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Please, do. Should be interesting.
After seeing several similar omissions I have concluded that your powers-that-be allow this as long as there is sufficient information available for a change diligent reader to do the 'crucial' calculations. BTW: IPIX not reporting numbers for cisplatin weekly schedule is not nearly the most appalling. How would you react to finding out about omission in FDA label risking some patients of not so diligent doctors (my bet: a fair majority) with surprise shortened life (situation since corrected in NCCN treatment guidelines but not in FDA label).
I have said before that even in such small field as oral mucositis IPIX is not alone.
1. Soligenix did the IPIX thing with a twist of messed group headcounts in peer reviewed publication adding to the degree of difficulty.
2. There is enough fudge oozing from Galera's "per IIT" numbers to make it impossible to reconcile which 'per protocol' group was actually used to calculate the reported percentages beyond this observation:" It ain't your usual ITT."
Seeking EMA's advice probably means getting EMA's approval for a protocol based on FDA's requirements - usually a formality. IPIX (plus necessary funding partner) would benefit from running parallel trials, one in USA the other in Europe. It would not only save time but would ease cost and recruitment concerns.
"A Phase 3 trial in Europe wouldn't act to secure FDA approval for distribution in the US, would it?"
Yes it would, as long as the trial is run according to FDA approved protocol and FDA is able to validate trial data with onsite inspections. The reverse is generally true for EMA approval of a drug based on a trial run in US. FDA has even granted initial approvals based solely on trial(s) conducted outside US. Votrient (pazopanib) is one of those drugs.
Readable overview about FDA's expectations for acceptable IND and non-IND trials conducted outside USA.
https://www.fda.gov/downloads/drugs/newsevents/ucm441250.pdf
ffrol, there are some other possibilities -
IPIX could be looking into doing the trial in Europe, which would probably be cheaper than doing it in US.
Yes, it is.
LR, you are asking a question for which there is currently no good answer. We need to know the results (numbers) from p2b before we can address what would had happened with interim analysis. And even then it would be statistical inference, not certainty. Remember also that those delays in running the trial might have prevented or perverted the interim analysis. We probably will never know with reasonable certainty.
In March 2018 Protagonist cancelled a trial of PTG-100 on ulcerative colitis based on CRO's bad endoscopic data (stupendous placebo rate seems to have been part of the problem).
My link was to later developments (August 2018) when it had become clear that Protagonist's CRO had messed up royally. New analysis of the discontinued trial: drug shows promise in ulcerative colitis contrary to earlier results.
The problem: new results were obtained from small subject groups with only the highest dose, 900 mg, showing promising separation from placebo. But still at p value of 0.33 only (memory refresh - prurisol 200 mg had ITT p value of 0.32).
Protagonist is now in a situation where it either
a. runs 200 subject dose finding study again to get indication if the trend for 900 mg holds
or
b. tries to convince FDA that current results will warrant phase 3. FDA may approve, but may also require larger trial(s) than it would have if the 200 subject trial had been completed successfully in the first place.
c. (later edit). abandon development of PTG-100 in UC. I admit that his alternative may results in savings when compared to completed 200 subject study, if that trial had still failed.
So, we have the cost of discontinue trial. Plus about 6 months of lost time (that has a cost). Plus cost of reanalysis. Plus potential cost of running dose finding study again (I think it is a strong possibility). Can you really say that this has resulted in obvious savings for stockholders? Maybe, if Protagonist decided to abandon PTG-100 in UC - otherwise I don't see it.
Modest proposal for entertaining pastime: Maybe we should start wondering what the possible re-analysis of prurisol p2b will bring. It could be that this was the hidden meaning SS wanted to bring to our attention.
Maybe you should read this Protagonist PR and then decide what to do with this post.
https://www.prnewswire.com/news-releases/final-results-from-the-protagonist-propel-study-support-further-clinical-development-of-ptg-100-for-the-treatment-of-ulcerative-colitis-300692199.html
looks like Protagonist ended up wasting 200 subject study on ulcerative colitis on CRO error and now probably needs to re-do it. Savings for stockholders? Oh man!
My guess is that Polymedix/Cellceutix/IPIX developed some idea of optimal concentration per rinse. Increasing rinse times or making the stuff to stick on mucosa longer (thickening, big sticky tablet) could improve efficacy.
Only thing I have to go by is this summary by Polymedix at the end of this:
http://files.shareholder.com/downloads/ABEA-4ITCYZ/1997024712x0x611205/FEA66C67-D02F-4FF2-B230-AA711F46ED7F/PMX-30063_Antibiotic_Fact_Sheet_Nov_2012_.pdf
It looks like results for rinse concentrations above 1 mg/ml are not that much different. But, that is darned mouse data - so, who knows.
