Roundtable Discussion; The Future of Mineral Sands. Watch the video here.
I'd be interested to know where you have that information from. The current vancomycin label is silent on it killing people!
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/060180s047lbl.pdf
Iclaprim MAY not have been proven to have killed anyone yet, but in their presentation to the 2008 ad.comm. the FDA suggested it might have been implicacted in some deaths.
One this is for sure, if iclaprim is associated with DILI, it will kill somebody once marketed. Again, have a look at the FDA'a DILI guidance to see where they are coming from.
SABs generally provide high level advice on corporate scientific strategy, what indications to seek, what efficacy will be required etc. They may be invited to sit on a protocol committee to look at a study design since they may have been involved in many other anti-infective studies. They generally have little or no detailed regulatory experience. They can also only provide an opinion on based on data that they are shown. I'd be very surprised if any of these SAB members have read the regulatory history of iclaprim or reviewed the IND or were asked about potential liver toxicity issues.
Clinicians do tend however to have a very keen sense of the benefit risk balance in populations of their expertise. Just take a look at the transcript of the original ad comm. meeting for iclaprim (November 20th 2008 briefing materials and transcript).
https://wayback.archive-it.org/7993/20170403222224/https://www.fda.gov/ohrms/dockets/ac/cder08.html#AntiInfective
Any such expertise in the MTFB SAB clearly wasn't harnessed appropriately.
If the other tox, clinical and regulatory consultants reviewed the EU regulatory files or the IND, assuming these contained the relevant data, then it should have been flagged.
Otherwise the individuals who took part in the due diligence exercise for MTFB at the time of acquiring the iclaprim assets should have found the oral LFT data and considered its implications for further drug development (assuming of course they had access to it).
It's embarrassing that the FDA had to point out the clinical relevance of data in MTFB's own IND and EU regulatory files.
MTFB stated on numerous occasions that the fixed IV dose had been "optimised" for efficacy and safety. That's clearly not possible when faced with idiosyncratic DILI, the development of which uncommon but is dose-independent and based on host factors (how to you optimise dosing to avoid a rare event unlikely to be observed in controlled studies? You can't).
MTFB is firstly going to have to come up with an explanation for the hepatotoxicity seen with the oral formulation (very difficult without implicating the IV formulation, at any dose), explaining why it's not relevant to the IV program (probably impossible given elevated LFTs already seen in IV studies) and if elevated LFTs are observed, how potential sequelae will be mitigated (difficult since we know stopping iclaprim doesn't affect the course of the LFT abnormalities), and once all of this has been achieved, is then going to have to run another study of sufficient size and treatment and follow-up duration, in the target population (ABSSSI, not VABP or HABP, which would have a difference benefit/risk balance), to attempt to demonstrate that DILI is not an issue in the TP with the target labelling (probably not possible in view of the unknown, but expected incidence of DILI associated with iclaprim).
Overall, I'm not sure that this would be possible for big pharma (or worthwhile) let alone for MTFB. In view of the uncertainties and FDA's absolute stance on the avoidance of DILI, it will just be easier for the FDA to say no! Why take the risk for a mediocre efficacy with a clear potential for toxicity to which the CHMP claimed resistance was already emerging!
To make matters worse for MTFB, in the REVIVE-II trial (ICL-24-ABSSSI2-01), the rationale for the study was stated as
"Liver function test elevations of uncertain significance were seen in the previous ASSIST protocols. There is a need for additional clinical studies to further demonstrate iclaprim’s safety and efficacy. For this reason, this Phase 3 clinical study is intended to demonstrate that the safety, tolerability, and efficacy of iclaprim are non-inferior to that of vancomycin. This adequate and well-controlled study will thus provide important evidence for the marketing approval application of iclaprim for the treatment of ABSSSIs".
So they previously failed to achieve the stated objective or to answer any of the important questions. Are they really worth another multi-million investment with these odds?
RE: EMA. In the EMA Withdrawal Assessment Report, the CHMP reported of the IV studies "LFT values observed during iclaprim treatment did not disappear at completion of treatment and numerically more patients had marked increases in ALAT values at late follow-up visit than at the time of EOT. For instance, 13 patients treated with iclaprim (2.6 %) presented increase in ALAT between 3 ULN and 10 ULN at the follow-up visit as compared to 3 (0.6 %) in the linezolid-arm. Of all treated patients, 14 in ASSIST-1 and 9 in the ASSIST-2 studies demonstrated elevated ALAT and/or ASAT levels at baseline (< 5 ULN). Of those, in 12 and 7, respectively, LFT values continue to rise during iclaprim treatment.
The applicant’s response to the CHMP’s major objection [at D180, Arpida withdrew at D181] gives 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".
Faced with this, I think that when Arpida saw the oral data, they simply withdrew the application rather than submit the data to the CHMP. Arpida stated that they withdrew because "The CHMP considers that the data provided do not allow the CHMP to conclude on a positive benefit risk balance" - not a normal reason to withdraw at D181, with the possibility of an oral explanation (no pun intended).
