The latest Investing Matters Podcast episode featuring financial educator and author Jared Dillian has been released. Listen here.
1) During the Revive I and II trials, did MTFB conduct liver function tests: A) at the end of treatment (EOT) visit, B) at the test of cure (TOC) visit (7 to 14 days after the EOT), and C) at the late follow-up (LFU visit)?
2) If they answer yes, how did the results compare to the Assist I and II trials? In particular, did the AST/ALT levels of a set number of subject continue to increase between end of treatment (EOT) and late follow-up visit?
3) If they say the question lacks relevance, ask them why they went to great length to discuss the Assist trials liver toxicity data in the 2019 20-F (SEC Annual Report) but not in the 2018 20-F? Then proceed with repeating questions 1 and 2 back to them.
4) If they say they did not re-perform the same liver toxicity studies for the Revive I and II trials, ask them how could they not have re-performed the studies since Arpida could not explain the reasons behind increases in ALT values developing after stopping iclaprim?
5) If they say the fixed-dose regimen used in Revive I and II trials resolved all previously reported liver toxicity problems, ask them how could they be comfortable with the safety profile of the new dose regimen if they did not re-perform the same liver function tests they conducted during the Assist I and II trials?
@Bermudashorts - I have taken notice that you are a very good scenario forecaster. That said, I was really hoping that you would disclose what your gut is telling you. Let's hope the FDA gives a much deserved break to Iclaprim: an investigational drug that has been in development for what seems like ages!
@86DA: I am familiar withe the NDA re-submission process following a CRL. My question has more to do with what would MTFB have to provide to the FDA to resolve the CRL (in terms of new clinical trial results, supplemental data analyses, or agreement to change the Label, or to conduct post market approval surveillance)?
Based on what we think we know as far as FDA's concerns are, what do you think are the odds that the Type A meeting would provide a relatively easy path to market approval?
I happen to think the FDA used the CRL to buy itself more time to complete its review of the NDA. I know that sounds controversial. However that's one of the dirty secrets of the Pharma industry. As such, it's my belief they will provide an easy path to market approval such as supplemental data analyses, label change, post market approval surveillance.
I get that we will get all the skinny details on the path forward for Iclaprim within the next two weeks. However, it would nice to hear your thoughts on how you see the regulatory approval process unfold.
@Bermudashorts - All your points seem valid to me. In any case, there will no longer be any mystery to solve by the end of the next two weeks. MTFB will have no other choice but to clearly spell out what the deficiencies are and provide details on the agreement they have struck with the FDA to remediate them. Until then, the wait continues.
@Bermudashorts - Just as yesterday, you brought more clarity to the conversation today. Thank you.
@Lawson: I DO NOT have any authoritative expertise in medicine, pharmaceutical research, FDA approval, or share investing. I am just a regular John/Jane Doe trying to make a little bit of money speculating on which company's share price will experience a meaningful increase in the near to medium term. I have made more bad than good bets in the stock market.
My interpretation of the series of events is that something happened between 2018 and 2019 that compelled MTFB to include in the 2019 Form 20-F a detailed discussion of the observed liver toxicity effects of Iclaprim during the Assist-1 and Assist-2 phase 3 trials? The key event that comes to mind is the February 2019 CRL from the FDA denying approval of Iclaprim based on liver toxicity concerns.
MTFB came to my attention several weeks after the CRL was issued so I am not as intimately familiar with the history of the company as some on this BB are. I do however remember various posters saying that the MTFB BOD/Management was shell shocked by the FDA's decision. How can a company's BOD/Management not be caught off guard by an unfavorable regulatory ruling stemming from clinical research that took place 10 years ago and that most people (including London/Wall Street research analysts, MTFB BOD, retail investors, pharma publications) thought would be irrelevant the FDA's ruling?
Some may wonder why would the Assist 1 and Assist 2 trials have any bearing on the FDA's decision? That is really anybody's guess. My take is that if the results of the Assist-1 and Assist-2 trials are part of the NDA submitted in 2018, then they are fair game from the FDA's perspective. Plus, let's not forget that the FDA is both judge and jury when it comes to the NDA review process.
