swimmers’ Plot” — 90 mg v PBO

The game score:
count how many WTF moments you had.
Homework if no WTF moments experienced:
1. Try to reconcile the above slides with each other.
2. Essay: What is FDA's preferred trial population for use in analysis and why?
Extra bonus:
See what you get when you convert the swim lane plots (as people outside clinical trial arts have called it for decades) to Kaplan-Meier graph for SOM incidence GC4419 90 mg vs placebo.

Wot? But MXAMDUD said IPIX short interest is skyrocketing! How do you skyrocket to low numbers? With a dud?

Thanks for your efforts, LR, and keep at it. You are one of the few here still worth reading.

Short answers
No, FDA does not always require control group in trials supporting drug approval. Some drugs have been approved based on uncontrolled trials. See: Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999–2014

Brilacidin rinse is given to prevent the development of oral mucositis during radiation treatment, if a patient develops SOM (ie. oral mucositis so bad that it might prevent rinsing) then it is a treatment failure, not a drop-out issue.

My first reaction: impossible question to answer and that means I like it. Trials can fail or succeed at any interim analysis (shortish time to failure/success) or in the final analysis (longish time to failure/success), different medical fields have widely different clinical trials and trial durations etc...

About trial success rates in general the largest study of its kind was published in January 2018 Biostatistics. It that is too daunting this is a nice summary article.

To be annoyingly precise:
In trials for moderate to severe psoriasis historical mean for placebo PASI 75 response rate is 5.78 %.

Proceeding to being insufferable:
One in every 6 trials reports placebo PASI 75 response of 10 % or higher. And only 1 in every 16 reports placebo PASI 75 response of 13 % or higher.

So funny. Now, here is a real life clinical study report for a phase IIa psoriasis trial:

gsk-114296-clinical-study-report-redact.pdf.

Even slightly below average American schoolboy can whip that up in a single afternoon while playing video games and cruising between porn sites. Because access to latter educational pastime is rumored to be severely limited in the northern plains of China one might expect even speedier delivery. Yup, for sure.

Warning: pdf pointed by the link to which the above link is pointing to is quite large.

Exactly!

Daubers. No it is not. It is based on p2a headcount and responses. I feel very uncomfortable with any guess estimate for PASI 75 response corresponding to increased dose (one assumption more). I did, however, provide in my answer to SS confidence intervals based on PASI 75 responses in p2a with p2b head counts plus p-value sensitivity analysis accounting also for trial size. They do look better.

No they don't know that. Yes, they do argue over how stable a p value for small sample really and especially over should one accept p value below 0.05 for small sample as statistically significant. But...

There are two ways to account for small sample size: confidence limits and sensitivity analysis. Any good statistician will always provide both. Ask one you know.

And, I guess playing with numbers is still time better spent than making arguments based only on fact void opinions. Yes?

Nope. What the graphs say based on phase 2a trial

1. There is at least 72 % confidence that PASI 75 response ratios for prurisol and placebo are truly different.
2. There is at least 75 % change that prurisol's PASI 75 response rate will be good enough for commercialization if we take PASI 75 response of 25 % being a lower limit for viability (as it has been in the past)
I think those are decent odds considering the phase 2a trial arm population.

Note: Graphs I posted don't say a thing based on phase 2b head counts, only what we had in phase 2a. But if things stay as they were in p2a then p2b numbers will be better, actually achieving statistical significance (I checked, p < 0.01 by Fisher Exact test) even without any response improvements with increased dose.

I usually don't like to play with trials I have no data... But this time, I do it just for you, SS. Don't tell anybody.

This is how things would look for phase 2b the Bayes way if response ratios will not change from phase 2a trial.


And here is p value sensitivity analysis for phase 2b done by Fisher way.

It may or may not. We don't have credible evidence either way - only historical inferences from other trials. And historical data is biased in favor of blue skies - failures are seldom published.

Based on what little we currently know and assuming nothing else - no future improvement nor degradation, no past flukes or shenanigans in phase 2a trial - something slightly better than the graph for PGA 0/1 response below indicates. Note that two sided confidences are for PGA 0/1 responses being within shown limits - not outside. One sided limit is for being above (lower curve) or below ( upper curve). As an example:

I am 95 % confident that phase 2b PASI 75 response will be below 50 % but also 75 % confident that it will be somewhere above 25 %. This, of course, only if nothing changes compared to phase 2a trial (I am hedging, for sure).

I totally agree. But that is our perception. IPIX and many other companies would argue otherwise. Current information hiding practises will not change unless SEC makes a clear ruling about materiality of FDA communications. How likely is that?

So typical! People are missing the most important question: What kind of bike?

And a minor thing: it is hard to argue that not receiving BTD is material event when a good portion of biopharma industry is in no hurry to make public FDA's complete response letters. Let's start getting those to be recognized universally as material events.

My guess: irony - a species of speech sometimes hard to identify in the wild.

Thanks, kfc. Very interesting.

Well, I don't know about that. From the FDA label for plazomicin:

WARNING: NEPHROTOXICITY, OTOTOXICITY,
NEUROMUSCULAR BLOCKADE and FETAL HARM
See full prescribing information for complete boxed warning.
1. Nephrotoxicity has been reported with ZEMDRI. The risk
of nephrotoxicity is greater in patients with impaired renal
function, the elderly, and in those receiving concomitant
nephrotoxic medications. (5.1)
2. Ototoxicity, manifested as hearing loss, tinnitus, and/or
vertigo, has been reported with ZEMDRI. Symptoms of
aminoglycoside associated ototoxicity may be irreversible
and may not become evident until after completion of
therapy. (5.2)
3. Aminoglycosides have been associated with neuromuscular
blockade. During therapy with ZEMDRI, monitor for
adverse reactions associated with neuromuscular blockade
particularly in high-risk patients. (5.3)
4. Aminoglycosides, including ZEMDRI can cause fetal harm
when administered to a pregnant woman. (5.6, 8.1)

If my memory is not failing me it's the elderly and pregnant women who tend to get urinary tract infections- and, in my storied past, me due to a mistake of cooling my bare bottom plus 'culottes' on a cold granite bench after a visit to really hot sauna (further details not forthcoming!)

Aaah. From that scalp seborrhea inducing sign alone I suspect some of my distant relatives are at work there. Avoid closer contact at any cost.

About those missed deadlines. IPIX is hardly alone. Here is two interesting links:

Recuruitment forecast in Clinical Trials
FDAAA TrialTracker

The first one includes this little gem: 80 % of trials miss their recruitment deadline. Guess what that does to overall trial timeline?
The second one is just a fun tool intended to shame biopharmas that are, for various reasons, delinquent in their trial result reporting. Maybe the current head resident of The White House should check this one. Looks like the government is letting some serious income slip.

Enjoy.

Well, alright. It looks like the Italian's lost their funding before they got to the planned clinical phase. How that is Leo's fault is debatable.

SS, how many times it needs to be told to you that the Italian Kevetrin pre-clinical study happened. As evidenced by this abstract.

..."Big Pharma salaries for typical penny stock results"

I must be somehow deficient because I have always thought that truth is sort of equivalent to fact. Well, one learns every day.

Average Massachusetts biotech salary (includes ALL employees) is over $ 100000. I guess you can calculate Leo's salary multiple. Then you might want to compare it to this list. About 60 % of them managed some profits last year.