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More debate for anyone interested quote below
What I do know is this is not a lifestyle Company simply spinning out the timeline to continue to benefitfrim their current employment.We don’t know the exact FDA concerns but let us look at what we do know or can reasonably assume.
1.It appears that apart from the dramatic dumping by Invesco and M&G on the day of the CRL which forced the price down to 5p and again the evidence is that it was purely as a result of their risk mitigation rules rather than their investment side.The institutions appear not to offloaded any more.A big positive.
2. The CRL highlighted additional data on liver toxicity.We don’t know what this entails but look at what it did not mention.No mention on efficacy,no mention on any cardiac safety or on any CMC issues.So again big positives over what happened with the Arpida submission in 2009.
3.FDA will approve if drug benefits outweigh risk.I am pretty sure this will be case for Iclaprim but may involve a labelling change,warning or more post marketing surveillance all of which you can still get Approval.
4.We know there were several interested parties I doing a commercial deal.
So the choice is have FDA Meeting and raise or raise and have FDA meeting.You can put the main expenditures on hold and I don’t think they will want to take this to the wire by having FDA meeting first unless they simply can’t get the raise.
So to me they will attempt to raise first and support of existing institutions is critical so they must have soothed their concerns in short term.MTFB will know the likelihood of what is needed to satisfy the FDA requirement and the actual meeting will just be to confirm the pathway forward imo.
I believe they will announce the financing before an FDA meeting and that is a huge clue as no one will support unless they believe there is an extremely good chance of success with FDA and MTFB will have to give more detail on the precise nature of the concerns raised in the CRL to these institutions and they will have internal experts to assess this detail.
So radio silence from BOD and then newswhen it Is finalised
quote below for anyone interested in debating the crl further
I had a good look at the paratek Phase 3 results, oasis1 and 2 and they did seem to present a lot more detailed data in the published version available on the net. They had the same raised liver enzymes with their drug but perhaps presented more data to show safe and got a straight approval.
Im sure motif have all the data in patient records of those who had elevated ast/alt levels. The fda need to be abvsolutely sure this is safe before they approve and allow on the public.
As an example is it acceptable to state - "all raised levels returned to base line" - or should full full data be provided on those patients effected and their monitoring through the raised enzyme period and the time taken to return to base line. Blood/heart/liver/breathing monitoring before during and after.
Thank you Four, same to you :)
Hi Four - I wish I was invested in motif also, I don't have that many funds I'm afraid, just starting out really, in my first few years of trading! They are posting a lot of research and debating on there so I am feeling encouraged and hopeful. :)
I have seen other boards where there was a single poster and then the price rise comes and people start to post again and the debates kick in, so I will remain hopeful - quote below
A former regulator colleague commented to me that given the small safety database for iclaprim versus established ABs, the extra data requested could just be a bit more follow up on the patients who did have raised liver enzymes. If so that could be good news.
Further research to help us understand and continue the debate quote below
Repost of my notes of liver data DR H presented on conference call - by way of comparrison---
I have made detailed notes listening again to the CC of Dr HUang, Liver tox presentation - Bio included before detailed res
David Huang, M.D., Ph.D, Chief Medical Officer
Dr. Huang is a senior pharmaceutical research executive, and the former Chief Medical Officer at ContraFect Corporation. Dr. Huang also led a drug development group in anti-infectives at Pfizer. Dr. Huang has over 15 years of clinical, academic and research experience in infectious diseases. He has served as a faculty member at Baylor College of Medicine and currently as an adjunct Assistant Professor at Rutgers New Jersey Medical School. He continues to see patients at the Veterans Affairs Medical Center in Houston. His research interests include bacteriology and virology, especially the epidemiology, pathogenesis, and treatment of multi-drug resistant organisms. He is experienced in designing, executing and closing out Phase I – III clinical trials for both antibacterials and antiviral agents. Dr. Huang completed his medical school at the University of Texas at Houston Medical School, and completed his internship and residency in internal medicine at the University of Texas at Southwestern and fellowship in infectious diseases at Baylor College of Medicine. He is board-certified in both internal medicine and infectious diseases.
Dr Huang -
R1 & R2 -
15 (5.5%) patients in Iclaprim group
10 (3.8%) patients in Vanc group
Had elevated Amino transferase (Ast/Alt enzymes) (1.7% difference)
Those are patients at least 3 times upper limit of normal.
No patients had BiliRubin increases greater than 2 x upper limit of normal.
Note -(Bilirubin is produced by the liver and other cells in the body as they break down the red blood cells, in particular the haemoglobin component.
Bilirubin then drains from the liver in the bile through the common bile duct into the upper part of the intestine.