I hope I answered your inquiry to your satisfaction. Having said that, I invite you and others to obtain your own corroboratory confirmation of the factual details I shared then draw your own conclusions.
@ColdFishPie - I have no desire to conscientiously work with any body here. I live and die by my own research and my own thinking. I am only interested in having constructive discussions. I am not a frequent poster on here. I try my best to post when I come across information (positive/negative) that that may me relevant to the group here. When I do post information and another poster uses dubious reasoning to discount my post, I reserve the right to call out his/her incoherent thought process. I will leave it at that.
I just finished skimming through the "Clinical Experience" section of the April 8 2018 Form 20-F and it has ABSOLUTELY ZERO discussion about the observed hepatic effects of Iclaprim during the Assist-1 and Assist-2 trials. Umm... I wonder why???? Why was that not relevant in April 2018 but is relevant in April 2019??? What changed between April 2018 and April 2019??? Let's keep in mind that Form 20-F serves, among other things, as a mechanism to disseminate new/old pieces of information that can have a bearing on the investment merits of MTFB.
So let me ask this question again, what could have changed between April 2018 and April 2019 to warrant a detailed discussion of Liver Toxicity results from the Assist-1 and Assist-2 trials in the 2019 Form 20-F???? Keep in mind, both of those trials took place between circa 2005 and 2008....
I will refrain from offering up my interpretation of these FACTS and leave it up to the reader to draw his/her own conclusions.
DYOR & GLTAH!
@Ivyspivey: It goes without saying that none of us on the BB knows exactly what the FDA concerns are. We are obviously all speculating. However, there is speculation based on sound reasoning and there is speculation based on incoherent reasoning.
You said: "The Revive p3 trials which are the fundamental basis of the NDA display no particular liver toxicity issues and don’t mention any issues regarding efficacy or QTc at all."
You talk as if you have an authoritative mastery of the NDA review process but you clearly don't. You may want to sound and act like it.
@Ivyspivey: How can you say the Arpida Assist data was in the NDA but it has limited relevance to the liver toxicity questions by the FDA? Any clinical research in an NDA is fair game as far as FDA approval is concerned. Had you said the Arpida data was not part of the NDA, then you can claim it has limited relevance. While you are obviously entitled to your opinions, your reasoning in this specific instance is not coherent.
========================================================================================
Ivyspivey said: "Purely posted for info as a few earlier posters had raised points re Arpida ASSIST phase 3 truaksvabdvthe liver results.
***Although it was submitted in the NDA it has very limited relevance as the dose rate of Iclaprim was variable.****
So info is totally indifferent to answering FDAs concerns imo."
@Bermudashorts: Quick correction, the Arpida clinical trials at issue were both Phase 3 trials (Assist 1 and Assist 2). However, it appears that those Arpida trials are part of the body of the research pertaining to Iclaprim. In other words, they seem somehow relevant to the NDA submission. Most recent scientific papers and analyst research reports include a meaningful discussion of the Assist 1 and Assist 2 trials. Again I could be wrong. However, we will all get the skinny details on the who/what/why/how/when/where of Liver Toxicity within the next 2 weeks. I will chime in again once NR on meeting minutes is issued.
Wishing all MTFB holders a great weekend!
@Bermudashorts: You are right that those trial results were from the Arpida days and it appears to me that those phase 2 results were part of the NDA submission. Feel free to correct me if the results of your research lead you to conclude that I am in error in my assessment.
@ColdFishPie: Not sure what's your basis for asserting: ***but i can now see why the fda would use a crl now to buy time and ask for follow up data.***
I am however in agreement with that remark. If the FDA has an expertise in anything it is "buying time". I won't be elaborating further on that observation. However if anyone does enough research on the validity and reasonableness of past CRLs, he/she will be able to relate to my observation.