Some lightweight pondering.
LR, I did a real quickie calculation. If I am correct Galera has around 140 M$ in equity funding (I assume most of it VC) when series A, B and C are combined. Plus some multiple of $80M payable as future royalties. According to link below that would put Galera's future sale/IPO value (assuming successful P3) above 1.5 B$. Probably in the neighborhood of $3B.
http://www.angelblog.net/Venture_Capital_Funds_How_the_Math_Works.html
Caveat: Heavy involvement of big pharma venture funds (Novo Nordisk and Novartis) may bring estimate lower. As far as I know, big pharma funds tend to operate with lower return expectations (because they can afford to) than traditional venture capital.
As I said this is pondering with not much thought put into it. What the above means for IPIX is anybody's guess.
As far as know (and I don't know much) they probably could increase Brilacidin concentration. But, I don't think that concentration is the main factor in improving efficacy. Increasing contact time with mucosa would probably benefit more - based on mouse data with brilacidin pouches.
Agreed. Different MOAs for GC4419 and Brilacidin plus the fact that Brilacidin has minuscule systemic absorption do support possibility for very beneficial concurrent use.
I agree about cherry picking or as pharma calls it 'highlighting' in PR. Things really get unfortunate when cherry picking manages to get into coverage of FDA approvals. Years back I once listened an eminent cancer physician start his put down of a kidney cancer drug candidate: "Now, when we have temsirolimus, do we really need another kidney cancer drug?" He had read PR plus what was in FDA label. Only.
I would add a guidance about night driving which applies nicely to biopharma PR:
Don't look at the light - it may blind you. Look beside it i.e. what was left unsaid. It is usually in plain sight.
Agreed. You make a valid point.
There may be one major benefit (of which I am a bit unsure): extending IPIX owned brilacidin patent life for certain uses of brilacidin i.e. even when the original brilacidin patent expires IPIX may still hold crucial 'use' patents.
Sorry, LR, been busy day and I am late with this reply.
I stand corrected. I should have written 'no evidence of BTD'.
I have doubts how complaint of omission to point out otherwise obvious fact would fare in legal actions. Reporting SOM incidence rates for intent to treat population plus only one out of possible two subgroups is like saying:" 5 minus 3 equals..." And leaving it to readers to figure out that it is 2 that follows. Seems to to OK as long as there is means for the reader to figure out what it was highlighted.
One enlightening example:
Yondelis was approved on 2016 to treat leiomyo- and liposarcomas (two most common soft tissue sarcomas, STS) based on statistically significant benefit in progression free survival (PFS). You can't find this tidbit in Yondelis FDA label or in the discussion section of published, peer reviewed article about the pivotal phase III clinical trial (comparator dacarbazine is generally considered borderline active in STS i.e. just above placebo):
Progression free survival in Liposarcoma overall Yondelis (trabectedin) vs dacarbazine
Yondelis: 3.0 months
Dacarbazine: 1.5 months
Progression free survival in Liposarcoma subgroups Yondelis (trabectedin) vs dacarbazine
Dedifferentiated
Yondelis: 2.2 months
Dacarbazine: 1.9 months
Myxoid / round cell
Yondelis: 5.6 months
Dacarbazine: 1.5 months
Pleomorphic
Yondelis: 1.5 months
Dacarbazine: 1.4 months
What do we see: Benefits Yondelis shows in liposarcoma are completely driven by Yondelis performance in ONE liposarcoma subgroup. This is not mentioned (no limiting clause for liposarcoma) in Yondelis FDA label and not in the discussion for Yodelis efficacy in the published, peer reviewed article about Yondelis phase III trial. So, how do I know about it: the above is from a table in Fig 2B of the trial article. That's it.
links:
Yondelis FDA label (the latest):
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207953s005lbl.pdf
Yondelis pivotal Phase III trial:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070559/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783302/
I could provide several other examples, but what would be point...
Get in trouble? Why should they? It is not like they would be falsifying anything, just highlighting selected results. More complete info will usually and eventually be in a professional meeting presentation (months later) or in a publication (year or more later), albeit sometimes buried in the end of presentation (we may not get to this slide before time runs out principle) or in 'supplementary data' (nobody reads supplementary data principle).
And that Soligenix BTD is my guess. I don't think they even applied for it.
