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And QTc and QT prolongation on ECG recordings are well known side effects on all Antipsychotic drugs currently in use and can easily be monitored .
So this is not a big deal either.
I will repeat Arpida failed in fda approval then because of efficacy in comparison to another AB and nothing else.
Staying put and hopeful until further news from motif.
One happy holder!
FYI, the FDA discontinued use of approvable letters and not approvable letters when taking action on marketing applications in 2008. Instead, FDA sends applicants a CRL to indicate that the review cycle for an application is complete and that the application is not ready for approval.
As GL pointed out with regard to timelines, the FDA starts a new review cycle after the resubmission of an application following receipt of a complete response letter.
The fact is that against all advice, Arpida selected a 12.5% inferiority margin, and iclaprim may have even missed that again Zyvox (see Ad. Comm. discussion). QT prolongation was an additional concern. I don't think the oral liver toxicity data was shared with the FDA at that time, although I may be wrong (the iv to oral switch data wasn't released until Dec 2008).
The EMA raised liver toxicity issues which Arpida was unable to address (according to the CHMP) at D120, writing in the Withdrawal AR “Similarly, there is insufficient assurance based on the limited available data that iclaprim is not hepatotoxic at the recommended dose level. It remains unclear why increase in ALT values develops long after stopping iclaprim despite the observation that in vitro mitochondrial toxicity data on human hepatocytes did not reveal adverse effects. Present limited patient database and analyses do not allow identification of patients (with normal or slightly increased LFT values at baseline) with increased risk for liver function test elevations in order to include targeted precautions in the SmPC for such patients. Although, in the light of present limited patient database a risk factor analysis (e.g. patients with underlying
conditions, concomitant medications) is not expected to generate conclusive findings the applicant should conduct risk factor analysis with the available data collected in clinical programme in order to identify patients with increased risk for liver function test elevations. Overall, the provided response of the applicant to CHMP Day 120 List of Questions does not change the earlier conclusion of the CHMP that on the basis of available data, the major cardiac and hepatic concerns outweigh the questioned benefit whereas there is no sufficient clinical evidence provided that Mersarex is beneficial in special patient groups failing other antibiotics or intolerant to standard antibiotics used in the treatment of cSSTI.
The CHMP didn’t mention the phase 1 and/or 2 oral liver tox data so one could assume that Arpida withdrew the MAA (in October 2009), rather than continue to argue the case.
FDA CRL to motif Iclaprim NDA
The fda rejected Arpida application due to inferior efficacy in comparison with another AB and not the liver toxicity...please get your facts right before posting here.
The fda never rejected motif application but asked for more data with regard liver enzymes/Dili to approve Iclaprim.
Motif Iclaprim application passed all fda requirement including its superiority in efficacy and nil nephrotoxicity in comparison to Vancomycin.
Please write here facts and your opinion negative or positive but based on facts not fabrication.
Many holders here are anxious and understandably so about their financial commitment here.
FUNDING,PARTNERSHIPS,TAKEOVER,RIGHT ISSUES. ARE MORE RELEVANT
I myself waiting further clarifications from motif of their “all bases are covered and clear pathway” but others here ,may be wiser, think no need yet.
Sitting and waiting patiently and remain hopeful .
Sorry, I was too hasty with that.
I think, a priori, iclaprim should be presumed dead because the likely investment and time required to generate the data need to resuscitate it will be prohibitive even assuming a positive benefit/risk balance wrt. potential for severe DILI in ABSSSI.
The problem is that a positive benefit/risk balance will only be demonstrated AFTER the required investment and with the liver toxicity issues that have been around since Arpida, it's easier for investors/partners to say no.
Just a case of money then. I feel better already.
There's light, but MTFB doesn't have enough coins for the meter to keep them on.
Maybe GL is hoping to hide behind the "fixed dose optimisation" strategy to explain that.
My rationale for suggesting so is that GL suggested (@35’15”) in the webcast that the “optimised fixed dose” was chosen with “optimal balance of safety and efficacy to further address any potential concerns around, in this case, liver toxicity”. Obviously that isn't true. It's not possible to run a toxicokinetic study with the handful of observations from ASSIST 1 & 2.
That position is also not supported by the published data. In “Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens” (See https://aac.asm.org/content/62/2/e01184-17), it’s stated “while available data indicate that bacterial killing is related to AUC0–24ss, AUC0–24ss/MIC, and T> MIC, safety, NAMELY QT PROLONGATION (emphasis added), appears to be linked to the maximal concentration at steady state (Cmaxss)”.
