A great post from Frank on YMB (added few edits):
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Posted On: 08/12/2020 8:24:07 AM
A great post from Frank on YMB (added few edits):
What is the situation? We still do not have a normal life, economy is kept alive by massive monetary and fiscal stimuli (costs), vaccines in the best case in March, April available (no developed country will approve vaccines developed at such low Russian standards, whether it works or not) and we still do not have an effective drug.
What will FDA and others do with the M/M results?
Results:
What we know: the primary endpoint (total clinical score) was better for leronlimab. Statistically significance favoring leronlimab for key secondary endpoint NEWS2 (which does not only tell the clinical improvement but says also something about the likelihood that a patients may develop severe/critical symptoms at a later stage (e.g. like this one: https://edition.cnn.com/2020/08/11/us/covid-s...ndex.html). So a statistically significant reduction of NEWS2 is really an achievement that will be seriously considered by the FDA and other drug authorities. I wonder what else would anyone had expected from the M/M trial ? Reduced mortality where there is no mortality in the placebo group? It seems that some had surreal expectations - it is it really just bad shorts?
Could be the results any better? Yes, there should be more valuable details in the report submitted to the FDA:
- results and p- values of the other secondary endpoint. If the majority or even all of them trend to the right direction in favor of leronlimab that would be very valuable and convincing even if their p-value was 0.06 or 0.08. ( Note: even a p-value of 0.08 means: 8 % just by chance finding, 92% due to drug effect. One such finding alone is worthless, because the 0.05 cut off is generally accepted (arbitrary) standard. But if most or even all the other secondary endpoints were better in the leronlimab group, this would be very valuable additional weight for this study. I know from the EU EMA we looked to the total evidence and not to an endpoint in isolation. UK certainly still applies the same scientific standard and I am pretty confident that FDA will do the same. We do not have all these details, but these should be part of the dossier submitted to FDA. We also do not have the immunological and virological results (viral load, T-cells and cytokines). I am not sure whether they looked for these in the M/M. But in any case the mode of action (MoA) on these parameters have been already demonstrated and should also be given to the FDA. It would be perfect, but not necessary, if they had measured these points again in the M/M trial. A reasonable or even demonstrated MoA gives a quite some additional confidence and support the clinical results. Not to forget the statistically AND clinically very significant reduction of the adverse events (many of them caused by the disease).
Everything I have seen and know about the M/M trial, looks very good and promising. The results are far better than I had hoped. I was afraid that (like some others expressed here) that the statistical power of this phase 2 trial may not be sufficient given that most patients with mild/moderate would recover anyway. But despite this fact we have these great results.
What will FDA do? FDA, UK MHRA and EMA always consider also the risk of the disease if untreated and the availability of effective drugs. We have only Remdesivir (little if any effect) and dexamethason (you do not give a strong cortison with all its side effects to patients with mild/moderate symptoms. So basically we do not have an effective drug here. This is in favor for leronlimab.
Now to be honest, despite all these factors above which speak in favor for authorizing leronlimab for M/M patients, there could be only one point not in favor: this was „only“ a Phase II study and under normal (non-pandemic) conditions you need a bigger phase III study. And: one could argue: the very most mild & moderate patient will be fine anyway - so albeit there I no effective drug available, the medical need is not that urgent to approve a drug which has been tested only in a Phase II. If I was still working at the EMA I would have not supported the marketing authorisation on the basis of of only a Phase II trial, and given that the very most patients will be fine anyway - for safety reasons!
However: two points Cytodyn MUST add and stress in their dossier to FDA, UK and EU drug authorities:
First is the safety data from the HIV phase III trial (so intact we have phase III safety data!) and safety data from M/M trial. In facts, safety profile in M/M trial is beyond excellent, 64% reduction in serious adverse events in leronlimab arm compared to placebo. Second is the reports where mild and moderate Covid patients developed later severe clinical symptoms like multi organ failure, thrombosis, lasting lung damage - because this stresses the medical need (emergency) for an effective drug. Safety should raise any concern.
Actually this risk is shown to be reduced by leronlimab (By NEWS2 and serious adverse events)
IMO:70:30 % emergency approval these days by FDA. I would approve it.