Yes, placebo rate in IPIX cisplatin Q1W group is a headscrather. Placebo rate in Q3W group was in line (sort of) with other trials:
placebo cisplatin Q3W
Brilacidin: 10 / 14 or 71.4 %
GC4419: 17 / 28 or 60.7 %
Dusquetide: 18 / 22 or 81.8 %
That brings up another anomaly between these three trials - placebo arm performance in general. Maybe risk ratios are the best way of pointing that out.
Risk Ratio (SOM incidence ratio) in placebo cisplatin groups, Q1W over Q3W.
Brilacidin: 0.64
GC4419: 1.11
Dusquetide: 0.76
Only Galera had worse performing cisplatin Q1W group. Granted, map of literature SOM rates resembles bird shot from shotgun on a barn wall. Still, I can't help but wonder the above ratios.
An old pharma tradition: if possible do not spell out unfavorable data, only imply.
BTW: Soligenix did exactly same thing with dusquetide - reported numbers for cisplatin Q3W group and left calculating the results for really awful weekly cisplatin group to rare enterprising reader. And then they made things interesting by accidentally (????) publishing wrong head counts for cisplatin Q3W group. Thanks to ClinicalTrials.gov consistency checkers the correct head counts enabling calculation of the results for cisplatin Q1W group can be found there.
As you can see, IPIX bunch are just amateurs...they forgot to fudge headcounts.
farell90, no argument. Data for cisplatin every 3 weeks is very promising. I just wanted to point out that unclear results for weekly cisplatin are the likeliest reason for not granting BTD.
Thanks for the link to ASCO editorial, I have been looking for that kind of data. Now, does anybody happen to know treatment utilization percentages for cisplatin Q1W vs Q3W?
More likely reason for denying BTD was performance in cisplatin weekly group which one can calculate using differences between all and cisplatin Q3W group. One can hardly be claimed to be a breakthru if performance in about half of the subjects is unclear (putting it politely).
SOM in subjects with cisplatin Q1W schedule in IPIX trial.
Brilacidin: 7 / 13 or 53.8 %
Placebo: 5 / 11 or 45.5 %
Note: surprisingly low SOM rate for placebo.
Dusquetide had similar (well, worse) failing in weekly cisplatin --> no BTD, applied for or approved.
Dusquetide: 9 / 12 or 75 %
Placebo: 10 /16 or 62.5 %
Note: in Dusquetide's trial placebo SOM rate was what one would expect.
Galera got BTD for GC4419 based on efficacy also in cisplatin Q1W group:
GC4419: 22 / 46 or 47.8 %
placebo: 31 / 46 or 64.9 %
Again: placebo SOM rate was what one would expect - and treatment percentage not so far from brilacidin's.
An interesting observation:
cisplatin weekly group as percentage of ITT in three trials we have data from:
Placebo:
GC4419 - 46 / 76 or 60.5 %
Dusquetide - 16 / 38 or 42.1 %
Brilacidin - 11 / 25 or 44.0 %
Treatment:
GC4419 - 46 / 76 or 60.1 %
Dusquetide - 12 / 36 or 33.3 %
Brilacidin - 13 / 21 or 61.9 %
Interesting percentages. Galera probably randomized based on cisplatin schedule - judging from very close percentages between arms. Others did not.
Sorry, LR, I was obscure. After the heading I copied IPIX claims that biomarker changes were observed in both subjects. I would be happier if they had provided more detail. For now I keep underlining the operative words.
Probably not platinum based therapy because eligible subjects were be resistant to it (of course, rechallenge is possible). Maybe gemcitabine or paclitaxel.
As to concurrent treatment there is this tantalizing sentence on study details side of filing:
Standard of care treatment, as medically appropriate and per local guidelines, outside of this study protocol can commence after the collection of the post-Kevetrin treatment biomarker samples (collected on Day 21±1 day)
One should also consider study time frame, which was at most 6 weeks, filing says 3 weeks for response. 3 to 6 weeks is rather short time to achieve partial response (at least 30 % reduction) or progressive disease (20 % increase) - not to mention complete response.
LR, I agree that nowhere in
https://clinicaltrials.gov/ct2/show/results/NCT03042702?term=kevetrin&rank=1
does it say that Kevetrin is effective against ovarain (or any other) cancer. But, the purpose of the study was to duplicate in vivo these assay findings:
http://cancerres.aacrjournals.org/content/77/13_Supplement/3221
Results listed under this primary outcome in ClinicalTrials.gov filing claims that they did:
Correct, LR. OM shows up with treatment (even without radiation) of several cancers, not only in HNC. Trials using HNC subjects happens to be the easiest (limited treatment time plus very high incidence of SOM) route to approval. Also, after approval nothing prevents attending physicians from prescribing the drug off label to treat OM occurring with other than HNC subjcets.