Just wanted to share some additional nuggets I got out skimming through Form 20-F. FYI, SEC disclosure filings can contain treasure troves of information.
Somewhere in the 20-F, MTFB provides a detailed commentary on the results of the various phases and aspects of the clinical trials. Most of what is said is already on the public domain. However there are 3 sentences that caught my attention in terms of what may have led the FDA to request more data on liver toxicity. When compared to the Linezolid-arm, the Iclaprim-arm had 3 times more cases of subjects with continued increases in AST aminotransferase 15 days or more following end of treatment. Furthermore, MTFB could not explain why the mechanism behind increases in ALT values continued after stopping iclaprim. Please refer to (1), (2) and (3) below for the info as disclosed by MTFB.
I am fairly confident that a combination of Label Change and Post-Market Approval Surveillance is the absolute worst outcome we can expect out of the Type A meeting.
AIMHO, DYOR & GLTAH!
=======================================================================================
Clinical Development Plans and Results
With respect to hepatic effects, the table below provides a summary of liver function tests: number of patients with extreme values. At the end of treatment (EOT) visit, 14 patients treated with iclaprim (2.92%) presented with ALT aminotransferase >3xULN compared to 17 (3.62%) in the linezolid arm. At the test of cure (TOC) visit (7 to 14 days after the EOT), 18 patients treated with iclaprim (3.87%) presented with increased ALT aminotransferase >3xULN compared to 13 (2.86%) in the linezolid arm.
(1) ***At the late follow-up (LFU visit), 24 patients treated with iclaprim (5.25%) presented with increased ALT aminotransferase >3xULN compared to 8 (1.83%) in the linezolid-arm.***
Neither patient group demonstrated a pattern of elevation in bilirubin or alkaline phosphatase or an excess in elevation in comparison to the other. No study drug discontinuations were observed due to elevation in aminotransferases, bilirubin or alkaline phosphatase in the iclaprim group. No cases met criteria for Hy’s Law [aminotransferase elevation greater than 3x upper limit of normal (ULN) with findings of cholestasis or elevation of total bilirubin 2xULN]. None of the deaths in the iclaprim group were associated with abnormal liver function tests or indications of hepatotoxicity.
Overall, subjects with increases in ALT and AST levels were asymptomatic, and the increases in ALT/AST were reversible.
(2) ***The mechanism behind increases in ALT values developing after stopping iclaprim is not known.***
(3) *** Drugs that cause severe liver injury in humans generally have not shown dose-related toxicity, and generally have caused low rates of severe injury in humans (1 in 5,000 to 10,000 or less). Such idiosyncratic reactions due to iclaprim may not be revealed in a safety population of
Below you will find a portion of the strategy discussion included in MTFB's Form 20-F filed with the US Securities and Exchange Commission (SEC) on April 15 2019. You can think of Form 20-F as a type of annual report that a specific group of foreign issuers have to file with the SEC.
Based upon the statements in between asterisks, MTFB has a good understanding of what it would take to allay the concerns of the FDA. It even sounds like MTFB and FDA had have ongoing exchanges from the time of CRL issuance through Type A meeting date. According to MTFB: ***At this meeting, we intend to discuss the existing data contained in the NDA submission and supplemental data analyses that have been provided to the FDA, anticipating that this may be sufficient information for regulatory approval in the United States***.
I don't recall that MTFB ever disclosed elsewhere that they provided supplemental data analyses to the FDA. The time required to prepare the supplemental data analyses may explain the delay in holding the Type A Meeting. Under normal conditions, the Type A meeting would have occurred no later than late March 2019.
I am fairly confident the publication of the outcome of of the Type A meeting will have a positive effect on the share price. The referenced disclosure was all I needed to buy as many shares as I could afford. As of today's trading session, I am done buying MTFB shares. I am ready to hear the FDA's verdict and hopefully celebrate a multiple fold increase of the share price.
