Member Info for Ivyspivey

PR yes the final $5m ofbthe Hercules loan is subject to Appoval.They can of course waive that clause.

Pooled Revive 1 and 2 Safety Results.

https://1v6gj215h9gy3y4dgh3it40h-wpengine.netdna-ssl.com/wp-content/uploads/2018/06/ASM-2018-Iclaprim-REVIVE-Safety-Poster.pdf

I have had a closer look at specifically the liver toxicity results associated with the p3 trials.You can see these in Revive 1 and Revive 2 under 2 references.These are the 2 liver enzyme levels which are generally indicative of liver issues these are AST and ALT.

The first thing to notice is the extremely low number of trial patients in both groups.On average about 6 out of 300 patients so approx 2%.So highly unlikely imo the CRL can be about a widespread liver issues with Iclaprim if only 2% of patients are affected.( don’t forget this targeted group are likely to have various co morbidities.).
Secondly in comparing the Iclaprim and Vancomycin groups they are very similar.
AST=2% for both Iclaprim and Vancomycin.
ALT=1.9% For Iclaprim and 2% for Vancomycin

So pure conjecture of my behalf but looks like it is about increasing a small subset to get a “proven” result hence the additional data required.
It could be about wanting a clean label or the FDA want further clarification on data to achieve a CI of say 95%.We don’t have enough data to extrapolate further but if this was rather case it may be MTFB simply require a very small trial to increase the numbers in the subset for whatever particular purpose is required by the FDA.
Hope this is of use

To show no hard feelings.

FYI Sareum attending

Https://www.biotrinity.com/biotrinity2018

If they had raised prior to Approval and the CRL hit dropping the SP, What do you think could happen.
You could have a class action against the BOD who would face long spells in jail for misrepresentation.
Why do you think GL is understated and not prone to wildly optimisti pronouncements about likelihood of success like many AIM CEOs.Of course he is confident and if it proves that the BOD have proved culpable in severely underestimating the risk here I will be really angry but until we know I am reserving judgement rather than jumping to conclusions befirecI have the full facts.

Will speak at some point but no one can say anything until the CRL is published and that is FDA prerogative.
It is that simple.They are subject to US law which puts all kinds of restrictions on what can and cannot be said.I understand that but it is a totally dfferent situation that pertains to AIM.

CFP.Everyone knew they would have to raise so hardly news.
If they had not included that it would have attracted US criticism of being misinformed.
Trek.You raise one of my main issues.What pre warning did MTFB have of “ liver toxicity” concerns if any. That is crucial to me in assessing where the blame may lie and what my future mood will be.
The institutions would be very closely involved with MTFB in run up to PDUFA and showed no signs of derisking so I assume it was a complete shock to them as well as me.
If it turns out not to be such a shock then that is my main issue but we will find out in the fullness of time but unless you are directly involved we are simply guessing.
Anyway other things to do

Hi CFP,
They have effectively put the big spend items on hold.HABP/EMA submission and any recruitment of commercial arm.
I know everyone will make comment on salaries etc as LTH have lot of pain and want it to be shared by BOD.
If I believed they were a lifestyle Company I would agree but cerainnthey are not. They will have lost millions in option worth’s and the institutions will be rightfully bending their ears
Yes director buys could help or taking part in any raise but still many will say it is not enough and may be counter productive.
They only employ about 8 people so 3 month worth of salary’s a drop in the ocean.
Many people think GL should go .I disagree but understand people’s thoughts.Imo he is best current chance to get us out of this mess and who would you bring in?