Again, MTFB must have had access the regulatory dossier, CTAs etc. etc., but obviously didn't understand what they were looking at.
Is anyone else interested in finding out what exactly happened here?
How could MTFB ignore a potential DILI signal from the IV data knowing the oral formulation was clearly hepatotoxic? Idiosyncratic DILI is uncommon, but ANY potential signal must be explored and explained, otherwise there is no route to approval (see Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation https://www.fda.gov/media/116737/download).
Arpida announced "positive" P1 data with oral iclaprim (OI) in 2006 and in Dec 2008 announced "positive top-line data from the P2 ‘intravenous-to-oral’ switch trial with OI" stating that it "was well tolerated; AEs were infrequent and not significantly different between both study arms. Importantly, no drug-related SAEs occurred and there were no patient withdrawals due to adverse events".
However, Arpida's 2008 AR (Feb 2009) states "In parallel with the P2 trial, the last ongoing study of the Phase I programme has been closed. Based on the review to date, further development work will be required in order to better understand the effect of OI on liver enzymes......." Clearly they knew about the potential knock-on DILI issue with IV based on the OI data way before Feb 2009, which is probably why the MAA was withdrawn.
Arpida also still had an open IND, to which the oral data should have been submitted (the "switch" study was submitted to the IND). Knowing the IND file, MTFB must have known the risks. With appropriate due diligence, they cannot have been surprised by the FDA referencing it and asking for more data.
I agree with you.
There are many, many examples of sterioisomers being biologically indistinguishable (see https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-new-stereoisomeric-drugs). However, biological systems are chiral entities and stereoisomers or isomeric mixture can have different pharmacokinetic, pharmacodynamic, therapeutic, and adverse effect profiles.
For example, Dilevalol, the (R,R) stereoisomer of labetalol, avoided postural hypotension due to its lack of alpha-adrenergic receptor antagonism, but was associated with an increased risk of hepatotoxicity compared with labetalol and was not approved by the FDA.
Increased mortality was observed in patients given d-sotalol, a class III anti-dysrhythmic essentially devoid of the beta-antagonism of the racemate.
Development of the active isomer (R)-fluoxetine ceased after dose-dependent QTc prolongation emerged in clinical trials, and its efficacy compared with racemic fluoxetine was questioned. Any of this sound familiar?
In our case, there's no suggestion that separating the AR-101and AR-102 enantiomers of iclaprim would necessarily resolve the DILI issue. Again paralleling the fact that AR-101 was less cardiotoxic than AR-102, it unfortunately appeared that AR-101, while less cardio toxic, was also less efficacious than AR-102 based on ED50. At the time of the withdrawal of the MAA in Europe, the CHMP, commenting on the cardiotoxicity of iclaprim, concluded that dosing AR-101 at high doses to maintain efficacy (compared to the more cardiotoxic AR-102-containing racemate) would most likely not be possible because of the narrow hepatic safety margin!!!!! (although interestingly, the CHMP did not directly reference the oral hepatox data referenced by the FDA!)
Back to the issue at hand. Iclarprim-related idiosyncratic DILI irrefutably exists and is a complex issue. In IMHO, the drug development failures of MTFB so far demonstrate that its resolution is beyond their understanding or capabilities. As has been pointed out previously, conducting new, large studies, even with extended follow-up is an expensive and probably pointless exercise, which will not add to the knowledge of this idiosyncratic issue.The focus should be on why it occurs, in whom and how it might be mitigated, in order to shift the benefit/risk balance towards treatment benefit in an appropriate patient population.
IMHO, iclaprim is finally dead, as it was and should have stayed after the 2008 FDA debacle. During the P3 studies of the iv formulation, an oral capsule was developed and touted as allowing an iv to oral switch to reduce in-patient care costs and to add millions to the value of the franchise. Unfortunately, whilst early development looked promising, multiple oral doses were found to be profoundly hepatotoxic. The „delayed“ nature the toxicity and its dose independence suggesting host factor-related idiosyncratic drug induced liver injury (DILI) resulting from metabolic activation. Although first-pass exposure is much higher following oral admin, we now know a similar profile of toxicity has been observed following iv admin.DILI is rare and unpredictable but is the leading cause of liver failure and requirement for transplantation, hence it has the FDA‘s attention here.MTFB has probably been asked to investigate the cause of the toxicity, its incidence and any relevant host factors, none of which lies within their capabilities.Another issue to remember is that iclaprim is chiral which may be relevant (e.g. enantiomer 002 was 10x more cardiotoxic than 001) but separating them is difficult. I‘m sure that appropriate due diligence and access to all of the relevant data would have revealed all of this background (it’s all in the public domain anyway) but it staggers me that MTFB thought they could overcome or ignore these, ususlly terminal dtug development issues. Game over