Higher than normal levels of bilirubin in the blood suggest that either larger amounts than usual are being produced through unusually high levels of blood breakdown called haemolysis, or that the normal drainage of bile containing bilirubin is being prevented.)
No patients met HY law criteria in R1.
(Hy's law is a rule of thumb that a patient is at high risk of a fatal drug-induced liverinjury (DILI) if given a medication that causes hepatocellular injury (not cholestatic injury) with jaundice. The law is based on observations by Hy Zimmerman, a major scholar of drug-induced liver injury.)
In R1/R2 -
11 patients 3.7% In Iclaprim group v 9 patients 3.0% in the Vanc
Had increase in AST/ALT 3 x upper limit of normal
Note in R2 - Outbreak of Hepatitis A - 1 in Iclaprim group and 2 in Vanc group.
2 of these had Bilirubin levels greater than 2 x normal (1 in each group)
No study in R2 met HYS law cri
There are some very well researched posts coming through quote below:
Yes parateks drug Omadacycline was approved with there phase 3 trials oasis 1 and 2 results both showing increased Liver toxins - taken this form their P3 Results -
The liver safety findings are summarized for the pooled data from the 3 pivotal Phase 3 studies in ABSSSI and CABP. Overall, 5.4% of omadacycline patients, 4.9% of linezolid patients, and 7.2% of moxifloxacin patients had hepatic AEs of interest during the pivotal Phase 3 studies. The incidences of all hepatic AEs of interest, including increased ALT and increased AST, were similar between the omadacycline and comparator groups. In the omadacycline group, all hepatic AEs of interest were mild or moderate in severity, except in 1 omadacycline patient who had a severe TEAE of hypoalbuminemia. A total of 5 patients had hepatic TEAEs that resulted in discontinuation of test article, which included hepatic failure following a cardiac arrest in
1 (0.1%) omadacycline patient (serious TEAE; not related to test article; event resolved on
Day 29), and laboratory-associated TEAEs (eg, AST, ALT,) in 2 (0.2%) omadacycline patients and 2 (0.5%) moxifloxacin patients. All hepatic AEs were either resolving or resolved without sequelae during or following completion of treatment, except in 2 omadacycline patients (TEAE of ALT increased which was considered mild in severity in 1 patient and not related to test article and TEAEs of ALT and AST increased which were considered mild in severity and not related to test article in another patient). Although these patients were considered recovered/resolved with sequelae by the investigator, no additional AEs of sequelae were reported.
The incidences of post-baseline elevations of ALT or AST by 3 × ULN, 5 × ULN, and 10 × ULN with omadacycline were similar to comparators in all patients (Appendix Table 54, page 111), patients who had normal values at Baseline, and patients who had abnormal values at Baseline. Increases in total bilirubin to > 2 × ULN were similar between treatment groups.
Elevations in ALT and AST were mostly asymptomatic, transient, of low magnitude, resolved following the completion of therapy, and did not result in discontinuation.
No patient met the criteria for Hy’s law as defined in FDA guidance.61
The use of tetracyclines has been associated with hepatic AEs, characterized, in general, as low frequency and low magnitude elevations of liver enzymes. The effects of omadacycline appear to be similar to that of linezolid and moxifloxacin and older tetracyclines.62,63 Hepatic AEs occurred at similar with omadacycline compared with linezolid or moxifloxacin treatment and treatment discontinuations were infrequent. Elevations in liver enzymes observed in patients who received omadacycline were generally asymptomatic, of low magnitude and transient (ie, reversible to baseline values during or following completion of treatment).
Further evidence of hope for approval quote below
I believe Paratek encountered higher AST/ALT levels during their P3 trials with omadacycline and received FDA approval?
If anyone is hopeful as I am about reaching levels before the 13 feb then do not worry as there may be hope, quote below to keep up spirits and continue the debate.
you may well be correct about the subset info as these numbers are so small they are unlikely to be statistically significant so depends a lot on whether MTFB wanted a clean a label as possible and that what additional data is required.
We simply don’t know and also what biomarkers are available if any to predict which patients are likely to developedvrsused AST and ALT levels.
Crucial thing to me is no permanent liver damage and enzyme levels returned to normal as the liver is the most regenerative and responsive major organ of the body.
It may be that a simple labelling change can allow Approval in the future...
Indeed they could become very valuable, fingers crossed. That is why I chose Amp because of this point exactly, I thought it had more options. Evidence why some believe mtfb is being held down currently quote below
I posted others to get IG quotes ( as they are RSP driven unlike you big standards brokers) to show what the real book is.
And to sell 500k it’s always close to the bid - 3pc.
The ask, that’s the joke - varied from 23.5 to 8.95 throughout the day. Check out the CPX example for normal mm quotes.
