Updated message (since board told me I was too late):
Not saying it is not good news, just saying it will take time and experimentation to figure out the best regimen (which dose to start, when and how to lower, increase again when, etc.). For me it is not a clear cut message that you can reduce to 15mg from the beginning and still get the same responses.
I tend to believe the french study that shows thrombotic SAE being around 7 times higher compared to competitors (maybe the numbers are somewhat off because the population is small and maybe they included only patients that have a high risk factor (maybe bacause others were eligible for bone marrow transplant)). So this is the factor we must be shooting for if we ever want to get back to 2nd line.
Excluding previous heart problems will reduce number by 30% or 40% (T Clackson mentioned this number in one of the conf-calls, basically the equivalent of HB saying that rate in heart patients is 5-7times higher).
Dose reduction as shown here will give us something, just don´t know how much exactly. Keep in mind that a large percentage of patients in PACE had their dosage reduced in the trial. The reported SAEs are the result of the total patient population. So how much further can we reduce in the average patient. Yes if everybody was at 45mg and we could reduce to 15mg, that would be great and reduce number of SAEs by 2/3. But this is not the case since most patients were already on a lower dosage. So were we in average at slightly above 30mg and can maybe reduce another 5mg or 10mg or 15mg or 20mg? I don´t know.
Also, we don´t know when the dosage was actually reduced. Did they only reduce when AEs became visible or did they lower early on. And are these timelines included somehow in the modelling. If not the correlation could actually be stronger (bigger reduction with lowering of dosage). If you think about it, if they treat at 45mg for a year and then reduce to 30mg. Some time later an SAE occurs. Now is this patient counted in the 45mg cohort or in the 30mg one. If he is counted in the 30mg cohort, but the SAEs are an effect of the cumulated dosage over time, then maybe the SAEs reported in the 30mg bucket are larger than they would be if treatment was done at a consistent 30mg. So maybe the correlation is actually stronger.
Another factor to consider is that the poster had a few numbers that I thought were confusing. It seems to be that better results are achieved when treatment is started at 45mg and then reduced when MCyR or CCyR is achieved. In this case the response rates seem to be quite comparable. In another poster they compared response rates at different dosages and it showed quite a drop-off at 15mg. I don´t quite know how this data was generated (is this truly patients that never saw a higher dosage, e.g. P1 experiments?). So this concerns me a bit that I cannot quite align the two results.
Also other factors (platelets, etc.) strongly correlate to AE incidence rate. This could be very valuable to reduce AEs further, but the mechanism needs to be understoood. And I just hope that it does not require a new trial to ascertain these findings.
So, I am not unhappy with the results. But it is also not a clear cut victory. More data and analysis and (hopefully not, but maybe) trials are needed. Definitely so if you want to get to earlier lines of treatment.
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