I keep on repeating myself until we know exactly what work needs doing none of us knows how much it will cost.
I get the anger and the need to vent.I am angry myself but it is calm heads and detached minds that are best in these situations.
GLA

Morning Trek,
Let us take your pronouncements one by one.
Iclaprim was “ not comparative to a baseline”.Of course it was it was comparative to the standard of care VancomycinThat is how the FDA runs p3 trials using NI margins against the soc rather than a superior inferiority trial against say a placebo.
We don’t know the “shortcomings” and neither do you unless you have the inside FDA track which I doubt.
Yes the MMs would drop the SP to the lowest level they can get away with and my understanding is the selling by Invesco and M&G is an automatic kick in process imposed by the risk management side of the institutions rather than the investment side.
I thought the selling was SG given the 33m figure in the big trades and the fact they were for a catalyst but itv as obviously the others.
Invesco have been there from the start and only ever sold very small amounts to stay below the takeover threshold.
No institution was selling before PDUFA in fact M&G were buying so they were happy to hold and not Derisk so I guess they were as shocked as all of us at the decision.
We are all,speculating about the exact detail of the CRL and none if us know for certain what it contains.Let us kust wait and see what happens.
ATB

Hi Thoth,
Not wanting to get into an argument with you as don’t know why anyone wants to post on any board where they are not invested/ interested in investing there.
Your argument a year ago was nothing to do with the chances of Approval which has caused this drop but has consistently been about the size of the market for ABSSSI in the US given you consistently posted the high proportion if such people were IVDAs( intravenous drug users) who in the main were nit covered by insurance schemes.
I disagreed with you fundamentally on that fact plus we were not competing vs Vancomycin where cost is the issue.
If you did not come to gloat then why did you come here.You and Petch certainly did not see the CRL coming that is the issue.
Anyway I will just take this in my stride and carry on but I know from private contact that many on here have suffered enormously so feelings will be raw when outside people turn up with a hindsight opinion.
Many of the newer investors will be in nice profit here without taking any risks that the LTH on any bio take and GL to them as they will in the main have had days like the LTH had here on Wednesday.
This is part of the AIM ride and I wish everyone including you long term success.Anyway last comment from me on the subject as helps everyone move on.

Thoth
I see your desire to gloat over the misfortune of others has not diminished with age.This has fallen so much I don’t it is worth shorting.
Even Petch the arch troll on here thought it was getting Approved so plenty of Jeremiah’s who turn up after the event and then crow and position themselves as well I knew it was predictable are entirely disengenuous.
Any bio that suffers on AIM has a knock on effect on other bios.You should know that from your experience on SAR which is hardly a success.
Anyone who takes pleasure from the misfortune of others is a strange one to me and the stopping of novel drugs getting to the market when they are desperately needed is not something to be admired.
I admit I have made a big loss here I could hardly deny it.You will have lost money in SAR given its SP performance so suggest you go short on there a it has much further to fall but personally I don’t want anyone to lose money but guess that is the difference between us
ATB

Eviking,
All the data from the Revive 1 and 2 trials suggest no particular concerns over liver toxicity and there are a lot of drugs including many ABs which have restrictions on patients with liver issues.So I have no specific issue with Iclaprim at 40
Mg or 80mg in the targeted.
However the FDA hsve raised concerns and until we know what those are we are in the dark

Particular interest is LT01842 which is Trimethoprim which is a DHFR from the same novel chemical class as Iclaprim.
Class 4 pretty mid range

With liver damage “ concerns” including many ABs.

https://www.fda.gov/downloads/ScienceResearch/BioinformaticsTools/LiverToxicityKnowledgeBase/UCM606243.xls

PR.
The FDA will publish the CRL first.It is just the way they are.Thet are all powerful and you have to toevtge line.
Arpida trued to argue with them last time and if you read the AddComm transcript it was obvious the hostility in the room.yes the environment and attitude of FDA has improved immeasurably but still found vreasons to issue the CRL

Spike the CRL will be published in due course and yes MTFB will have received a copy.Normal protocol is not to comment on details until they have clarified this at the FDA meeting.Any release of information can prejudice an upcoming meeting a bit like a court case .
I know SH want to know of course we do but until the FDA clarify and MTFB get an agreement on how to move forward they imo will not comment publicly on the detail of the CRL until they have their meeting for fear of antagonising/ prejudicing their case.
Whatever our individual thoughts they are best judges of what to disclose in advance if any meeting