The other and nitpicky (there is some interpretational disagreement around) point: Oral brilacidin has minimal systemic absorption so it doesn't have effect on what happens deeper in human tissue (IV version would). Hence and strictly speaking, oral brilacidin is for treatment of oral mucositis, not for prevention of it. Well, yeah, it can prevent OM from developing into severe OM, and can snub out instances of mucositis before they are detected in weekly or bi-weekly examination, but principally it treats condition that has already emerged.
"A little bit confused by this: "
Sorry, I was not very clear. Soligenix trial accepts subjects only on cisplatin Q3W schedule. 80 - 100 mg/m^2 in Soligenix filing is shorthand for 80 to 100 mg/m^2 once every 3 weeks. Both Galera and IPIX got approval for both cisplatin schedules Q3W and Q1W (30 to 40 mg/m^2 weekly). Jabbering about doses in Galera's P2 is about total number of doses needed for 6 to 7 weeks of radiation treatment.
Of course, FDA's approval does not mean that IPIX will elect to run a trial with both cisplatin schedules. I would go for more certain approval - trial with cisplatin Q3W schedule subjects only and worry getting approval for Q1W schedule later. Soligenix would not be running it's trial as it is unless FDA has approved including only subjects on Q3W cisplatin schedule.
Before IPIX is allowed to start P3 with brilacidin sachets they need to show to FDA that brilacidin powder is easily and evenly mixed into water. I don't see much difference between patients taking home ready mixed rinses in closed measuring cups or taking bunch of sachets, a measuring cup plus instructions how to mix the rinse.
LR, all below are more or less educated guesses.
1. I think that trial size of 200 subjects per trial with 1:1 allocation is sufficient for typical FDA requirement of TWO p3 trials. In any case, Soligenix has not changed their's after getting FDA's approval for P3 in May 2018. I don't expect IPIX getting any special treatment for better or worse on this.
2. Galera ran it's 200 subject p2 trial in about 2 years --> Soligenix time estimate make sense to me.
Worth considering: Soligenix trial has tighter subject rejection filter than IPIX's (and Galera's) forthcoming trials - only cisplatin 100 mg every 3 weeks --> Both IPIX and Galera should have a bit easier time recruiting --> chances for shorter overall trial duration to primary end. Of course, IPIX could be hampered with low funding which equates to low number of sites which equates to longer trial time.
BTW, It looks like Soligenix found funding for it's P3 only after getting FDA approval for P3 (may 2018). Public offering for $8M was priced after that. There are indications of early slow running (= tight funding) in Soligenix's ClinicalTrials.gov filings. For instance, first trial sites (3) registered in January 2018. Maybe we can expect shorter trial times with proper funding. For now that would mean only Galera. We'll see.
What worries me is the effect on recruiting time if there happens to be 3 phase 3 OM studies recruiting in US at the same time. Going for, at least partially, to Europe to find subjects in time manner?
Yes, I forgot that. Thanks for pointing it out.
I used this study of clinical trial costs as a basis for my estimate:
https://www.centerpointclinicalservices.com/blog-posts/driving-drive-drug-innovation-and-market-access-part-1-clinical-trial-cost-breakdown/
I took average oncology phase 3 trial cost from there: $22M around 2012.
Considering the fact that Brilacidin OM trial needs to cover overall costs for radiation treatment, cisplatin treatment, Brilacidin treatment and palliative care I rounded the cost to $30M. Palliative care cost alone may hit millions if more than 40 % of total subjects develop SOM.
I did not consider this:
The probable size of Brilacidin trial - probably 200 subjects (as in Soligenix p3 trial) is about 40 to 50 % of the size for a typical P3 cancer trial (my guess). That gives about 12 to 15 M$ per trial.
The above in other way:
IPIX anticipated clinical trial costs:
12 to 15 M$ per trial. If 2 trials are required total would be 24 to 30 M$.
A factor that might make OM trials costlier: There is a good change that some OM/HNC trials are recruiting at the same time (Soligenix, Galera and IPIX).
Here is the link:
http://www.edgarmaster.com/Inet/main/DataFeedHtml1.jsp
And here is the text:
Item 5.02 Departure of Directors or Certain Officers; Election of Directors; Appointment of Certain Officers; Compensatory Arrangements of Certain Officers.