And ignore auto volume- neutral.
So was your ultimate judgement right but a kink in the road. Up to you mate, but all is not well in the state of Denmark.
Forecast for tomorrow . Bid will drop to 6.5p about 2 mins after opening and 3 mins later the bid will pop back up.
Etc etc.
Then at 2.30, botty activity to slowly drop and a gentle close downwards ( with a UT at 7.2)
They will bore the pants of traders.
I posted others to get IG quotes ( as they are RSP driven unlike you big standards brokers) to show what the real book is.
And to sell 500k it’s always close to the bid - 3pc.
The ask, that’s the joke - varied from 23.5 to 8.95 throughout the day. Check out the CPX example for normal mm quotes.
And ignore auto volume- neutral.
So was your ultimate judgement right but a kink in the road. Up to you mate, but all is not well in the state of Denmark.
Forecast for tomorrow . Bid will drop to 6.5p about 2 mins after opening and 3 mins later the bid will pop back up.
Etc etc.
Then at 2.30, botty activity to slowly drop and a gentle close downwards ( with a UT at 7.2)
They will bore the pants of traders.
SETs is supposed to be more liquid and better prices ; normally correct.
Yet here, SEAQ is far better priced on comparable shares. Check out more to validate,
As ever, always ask WHY? There’s no such thing as random - just humans
I couldn't buy and they did it so fast. At one point couldn't buy any and did a fok at I think 7.3p. So manipulation was on yesterday. Also noticed when a buy came , they would have AT SELLS KICK IN. If no buy or sell they were happy to do Jack. So implies sp being controlled in a range until placing done?
more food for thought for anyone interested quote below
Anyone got any thoughts on why AMP has held up so well.
I was expecting them to be a total right off
However they are only back to where we were when we were in the early 30s
Fro a risk return basis AMP has been a better share all round
Higher multiples of growth on positive news
Less of a fall on negative news.
Unless The manipulation theory of motif is involved
Indeed because mtfb are at 7p currently it puts Amp in that position, but some people believe mtfb is being held down, and in any case they are due news on fda meeting etc which will change current mtfb share price. If there is positive news flow from mtfb and that price gets back up it will change the situation here. Once mtfb get above a certain point more people start to buy Amp again as there is a chance of better returns as our price is much lower than mtfb. So I have my fingers crossed that it will be the case. We also have to remember that mtfb have acted fast in terms of finance etc. quotes below to ponder from mtfb posters
They have already proved they will aggressively manage the finance, already with the early loan repayment
The SP rose in both AMP and MTFB for a few weeks, the reason being that people start buying in before news due, in this case the FDA decision. Probably more people exit just before the news to suit their risk appetite and to take an easy 20/30 percent without any further risk. The same will be repeated again once the FDA date comes
Some further discussions on the mtfb forum to help understand what may be the situation that caused all this, quote below.
In the clinical protocol for the Phase 3 it states:
"No formal statistical analysis of the safety data will be performed"
Could it be that the FDA wants to see the actual analysis that iclaprim is statistically safer than vancomycin? I believe the company only provided descriptive stats. Maybe this wasn't enough for the FDA?
In all the noise we have not talked about the 7th feb rns where the company halted the rise due to momentum 'confirms that it is not aware of any specific reason for this movement.' this makes me wonder if they could possibly have known about the fda staff shortage or that mtfb were considering a clean label or some other reason, just something to ponder, there could be many reasons for that which more experienced people than myself would consider?
It feels good to have open discussions and consider what may or may not be. I think it is better than radio silence, below another quote from people who are smarter and more experienced than myself which makes me feel more positive. I also feel we are in uncertain times and the market in general isn't very positive with regards to news flow.
Approx 588 of 600 patients in iclaprim group had no liver tox issues, 12 had raised liver enzymes, asp/alt. Of those 12 all returned to normal after dosage with no liver damage.
Approx 591 in vanc group had no liver tox issues, 9 had the same elevated enzymes, ast/alt as Iclaprim.
600 patients out of 600 in the iclaprim group had zero kidney issues.
593 patients in vanc group had no kidney issues, 7 sustained kidney injury from Vanc dosage.
Zero patients died in Iclaprim group
3 died in the vancomycin group
Which looks the safer drug? I expect a re-label to monitor patients with raised liver enzymes.
The USP targetting renal injury patients is still intact.
These are the points that make me feel there may be light at the end of the tunnel, we just have to wait and see what will happen. Another quote
It does make you wonder about the 3 month fda shutdown and the fda running on a skeletal staff for 90 out of the 180 days allotted to the review..
