The latest Investing Matters Podcast episode featuring Jeremy Skillington, CEO of Poolbeg Pharma has just been released. Listen here.
Have a look at this concerning court decisions involving biotech companies alleged to have made false or misleading statements concerned clinical trials or the FDA approval process
https://www.dandodiary.com/2017/03/articles/securities-litigation/biotech-companies-sued-frequently-really-represent-heightened-risk-class/
Titanic and violins spring to mind!
Will take years to set up, no upfront payments to MTFB, but MTFB to supply API, reducing inventory. Results years too late.
Just a ruse to keep drawing indefensible salaries for the indefensibly incompetent management team!
Apropos the requirement for a new study for iclaprim in HABP/VABP (which “would take several years to enrol and complete and is expected to cost tens of millions of dollars”) PLUS data on potential mechanisms of hepatic injury associated with it, Paratek just withdrew their MAA for NUZYRA (Omadacycline) because the CHMP would not render a positive opinion in NUZYRA for ABSSSI AND CAP. Despite the fact that an ABSSSI indication was offered, in their withdrawal letter (published on the EMA home page) Paratek wrote;
The withdrawal decision was taken for strategic business reasons. This decision is mainly due to the inability of Paratek to secure a partner to support the commercialization of NUZYRA in Europe with only the ABSSSI indication. The insistence for a second CAP study to support approval for this indication in EU has significantly changed the value proposition for NUZYRA in EU and thus all partner discussions have now been discontinued. The inability to find a way forward for this indication will now delay approval for CAP and availability of NUZYRA to patients in Europe by almost 5 years.
So it appears the no (big or other) pharma company was interested in an ABSSSI indication NOW, plus a line-extension in 5 or so years to add a CAP indication. And this in a market at least as big as the USA.
This situation is far better than that of iclaprim, which is several years and a whole lot of hepatotoxicological risk away from any indication at all.
Where does incompetence end (lack of due diligence/data review, failing to appreciate the impact of the profound hepatotoxicity of the oral formulation (as admitted by Arpida in 2009 AR) on IV development) and negligence (wilfully ignoring/disregarding/hiding negative/problematic data) start? Shareholders must have some comeback surely?
In what indication??????????
Minutes "confirm that a single well-designed adequate and well-controlled Phase III clinical trial demonstrating safety and efficacy of iclaprim in patients with HABP, including VABP, along with data on potential mechanisms of hepatic injury, would enable submission of a New Drug Application for approval by FDA". For what? HABP/VABP only or HABP/VABP + ABSSSI?
If the broad (HABP/VABP + ABSSSI) indication was on the table, don't you think GL would have highlighted that?
Ivy,
The QT scenario was just an example of a potential outcome which could be difficult to interpret without a control group. This is from the Huang paper 2017 on the P2 HABP study, which was stopped early and was therefore too small to conclude much.
"22 patients had QTc intervals corrected by Bazett's and Fridericia’s formulas 4500 milliseconds or increased by 430 milliseconds compared with baseline: 11, 7, and 4 patients in the iclaprim q12h group, iclaprim q8h group, and vancomycin groups, respectively. The QTc prolongation was reported as an AE in 2 patients in the iclaprim q12h group, and 1 of these patients was withdrawn from treatment. One patient in the iclaprim q12h group, who had a medical history that included hypertrophic cardiomyopathy, paroxysmal atrial fibrillation, arterial hypertension, coronary artery disease, and first-degree atrioventricular block, experienced ventricular tachycardia after 1 day of treatment and died the same day".
Sorry (and to Scott), messages crossed. What is the "inspire protocol"? Can you provide a reference?
Thanks
Hasiba,
Except under very special circumstances (no approved comparator and well understood course of disease progression/outcome), it's not possible to conclude anything from an uncontrolled study (see ICH Topic E 10 Choice of Control Group in Clinical Trials) and they are very rarely accepted as substantial evidence of efficacy.
Imagine an uncontrolled HABP/VABP study in which 10% or 30% of patients died within 28 days (it was 22% in the vancomycin arm in the P2 study). What could you conclude about efficacy? Right! Nothing! Some would claim 10% showed better efficacy than expected, others that the 30% mortality rate was due to the more severe baseline characteristics of the enrolled patients. Same with safety. What is the underlying rate of cardiac arrest (iclaprim has a QT issue), or elevated LFTs in the HABP/VABP population? Unknown and a control group is critical and absolutely required to see any TEAEs.
HABP/VABP is a new indication and requires an adequate and well-controlled comparator to conclude anything concerning efficacy and safety. There is no way an uncontrolled study is going to be acceptable. Getting away with a single adequate and well-controlled study, assuming non-inferiority is robustly demonstrated with adequate safety (following appropriate follow-up period), is good news.
Interestingly, even if the hepatoxicity of the oral formulation can be explained and shown not to affect the B/R balance of the IV formulation (a big IF), I didn't see an indication in ABSSSI being discussed. As I have suggested previously, with the current uncertainty and oral data, I think the B/R balance in ABSSSI is negative and will remain so no matter what. HABP/VABP though is a more urgent medical need and with a good outcome from an adequate and well (active comparator)-controlled study, an indication might be available.
Anyway, since starting discussions with the FDA following the CRL, GL has always stated that another controlled trial would be required, and in the webcast stated it would be an active comparator with safety and efficacy outcomes with appropriate follow-up to provide additional data on the potential for DILI. I think however he was expecting it to be in ABSSI. Now the indication is more likely to be HABP/VABP, a controlled study is absolutely required in that population.