On December 11, 2018, Dr. Krishna Menon resigned from his position as a director of Innovation Pharmaceuticals Inc. (the “Company”), effective immediately. His resignation was not a result of any disagreement with the Company.
Item 8.01 Other Events.
On December 14, 2018, the Company completed its review of preliminary topline results for its Phase 2b clinical trial of oral Prurisol in moderate-to-severe chronic plaque psoriasis. Data was received the previous week.
The investigational treatment Prurisol did not meet the primary endpoint in either treatment arm (300mg and 400mg) assessed as a measure of efficacy (active versus control) using the Psoriasis Area and Severity Index (PASI) scale—specifically, the proportion of subjects achieving at least a 75 percent reduction from baseline in PASI score (PASI75) at Week 12.
While additional analysis of the Prurisol data is planned, based on these trial results, the Company will discontinue the Prurisol psoriasis program, focusing development efforts on advancing its other clinical assets, Kevetrin and Brilacidin, both of which have shown therapeutic potential in treating multiple indications.
Yup. Have to admit a defeat on prurisol. It would be educational to see their further analysis. I doubt that we will.
Mildy pleasant surprise with B-OM, thou. FDA allowed both cisplatin schedules, Q1W and Q3W. I was expecting Q3W only. Somebody must have done nice job explaining in EOP2 meeting.
Now it is purely question of money. A P3 trial will probably need headcount around 200 subjects or so. At least that's what soligenix is doing. Cost probably $30M or more. From where and when?
I was thinking more along the lines IPIX interpreting cumulative radiation dose to be below 55 Gy, which was the exclusion/inclusion limit for mITT. Then FDA saying that it looks like above 55 Gy. Or rejecting subjects because of other protocol violations and FDA not agreeing.
Head count ratios cisplatin Q1W/Q3W for Brilacidin and placebo seem to indicate that Brilacidin Q3W group was subject to more rejections than others. Still, it would take a good and unlikely number of FDA reversals involving SOM subjects to bring response rate in cisplatin Q3W group above that reported for dusquetide. Also, it is quite possible that IPIX did not stratify by cisplatin schedule, in which case my comment is moot.
I Agree. It looks like, at minimum, Soligenix style phase 3: cisplatin 100 mg every 3 weeks and cancer location limited to oral cavity and oropharynx. Unless there was something in brilacidin p2 trial data we are not aware of.
Only thing I can think of is that IPIX did heavy exclusion of subjects with SOM in cisplatin Q3W group and FDA thinks they do belong. That would have to be really, really heavy exclusion.
Thanks slcimmuno. I always appreciate your contributions.
I did the latest comparison mostly to see how brilacidin vs dusquetide looks and came to conclusion which is probably best stated using terminology made famous by Donald Rumsfeld.
"Based on dusquetide's approval for phase 3 in SOM and our current knowledge about Brilacidin vs dusquetide, brilacidin should also obtain phase 3 go ahead unless there are Brilacidin related negative known or unknown unknowns."
I concur. You have a point. I based my opinion on the list of topics for EOP2 form this source:
https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM349907.pdf
on page 23 these topics are offered as example for EOP2
- Phase 3 trial design (including dose selection and endpoint selection)
- Adequacy of safety database
- Pediatric studies, including studies required under PREA and Written
Requests issued under the Best Pharmaceuticals for Children Act
- Additional information needed to support NDA/BLA
- Context for SPA submission
- Adequacy of supporting nonclinical data
- Adequacy of supporting clinical pharmacology data
- Adequacy of supporting abuse related data
- Use of data standards for submission
It seems that some reconciliation between your quote and my list is needed. Maybe FDA can give a conditional go ahead to phase 3. Something along the lines: "do these checks first and if no issues arises then you are allowed to start phase 3". Or maybe by expanding phase 3 trial protocol. Otherwise I don't see how one can address, for instance, a finding that current nonclinical data is inadequate. Dunno.
I concluded some time ago that when it comes to FDA very few things are written in stone. But let me try.
1. Generally: No reason to think that FDA would come up with new 'issues' during waiting period. But I can imagine one: if new information develops during the 30 days period - for instance, another trial reports unexpected grade 4/5 (5 is death, BTW) adverses effects for a similar drug.
2. In my opinion second EOP2 would require new information submitted to FDA in response to possible issues pointed out by FDA. In this context new information usually means that some additional lab or trial work needed to be done.
3. It will take a bit more than haggling to change FDA decision.
LR, I have the same problem and honestly hoped that nobody would ask. That went well...