I sold my shares because of 10 extra milliseconds. 2-Apr-09 10:06 pm ...I distinctly heard a response to a question when the 10 mg quindine dose was announced that the FDA would have no cardiac issues with such a low dose (10 mg) of quinidine.
...Although this was a brash statement and I probably should not have believed it, I did. So I was not even expecting a QT study to be part of the submission.
...Then, to see the QT is prolonged by slightly over 10 milliseconds was a shock. Especially, because Eric Brandt, the former CEO came out of his meeting with the FDA after the Approvable Letter saying he thought it would be very difficult to get a Zenvia formulation approved if it raised the QT more than 5 milliseconds. (Again, I'm pretty sure the way it works is the FDA uses a measured value of 5 milliseconds to be reasonably sure, ie. the "95% confidence level" that the real value isn't 10 milliseconds or more. 10-20 milliseconds used to be the FDA's intermediate or indeterminate range of concern, with over 20 milliseconds being of definite concern.)
...So 10 milliseconds makes me worried the FDA is going to punk out and not approve Zenvia for PBA on that basis alone.
...So 10 milliseconds of QT prolongation changes the fundamentals of my investment thesis. So much so that I have realized our AVNR paper loss and sold all but about 2% of our AVNR shares.
...If this 10 millisecond prolongation is as big a deal as Eric Brandt said it was, I have to wonder when AVNR began this study. Why is the data being given to us so late? It is two and half years since the Approvable Letter and recruitment for the STAR trial has finished.
...AVNR should have started this QT study as soon as they settled on the 10 mg dose as their choice for the STAR trial. I would have expected to have had this QT data almost a year ago. It does not take that long for 50 people to take Zenvia and moxifloxacin and placebo for a few days each and run some EKG rhythym strips and analyze the data.
...Although I have been very pleased with everything since the Approvable Letter, I am now overall very displeased because of this revelation so late in the game after being told the FDA would have no cardiac issues with dosages of 10 mg quinidine.
...One crass possibility is, it is hard to fold up shop and give up high paying jobs. I hope that is not the reason we have been led this far to be given this 10 millisecond shocker at this point.
...I hope there is more to it than I am seeing.
...I hope even more that I can be made to see why Avanir has continued with the study given this data. Perhaps Avanir has assurances that the FDA will not be stopped in its tracks by a 10 millisecond QT increase. If so, I would like to know that and I'll buy back the shares.
"You do not understand max mean"
...I think I understand maximal QT prolongation and mean QT prolongation.
...You do seem to be right that the maximal QT prolongation does not refer to the 95% confidence intervals of what the real maximum QT prolongation might be, but instead refers to the QT prolongation at the expected time of the maximum quinidine
concentration, but that changes nothing.
...Less than 5 milliseconds was the goal, 2.3 milliseconds was expected by AVNR, 3.0 milliseconds was expected by the FDA and what they got was the same 10.3 milliseconds that they got with the 30 mg quinidine formulation.
...Especially since Eric Brandt said it would be very hard to get the FDA to approve a formulation of Zenvia that prolonged the QT by more than 5 milliseconds and this was echoed in the statement of around 2/07 that was posted here today, the QT prolongation issue is clearly a major issue for approval and your statement that the QT prolongation is "a dead issue" is false.
Moreover, you contradict what you wrote to Nirvana in June, where you said we would only be geting mean QT prolongation data out of the STAR study. Obviously, a thorough QT study (which is done above and beyond the normal QT monitoring of a Phase 3 study) carries more weight with the FDA.
Of course you do. That was the most twisted regurgitation and misstatement of my posts to you. You do not understand max mean and then proceed to make a medical deduction/conclusion relative to dosing based on that misunderstanding. That was hilarious!
You are dangerous. You are literate AND an idiot.
"You are correct in your deduction re: super dosing, or accidental overdosing, as you referred to it. That is precisely what the FDA was/is concerned about. The Data now support the conclusion that triple the current dose will not go past a 10 ms MAXIMAL MEAN QT prolongation."
...I think you're wrong on this. An accidental double dose at the old formulation of 30 mg quinidine would not create the steady state concentration of a regular regimen of 60 mg quinidine twice a day. You would need to accidentally take a double dose 4-5 times in a row to get the quinidine concentration achieved with 60 mg twice a day (steady state concentration).
So it makes no sense that the FDA would be worried about someone taking two pinches of quinidine one time instead of one pinch of quinidine one time.
The odds of any arrhythmia from
that are microscopic.
"...The data from the Phase III trials before the original NDA did not, and in fact could not, contain MAXIMAL MEAN QT data. They contained mean data which was under 5ms QT prolongation.