Hasiba,
I think you're wrong about that. A single trial means only 1 adequate and well controlled trial, rather than the normally-required 2 adequate and well controlled trials. It DOES NOT mean a single arm (uncontrolled) trial since such a design would not represent an adequate and well-controlled trial. The single trial will therefore need to be an active control (comparator) trial.
From CFR 21 Sec. 314.126 Adequate and well-controlled studies (with comments)
(b) An adequate and well-controlled study has the following characteristics:
(1) There is a clear statement of the objectives of the investigation and a summary of the proposed or actual methods of analysis in the protocol for the study and in the report of its results.
(2) The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect. The protocol for the study and report of results should describe the study design precisely; for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover, and whether the sample size is predetermined or based upon some interim analysis. Generally, the following types of control are recognized:
(i) Placebo concurrent control (not ethical in HABP/VABP)
(ii) Dose-comparison concurrent control (N/A - 80mg BID)
(iii) No treatment concurrent control (not ethical in HABP/VABP)
(iv) Active treatment concurrent control. The test drug is compared with known effective therapy; for example, where the condition treated is such that administration of placebo or no treatment would be contrary to the interest of the patient. An active treatment study may include additional treatment groups, however, such as a placebo control or a dose-comparison control. Active treatment trials usually include randomization and blinding of patients or investigators, or both. If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity of test drug and active control can mean either that both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous placebo-controlled studies of the active control drug.
SP
No oral iclaprim safety data has ever been reported anywhere, except this mention of the elevated LE levels from oral iclaprim in the 2008 Arpida AR which stated;
Oral iclaprim in cSSSI - in-depth analysis ongoing for further design of development plan
In December 2008, Arpida announced the top-line results of a Phase II "intravenous-to-oral" switch trial with iclaprim in patients with cSSSI. In parallel with the Phase II trial, the last ongoing study of the Phase I programme has been closed. Based on the review to date, Arpida expects that further development work will be required in order to better understand the effect of orally administrated iclaprim on liver enzymes and to explore optimal dosing‘
I‘m pretty sure Huang hasn‘t discussed any detailed elevated LE data or Hy‘s law cases with oral iclaprim (please correct me if you know otherwise). So we still don‘t what the oral data showed or why the FDA was so spooked by it.
Instead of just congratulating each other for showing up for work, why hasn't MTFB described what the issue raised by the FDA with oral iclaprim actually is (what proportion of patients presented with elevated liver enzymes (I guess that only about 50 patients were ever treated with oral iclaprim, including those in the iv to oral switch study, so the incidence must have been a lot more than 3%), how many at 3x, 3-10x and >10x ULN? Any instances of Hy's law etc., etc., and the proposal(s) that have been made to address the issues raised?
It's not possible to prove a negative (no risk of DILI), only to estimate the level of risk. GL already suggested a powered, controlled study including efficacy endpoints would be required (large numbers will be required to identify and follow elevated LEs for the required time to assess outcomes, sequelae etc. If a major new phase 3 study is not being proposed, shouldn't he explain what has been proposed and why? Of course he should but strategically this would be a bad move, for obvious reasons.
BTW, I still think it will be WRO. A meeting would be a positive!
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.
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.
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.
Yorkshireboy,
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.
https://www.fda.gov/media/109951/download
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.
This was a post-hoc subgroup analysis. When the outcome for a subgroup appear better than the ITT population, the outcome in the excluded subgroup was worse. The outcome in the ITT population is the important one, and that was fine.
Very high-level timeline and cost estimates for comment/discussion.
Thinking time, oral and IV data review, external consultation, etc. (1m from today. total +1m)
Submit Meeting request (Type B meeting, Post-action meetings requested 3 or more months after an FDA regulatory action other than an approval (i.e., issuance of a complete response letter).
Package submission (no later than 30 days before the scheduled date of the meeting or WRO response time)
Clinical trial design proposal including treatment duration, safety assessment schedule, long-term follow-up and data collection etc., etc.
Study size 550 (expect active controlled study, therefore statistics require that if there is truly no difference between the standard and experimental treatment, then 550 patients are required to be 90% sure that the upper limit of a one-sided 95% confidence interval (or equivalently a 90% two-sided confidence interval) will exclude a difference in favour of the standard group of more than 10%)
FDA action (Type B/WRO) 60 days from receipt of request (total +3m)
Clinical Plan modification etc. IND submission (1m; total +4m)
CRO contracting, site selection, study set up etc. (6m; total +10m)
Regulatory/EC approvals ahead of FPI (2m; total +12m)
Study duration 24m to LPO (24m; total +36m)
Data review, reporting, NDA compilation + submission (6m; total +42m)
Acceptance of file (2m; Total +44m)
PDUFA date after acceptance of file (6m; total +50m). Round down to 4 years
Costs
Background annual burn rate (AR 2015,16,17,18) $7.5m x 4 = $30m
CRO costs (50% of REVIVE 1+2) $25m
Total $55m and 4 years to potential approval
Nothing's for certain. There's no data that I have seen that suggests that iclaprim causes sever DILI.
If appropriate studies can be conducted and the clinical and laboratory data are properly evaluated for evidence of liver injury (that may not be severe, but may predict the ability to cause more severe injuries), this would allow the FDA to distinguish a signal of DILI likely to cause severe liver injury from a signal that does not suggest such a potential.
This is what the FDA needs.
Re: what will happen IF iclaprim DOES (have the potential to) cause severe DILI; the literature is replete with examples of withdrawals of drugs thought to be safe but found to otherwise following post-marketing surveillance.
You guys probably know that a wheel can come off of a development program at any time, usually completely unexpectedly. If you can move on to the next drug, that's what you should do.
If you've got too much invested in the drug to move on (inventor, early investor), then you have a very careful cost/benefit/risk assessment to do. Information and the development team involved are key considerations