What is the situation? We still do not have a normal life, economy is kept alive by massive monetary and fiscal stimuli (costs), vaccines in the best case in March, April available (no developed country will approve vaccines developed at such low Russian standards, whether it works or not) and we still do not have an effective drug.
What will FDA and others do with the M/M results?
Results:
What we know: the primary endpoint (total clinical score) was better for leronlimab. Statistically significance favoring leronlimab for key secondary endpoint NEWS2 (which does not only tell the clinical improvement but says also something about the likelihood that a patients may develop severe/critical symptoms at a later stage (e.g. like this one: https://edition.cnn.com/2020/08/11/us/covid-s...ndex.html). So a statistically significant reduction of NEWS2 is really an achievement that will be seriously considered by the FDA and other drug authorities. I wonder what else would anyone had expected from the M/M trial ? Reduced mortality where there is no mortality in the placebo group? It seems that some had surreal expectations - it is it really just bad shorts?
Could be the results any better? Yes, there should be more valuable details in the report submitted to the FDA:
- results and p- values of the other secondary endpoint. If the majority or even all of them trend to the right direction in favor of leronlimab that would be very valuable and convincing even if their p-value was 0.06 or 0.08. ( Note: even a p-value of 0.08 means: 8 % just by chance finding, 92% due to drug effect. One such finding alone is worthless, because the 0.05 cut off is generally accepted (arbitrary) standard. But if most or even all the other secondary endpoints were better in the leronlimab group, this would be very valuable additional weight for this study. I know from the EU EMA we looked to the total evidence and not to an endpoint in isolation. UK certainly still applies the same scientific standard and I am pretty confident that FDA will do the same. We do not have all these details, but these should be part of the dossier submitted to FDA. We also do not have the immunological and virological results (viral load, T-cells and cytokines). I am not sure whether they looked for these in the M/M. But in any case the mode of action (MoA) on these parameters have been already demonstrated and should also be given to the FDA. It would be perfect, but not necessary, if they had measured these points again in the M/M trial. A reasonable or even demonstrated MoA gives a quite some additional confidence and support the clinical results. Not to forget the statistically AND clinically very significant reduction of the adverse events (many of them caused by the disease).
Everything I have seen and know about the M/M trial, looks very good and promising. The results are far better than I had hoped. I was afraid that (like some others expressed here) that the statistical power of this phase 2 trial may not be sufficient given that most patients with mild/moderate would recover anyway. But despite this fact we have these great results.
What will FDA do? FDA, UK MHRA and EMA always consider also the risk of the disease if untreated and the availability of effective drugs. We have only Remdesivir (little if any effect) and dexamethason (you do not give a strong cortison with all its side effects to patients with mild/moderate symptoms. So basically we do not have an effective drug here. This is in favor for leronlimab.
Now to be honest, despite all these factors above which speak in favor for authorizing leronlimab for M/M patients, there could be only one point not in favor: this was „only“ a Phase II study and under normal (non-pandemic) conditions you need a bigger phase III study. And: one could argue: the very most mild & moderate patient will be fine anyway - so albeit there I no effective drug available, the medical need is not that urgent to approve a drug which has been tested only in a Phase II. If I was still working at the EMA I would have not supported the marketing authorisation on the basis of of only a Phase II trial, and given that the very most patients will be fine anyway - for safety reasons!
However: two points Cytodyn MUST add and stress in their dossier to FDA, UK and EU drug authorities:
First is the safety data from the HIV phase III trial (so intact we have phase III safety data!) and safety data from M/M trial. In facts, safety profile in M/M trial is beyond excellent, 64% reduction in serious adverse events in leronlimab arm compared to placebo. Second is the reports where mild and moderate Covid patients developed later severe clinical symptoms like multi organ failure, thrombosis, lasting lung damage - because this stresses the medical need (emergency) for an effective drug. Safety should raise any concern.
Actually this risk is shown to be reduced by leronlimab (By NEWS2 and serious adverse events)
IMO:70:30 % emergency approval these days by FDA. I would approve it.
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