Member Info for Ivyspivey

CFP
Not seen their liver tox results specifically but coukd look at the SPC.
What you have to remember is if a drug like Linezolid or Vancomycin has been around for 30-40 years at the time of Approval the licensing regs were probably less rigorous.Yes they Wouk day have been subject to reviews but not the same level of scrutiny as newer drugs.
The point I am trying to make is that all drugs have side effects and if it is not liver it is renal like Vancomycin or CNS.
So is a balance between safety and efficacy and trade offs.
Remember the alternative for many of these patients is AKI ai(Acute Kidney Injury) in case of Vanco for so a temporary liver enzyme elevation is unlikely to be an exclusive reason not to use Iclaprim imo

Look at Delafloxacin Approved earlier this year with a Black Box warning

https://baxdela.com/

CFP
The main issues are effects diabetic patients.Also effects Seratonin so contravinducated in CNS treatments.

https://pbs.twimg.com/media/CsAeGZEWYAE2bYm.jpg

Hi Tobias,
Dont get hung up on metabolism mechanisms I just posted fir completeness .
Comment by my medical professional friend was

re. slow metabolism; i'm not sure that really holds. Iclaprim is metabolised by CYP3A4, which although demonstrates polymorphism, I don't think it leads to any particular clinically relevant alterations (But this could explain why some people metabolise it will and some don't). It's worth noting that even an inflammed liver with perhaps a 10-20fold rise in transaminases can still perform it's function perfectly well in many regards, and CYP3A4 is present in intestine too.

So important but if Iclaprim raised AST and ALT liver enzyme levels say above 3x normal in a very limited number of patients and returned to normal and did not cause any severe liver episodes then as my friend says even if they were raised 10-20x normal the liver can still function perfectly well.

Hope that helps

Comment from a medical professional who also attached previous article

re. slow metabolism; i'm not sure that really holds. Iclaprim is metabolised by CYP3A4, which although demonstrates polymorphism, I don't think it leads to any particular clinically relevant alterations (But this could explain why some people metabolise it will and some don't). It's worth noting that even an inflammed liver with perhaps a 10-20fold rise in transaminases can still perform it's function perfectly well in many regards, and CYP3A4 is present in intestine too.

Read 'Human Pharmacokinetics' Paragraph 2 in this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798018/

See p8 under Human pharmakinetics para 2

Plus of course things like paracetamol
In addition drugs like Aspirin which are classified as NSAIDs have potentially very severe effects on GI bleeding and causing gastric ulcers due to the fact they are very COX 1 specific

Yes have seen the SEC amendment but the critical thing is the IP is not at risk

Just the private twitter group

All for balanced posts but definitely a curates egg today.
We can ask legitimate questions about should the BOD have been better prepared for the CRL and did they have an adequate contingency plan.My guess on the info available and the current response is no.So yes that is a big disappointment,but we are where we are so let us give them the opportunity to get us out of this mess.
We may only be PIs but we can see in the p3 data why the FDA have asked the question about raised liver enzyme levels but again the evidence so far is that is not a rejection issue so as long as additional data can be submitted to FDA satisfaction then we are in business.Obviously we won’t find out until at least the meeting but nothing that has come to light so far to indicate that any current objections can’t be overcome.
The fact that the FDA have accepted the efficacy and seemingly CMC aspects of the NDA are huge positives.Dint forget in the original Arpida application the regulatory authorities had concerns over efficacy as well as some raised liver enzymes and CtC issues.So definite progress been made.That is I ndusputable.
Also what is not in doubt is the critical need for new ABs and the fact the FDA will want to Approve Iclaprim.
As we have seen from recently Approved ABs it can be done with a black box warning which obviously we don’t want here but can be done.
As for funding yes they need money and why would institutions not buy in.Likes of Invesco have lots of money invested here( until we hear different) so am sure to protect the rest of their investment they would imo be happy to take part in a further raise as would many others.
Of course there would be a price to pay a low placing price and possibly warrants and they would want to know more about the specific issues revthe FDA have asked for but if they invested it would be a huge sign of confidence.
As Ian B has said the risk/ reward from these levels is much better than when Invesco bought in at 50p and 32.2p.
As for MTFB going bust.Absolute nonsense in that the Hercules agreement buys some time but their risk mitigation was expected.The IP here assuming FDA concerns can be met is huge well over $1bn so sure some will take the gamble.
See Merck drug Keytruda did not get Approval either so may or may not be related to resource issues within FDA during shutdown but does indicate the difficulty’s of a Company like MTFB getting Approval.
Still risks ahead but I for one accept them but hopefully MTFB have learnt the hard lesson that many LTH have andvthst is to have a Plan B in case Plan A does not go the way you think however confident you are.
ATB

Interesting one is SG who hold 11%
Feeling was they we’re only here for a catalyst but of course it was in the wrong direction

Hi Max/Jimzi
Makes a lot of sense.
Dont forget Invesvo hold loads of warrants at 32.2p from Nasdaq listing so they could have off loaded a lot more shares if they wanted too and still have a lot of safe exposure.
They have also been very supportive all way through.They took part in 2015 placing paying 50p.
GLA

No doubt Private Ryan always follows the General Jimzis lead.

Yes Jimzi,
Could be an interesting conversation when we next meet up.Did not even get the chance to ask any questions as event was controlled to ensure no heavy criticism.
All in all I was reasonably happy with Conf Call.I did not expect any more and yes GL was very monotone but that does not bother me as all I interested in is moving forward to try and sort out this mess.
Pretty clear on my strategy moving forward so much happier now but each to their own.
FDA meeting is key and nothing in CC to over concern me that it is nothing more than than a delay but we still await further info.
The funding will get sorted and this will be be very volatile and still risk but if the regulatory pathway becomes clearer then I am very positive about the future from these SP leveks in particukar

CFP
Yes wish there was more time to ask questions but they wanted to control it

Yep Ian
Was expecting that given FDA and SEC requirements.
Looks like concerns were over the AST and ALT levels but my understanding is all went back to normal when drug discontinued.
They had engaged with liver experts in response to preparing for AddComm which did not happen.
FDA have agreed to meeting a slip.
Various interested parties around the world in play so all on Approval.

PR unless I have missed something there is nothing in the data summary to show any issue with general liver toxicity only 2% of patients effected in both Groups so nit enough to cause an issue imo.
But until we know what additional data is requested we can only guess but much more likely imo to be based on a subset viewing the currently available evidence

Jimzi /TP yes we need more data but my hope is that it is just the sample size needs to be increased to achieve say 95% CL.
I am not talking about the whole trials which were large enough but specific subsets like raised liver enzymes etc

Tobias.Have read and a lot of stuff there.
Some if it is from original Arpida trial ie AUC stuff as think that us oral Iclaprim from memory.
The fixed dose 80mg I/v was to help reduce that and Revive trials seem to support that.The lack of biomarkers coukd be important but a normal blood test would be fine at start to check liver enzyme

TP23
Yes at looked at those stats however some of triallists would be IVDAs so you need to know more detail about individual patients but there was nonAddComm.
The interesting bit to me was the very low levels of raised AST and ALT in the whole group.