It was only in the "thorough QT study" done in 2006 under Brandt that the maximal data was provided....
...We will not get Maximal mean data form STAR, only mean data...."
...Then in a separate post to me you said the maximal QT prolongation refers to the concentration of quinidine at the time the QT is measured.
"The AE's will be down and the mean data should be somewhat in line with past trials. Hence the bullish price action as we enter data season."
...So now we have that mean data, which you admitted carries little weight relative to the maximal mean QT prolongation, yet you say this mean data now means the QT prolongation is a dead issue.
...I don't think you are being consistent or making good sense.
...As always, feel free to explain yourself.
...More evidence that your distinction between maximal mean and mean does not matter is AVNR is saying, "the EKG data suggests a flat QT dose-response between 10 and 30 mg of quinidine.
...That means that the same QT problem the FDA had with the 30 mg dose is present with the 10 mg dose.
...I think you are overstating the case to emphasize the FDA can now take comfort that triple the maximum dose will not cause more QT prolongation.
...That wasn't the issue as stated by Eric Brandt. The issue was simply 5 milliseconds of QT prolongation. Just like it still probably is the issue, is my guess.
...Medically speaking I don't think it should be an issue. But I don't think the FDA will rise above their fears of having fingers pointed at them later when inevitably large numbers of people taking Zenvia have sudden cardiac death (the vast majority unrelated to Zenvia--just having sudden cardiac death like the frequent cause of death that it is in the general population and especially those with Alzheimer's , stroke, diabetes, advanced multiple sclerosis etc.
But those people are going to be on Zenvia and their lawyers are going to be pointing undeservedly at Zenvia as the cause. I gather the FDA is unwilling to take that storm of controversy on for what they consider to be a minor problem (PBA) without data showing the risk of torsades was lower than other drugs on the market.
...Just my take.
was measured at the maximum qunidine concentrations (i.e. at the time interval after dosing when the quinidine level would be expected to be the highest) it seems to not matter because this is the FDA is concerned when that maximal mean QT prolongation is more than 10 milliseconds.
...I think they are concerned when it is over 5 milliseconds because then the 95% confidence interval is over 10 milliseconds).
...From AVNR's press release on the subject:
"In the ACSS, the overall effect of the Zenvia 30/10 mg dose on QT interval was less than the effect of the moxifloxacin 400 mg positive control. In the study, Zenvia 30/10 mg and moxifloxacin 400 mg produced maximal mean QTcI changes of 10.3 msec and 12.2 msec and upper bound 95% one-sided confidence intervals of 14.3 msec and 16.2 msec, respectively. Additionally, no subject in the study had an absolute QTcI greater than 480 msec and no subject had a change in QTcI greater than 60 msec. Zenvia 30/10 mg had no significant effect on PR and QRS interval duration or cardiac morphology. In accordance with FDA guidance regarding drug candidates that demonstrate an upper bound 95% one-sided CI above 10 msec, AVANIR will continue to conduct detailed ECG monitoring throughout the STAR trial and provide this important clinical cardiac safety information in support of the full response to the FDA approvable letter."
even if maximal mean QT prolongation refers to the QT prolongation at the peak dose of quinidine--I don't think it changes the fact that the mean QT prolongation for the 10 mg quinidine formulation was over 10 milliseconds when AVNR had created the formulation with the idea it would not cause mean QT prolongation over 5 milliseconds and was projected to actually be 2.3 milliseconds. In fact AVNR had said QT prolongation would not be an issue with the 10 mg formulation and that no QT study would be needed.
...Furthermore, you have to reconcile any thoughts you have with the former CEO's comment that he thought it would be very difficult to get the FDA to approve any formulation of Zenvia that prolonged the QT by more than 5 milliseconds.
...In regards to your definition of the maximal mean QT prolongation, so far I've found this, but I would like to review AVNR's reports, if I get to it.
...This is from a study on moxifloxacin:
"With moxifloxacin, clinically relevant QTc prolongation is seen at a concentration that produces ~10% inhibition of the hERG current (Figure 6), similar to many IKr/hERG blockers (e.g. dofetilide, E-4031, cisapride, terfenadine, and risperidone) tested in our laboratory. In the telemetry dog study, mean maximum serum concentrations (Cmax) of 3.9, 10.6, and 27.8μM (unbound) were obtained following 10, 30, and 90mgkg−1 doses, respectively. These concentrations represented a 0.7-, 1.9-, and 4.5-fold exposure, respectively, of that in humans repeatedly dosed with 400mg. These exposures were associated with mean maximal QTc prolongation of 6, 11, and 17% (vs predose), respectively. Comparable responses in APD and transmural QT interval were observed in the arterially perfused wedge preparation as well."