They addressed both liver and CtC( cardiac) but that was all about it being a weight related rather than a fixed dose.
The change to a fixed 80 mg dose suggested by the FDA to improve safety without compromising efficacy was a major change from 2009.
The p3 trials supported this including the non significant differences between the Iclaprim and Vancomycin groups revraised liver enzymes.This seems to be the area the FDA are questioning and nay well be it is snout getting enough numbers to achieve statistical significance within the agreed CI

Or alternatively they could resubmit with a black box warning on do not use in patients with liver impairment.Some drugs have these warnings and get Approved,It can of course limit their target audience which MTFB aretsrgeting renally impaired patients but many of these patients have a few additional risk factors

These were the changes made to Assist 1 and 2 by MTFB to get Iclaprim through p3.This seemed to work well.
We have the issues of liver toxicity raised by FDA.Now we know that the raised liver enzyme levels were nit significantly different between the Iclaprim and Vancomycin group so why do the FDA have an issue.
Is it because MTFB went for a clean label( ie no restriction on say mild impaired liver) We know that moderately impaired requires 40 mg or half dose.Ifvthis is so perhaps there were not enough in the subset if patients as highlighted by Liver Function tests on p63.See below exclusion criteria

Treatment-emergent LFT abnormalities (see Section 7.6.2.6.4 for expected evaluations):
o Patients who have confirmed AST or ALT elevations of > 5X ULN should be discontinued from study medication and followed through LFU for safety; and
o Patients who have a bilirubin = 2X ULN with an AST or ALT = 3X ULN and with an alkaline phosphatase (ALP) < 2X ULN should be immediately discontinued from study medication and followed through LFU.

Or is they wanted more patients in the moderate impaired liver group to get a full clean efficacy label based on 40mg..
If so this should be relatively easy to sort out but will take time to resubmit etc.
However if it is something more I simply don’t understand based on p3 liver enzyme results and likely shock ofvMTFB.
Until we see the full context of the CRL or hear from MTFB we simply don’t know and anyone who claims they do know are being entirely disingenuous imo.
Until we know this we don’t know the full extent if any rework and resubmission.
GL

Antra.All depends on how much work needs to be done to get Approval.Iclaprim is if Approved still a very valuable asset and many pharma Would day snap it up.The issue now is if MTFB can get it over the line then a lot of this value can still be achieved but if it can’t or needs dilutive funding then it will just be a much less rewarding position.
That is why we need info but I just can’t see that being available soon to us SH.
Sheltie,Come to grips with it now and all about damage limitation and how best to move forward based on available evidence and what I can glean moving forward.
Feel much better now and will have a good w/end.

Evening Sheltie,
No still in.Sold the few I bought yesterday morning to defray a very small part of the heavy cost of yesterday.
Damage limitation now and try and trade a little if opportunity allows but basically think this will take news and clarification of the situation.
I always said I would stay in this until the science changed and this is the first but a huge jolt to the system.Until we know exactly what the concerns are re hepatoxicirty it is hard to decide exactly what the FDA require MTFB to do.
In some ways I think the more difficult the situation the easier it is to work through it.
Hopefully the amount of work required is not huge and yes will take time but happy to wait.However if it is more fundamental then will require more effort.
My gut instinct tells me it is the former and if the BOD were truly shocked as I certainly was then that is a good sign in that it may be something that they were hoping to get like a clean label rather than a must have.We simply don’t know.
Then there is the question of raising the necessary funds.There is still a lot if value in Iclaprim but if course MTFB is not in a strong position.
Maybe some philanthropic or charitable funding like BARDA can come in or a commercial partner or white knight comes in and moves the thing forward.
Much of the potential reward could be reduced and like many LTH I have altered my exit strategy and as always will act one if the opportunity arises like a rising SP or if it does not react but will wait until we get a better idea moving forward.
GLA