Could they spare staff/time for adcom meetings, or is it easier to stall the approval and by some time until they get back to full strength? - not sure we will ever know the truth but if that is the senario they have caused some serious damage here.
Another quote which makes me feel with time it will reverse because we were not rejected just asked for more data.
The mcap was £130m a couple of weeks ago before the FDA said they require some more data on liver enzymes. If approval had been given it would have doubled as a starter. Now just £21m mcap
I have studied the Phase 3 results to bloody death and discussed them even more with pharma investors, i just cant see how they cant approve it , with or without a label to monitor liver enzymes the world needs this drug.
A lot of ground to claw back but this is a billion dollar drug once approved. (If)
Indeed that has been said and I do appreciate your comment thank you and that is why I have said it is wise to wait and see, but nothing has changed in the past fortnight other than the clr being issued and the share price here gained momentum and rose up to 2p with the same fundamentals on 13th feb. Good news inevitably brings in momentum and that inevitably means rises in share price. Nobody would have predicted the rise here when mtfb was 40p but it happened. Nobody can really claim it wont happen again, and nobody knows about the approval. Below is another quote from a more experienced poster than myself which makes me feel hopeful.
Pretty clear they will need more cash in the next couple of months. How much depends on what requirements the fda have. Funding will come after the type A meeting imo, though im already hearing a strong rumours of whats going on backstage but rumours are just that until proved.
Best case senario for me is re-submission of NDA with amendments and data required by FDA. As per the conference call - unlike in the aripida CRl the fda have not stated any further clinical trials are required.
Once known a small raise to cover costs of NDA and overheads for 4 months. Then wait for approval and if given the mcap will be over £150mil at the bottom end.
Will they then need to raise again or at that stage will "interested parties" step in.
Tough times at the moment for us long term holders whilst traders make hay.. I take solice in the fact apart from the initial panic sell and stop loss crash, the ii,s have since held. No sells from sandgrove, M&g, with Invesco still holding 14% etc.. 100% GL will have met with and spoken to them all and discussed the way forward.
It’s also been said that Amp Mtb shares do not go near to Amps debt.
What happens in mtfb has an impact on our share price because we are invested. Here is another quote from an experienced poster which I believe is useful.
I take solice in the fact apart from the initial panic sell and stop loss crash, the ii,s have since held. No sells from sandgrove, M&g, with Invesco still holding 14% etc.. 100% GL will have met with and spoken to them all and discussed the way forward.
Its not a case of wrong labelling, opinion is Motif may have wanted a clean fda pass with no side effect warnings.
A label issue means approval with possible side effect warning on the label - what drug doesnt have that.
Below is a quote from an experienced poster on mtfb, I think it is a good idea to keep an open mind. It is useful to wait and see.
All you can do is look at what info you have.
1) additional data. It passed 2 Phase 3 trials that had FDA input in tailoring and was the same as an approved drug on liver tox .
These are facts and and you’d still invest on that basis the day before d day ( and kidneys 7-0 to MTFB )
2) a 5 pc holder puts the whole lot up on the ask on opening , not drip feed, no worked order and the auction was 75pc higher 1 second before trading opened. Who then dragged another 10 pc of a long term and witch in turn triggered 50 m of stop losses.
If anyone has seen or anticipated all of this before, let me know. Even the biggest derampers assumed approval was a given
Watch and wait imo.
I think it is important to see the bigger picture. I am certainly going to hold until we get past this bump in the road, even though I am heavily down as share prices can be unpredictable. There can be things going on in the background that ordinary people will not even dream up because we think differently. Lets not lose sight of what we really have here. Both shares here and in mtfb are wanted! Therefore I am going to ride the storm and the tree shakes. Let us see what will happens.
can we trade AMP today with almost a 30% spread?
Thanks Ian,
my point is though, that for PIs trying to research their investment, all available information is useful, be it pro or anti. All Northern explorer was doing on this board was repeating that wiki entry, maybe he's spun it a bit but essentially that's what he's done. I hope the drug gets approval because otherwise I've lost a lot of money but with hindsight you would have to say that the message boards for Mtfb and Amp were guilty of a pro bias and it has cost us. Anyway, fingers crossed, things will come good and worse case I've learnt an expensive lesson.
Hi Jam,
As you say should not take what Wiki says as gospel but couple of comments.
Firstly the recent Revive trials demonstrated Non Inferiority(NI) to the comparator standard of care drug ie Vancomycin and QTc is to do with cardiac issues rather than liver issues.These were not raised as a concern by FDA recently.
This improvement is as a direct result if the changes to the dosing protocol of fixed dose Iclaprim
There are unresolved liver issues which was raised last time as well but there has been a dramatic improvement since the original Assust trials back in 2009 as well as a transformation in overall need forcABs