As discussed there and at length in the REVIVE-2 protocol (ICL-24-ABSSSI2-01; Section 5.4.3), the target dosing was designed to keep the Cmax below 800ng/ml, thought to be associated with QTc prolongation in a thorough QTc phase 1 study. The regimen of 80 mg administered over 2 hours q12h was expected to maximize the likelihood of antibacterial efficacy while minimizing the potential for QTc prolongation, not liver toxicity, which is not even mentioned in the article. So, if that was his plan to justify lack of diligence on the LE issues with both the IV and oral legacy data, it's not going to work.
bailedintime, 7 th June you say quite clearly Iclaprim is finished are you now seeing a light ?
Motif wont say it but that’s exactly how it’s going to play out. The fact they didn’t study fully the latency in the liver given they knew it existed from Arpida days is scandalous. How Lumsden stays after this catastrophe is beyond me
You might have missed this during your research. It's draft but it's what the FDA is working to at the moment, especially wrt. WRO instead of resource intensive, time-consuming meeting.
Anyway, I don’t think MTFB needs or is going to get any “further clarification”. What MTFB needs to do now put proposals together for FDA comment. I expect they will get WRO, no meeting. This doesn’t make much difference since they will anyway need to develop the protocol(s) according to those comments, file them to the IND and get set up to run them.
MTFB already has a pretty clear idea of what’s needed. During the recent webcast GL stated (@9'25") "I can share with you that a single arm study will not be what's expected, so there will be a comparator, although what that comparator is, I can't say....". He also said (@09'51") "I cannot believe that it would solely be looking at liver toxicity endpoints".
So it will be a comparator study with safety and efficacy endpoints with longer-term follow-up to see if LEs return to normal and to address the potential for latency in appearance of elevated LEs. It’s obviously going to need to be a large study both to ensure it’s powered for efficacy outcomes (why bother otherwise?) and to ensure that sufficient patients developing elevated LEs can be found and studied appropriately for outcomes to allow conclusions about the potential for severe DILI to be assessed. There’s also the currently unknown incidence of delayed (1 month after EOT) elevation of LEs.
Dose and patient population will be the same. The HABP/VABP idea in my view is a non-starter. It’s a very high-risk population (20-50% death rate) with a completely different benefit/risk balance. In any event MTFB inherited only half a phase II study and would need a fully powered P3 to get the indication, not feasible for the current additional data requirement.
One additional possibility would be to try to collect long-term outcomes in REVIVE 1&2 patients, as a kind of post-hoc medical history/chart review. This could be done in parallel to the new study and if sufficient data could be collected (IC, ethics etc., notwithstanding) could give some support at least to the long-term safety of iclaprim.
“Those certain individuals “...I hope scott is not one as he has nothing to lose now. He sold everything including garden shed to buy in motif dreams then in his wisdom sold all his holdings for pennies just covering a few McDonald,s cheese burgers!
I suppose community service might be in order...lol!
If certain individuals spent more time doing their research, other than continuously emitting negative and unfounded statements, they would realise that MTFB, may have most of the ‘bases covered’. See: -
Guidance for Industry Formal Meetings Between the FDA and Sponsors or Applicants
X. DOCUMENTATION OF MEETINGS......................................................................... 10
‘Before the end of the meeting, FDA attendees and the sponsor or applicant attendees should summarize the important discussion points, agreements, clarifications, and action items. Generally, the sponsor or applicant will be asked to present the summary to ensure that there is mutual understanding of meeting outcomes and actions. FDA staff can add or further clarify any important points not covered in the summary and these items can be added to the meeting minutes. The summary can be done at the end of the meeting or after the discussion of each question.’
IMO, MTFB are undertaking good practice and following due process. By seeking additional clarification from the FDA, one would hope resources are managed effectively and previous issues are resolved in a timely manner. However, patience is required as investors (myself included) are obviously extremely frustrated and irritated with the current state of play. Unfortunately, drug development is not a quick route to fiscal stability. But we should also not forget the humanitarian benefit to the patients, who are experiencing the consequences of a life-threatening ailment. They will also profit exponentially, when this gains approval.
Just to finish, I am totally in favour of Free Speech. However, certain individuals may want to research: - Defamation and Libellous!