========================================================================================
Our Strategy
Our goal is to help physicians to treat hospitalized patients with serious and life-threatening infections by developing novel antibiotics, designed to be effective against multi-drug resistant bacteria. We are pursuing the following strategies:
· Rapidly address, to the satisfaction of FDA, the issues raised in the CRL for Iclaprim. We have submitted a “meeting package” in response to the Complete Response Letter received from FDA and previously announced on February 14, 2019. FDA has confirmed receipt of the meeting package and has confirmed the date for a Type A meeting on May 3, 2019. ***At this meeting, we intend to discuss the existing data contained in the NDA submission and supplemental data analyses that have been provided to the FDA, anticipating that this may be sufficient information for regulatory approval in the United States***.
· Commercialize Iclaprim in the United States If Approved . We intend to commercialize iclaprim in the United States for ABSSSI either by building sales, marketing and market access teams ourselves, partnering with a contract selling organization or identifying a strategic partner with commercialization capabilities. We are seeking proven commercialization partners in other key global markets.
@Ivy : Thank you for your answer on whether Iclaprim is derived from a novel compound.
Because MTFB has very little in the form of bargaining power when it comes to negotiating a cash raise, I doubt that just a typical cash raise will have any signal value as it relates to the likelihood that the FDA will approve the NDA within a reasonable time-frame.
Now, if MTFB was to announce a major licensing/co-commercialization agreement for the USA with a significant upfront payment (+$75Millions) combined with significant milestone payments, that would indicate MTFB has high confidence that the type A meeting will be a formality.
@The.Italian:
I think your post references several comments including mine: "By FDA rules, a drug company that receives a CRL is entitled to a Type A meeting with the FDA provided *specific steps* are followed." with an emphasis on "specific steps". If a drug company is unable to put together a meeting request that complies with FDA's requirements, they have no business trying to commercialize a drug in the USA. We can agree to disagree but from my standpoint, that MTFB would be granted a Type A meeting with the FDA, was a foregone conclusion.
The share price was up more than 140% at some point during intraday trading after what I feel like was a yawn inducing RNS. By FDA rules, a drug company that receives a CRL is entitled to a Type A meeting with the FDA provided specific steps are followed. We also knew MTFB is in dire need to raise money.
So what can we attribute today's price action to? Me think there is a lot of existing and potential investors sitting on the sideline waiting for a strong signal that the FDA will approve Iclaprim within the near to medium term (6-12 month) to get in the share registry.
Quick question to the BB, can anybody confirm whether Iclaprim is derived from a novel compound (as in one that has never been approved before)?
Many thanks to N4@Penny for following up with MTFB's PR firm. If what the PR firm said is true then MTFB's management may have failed to abide to the continuous disclosures requirement that should be expected of a publicly listed company. If they received an information request pertaining to liver toxicity during the review cycle, they should have disclosed it to the market as this is material information. I would like to think the info request would have been framed in a way that would indicate liver toxicity may prevent the FDA from giving a clean bill of health to the NDA.
From failing to raise enough funds in advance of PDUFA day to not disclosing to the market the information request from the FDA, MTFB management has some serious answering to do.No wonder some heads have begun to roll. I hope the resignation of the Chairman is just the beginning of a much needed change in leadership because a number of key people clearly dropped the ball along the way. It appears that Richard Morgan & Company at AMP have an unusual appetite for debt and that may have influenced MTFB's choices pertaining to its sources of funding. But I digress...
Based on what the PR firm said, the MTFB Management should/must have a full understanding (even before that Type A Meeting) of what it is going to take for the FDA to approve the drug. I sure hope they walk in those interactions with the FDA with a real desire to play ball cause the FDA is both judge and jury when it comes to the approval of drugs in the USA.
Having said all that, I still believe the worse outcome we can expect is an FDA approval with labeling change and/or post-marketing study commitments.
The wait continues...
===================================
PR Firm Said:
"...The Company received an information request regarding elevated liver enzymes during the review cycle and provided a comprehensive response after consulting three of the top liver experts in the US..."
===================================