Biotech Values

[iwfal]

FGEN -

Given your stats background and knowledge can you comment on how passing quarterly DSMB data reviews derisks the program. I assume the threshold for stopping if MACE and other adverse events trend in the wrong direction is far lower than the opposite (i.e stop for safety in favor of roxa) - but i really can't quantify this. If you had a good sense of this, as well as how far they are in enrollment, i think you can start to really semi quantify how liklihood of success changes over time in a setting like this were efficacy is a given.

There are a lot of assumptions and rules-of-thumb that go into answering something like this. I.e. I do not have a precise crystal ball. That said, my guess is that currently they have something well in excess of 100 man-years of exposure in the on-going trials (total planned enrollment ~7000). But this will currently be climbing very rapidly - i.e. if in late April they had 200 man-years of exposure, then by late June they will have >300 man-years of exposure.

Notes/Comments:

1) The uncertainties are many in the above analysis - e.g. when do they plan to complete enrollment vs their planned end of trials (mid 2017)? My guess is at least 12 months prior to planned end of trial. Probably more.

2) Most of that exposure will be in the bigger trials with the lower expected event rates (i.e. the pre-dialysis trials will have higher total exposure because they are bigger because they have lower event rates).

3) How much will the DSMB combine across trials and different MACE/MACE+ endpoints (this was JQ's point)? (The DSMB does have a mandate across all trials per their last CC)

there is a higher risk of this type of a trial being stopped in favor of roxa if it is indeed safer/more effective

And what, pray tell, are the places you'd expect greater 'safety' for Roxa? (-g-). (I am amused that there is a giant elephant in the room that no one mentions directly. And I am no different - but I'll at least open the dialog now.)

Just better anemia scores? It seems unlikely they would stop early for this. So presumably the elephant is MACE or MACE+ (the latter of which include CHF - one of the leading causes of death in CKD, and hence my questions about HIF in on-going damage/healing races).

But other things matter as well:

a) another major cause of death in CKD is infection and decreasing hepcidin may increase infection rate.

b) and in pre-dialysis there is the risk of kidney side effects. Which can get fairly complicated - e.g. short term harm for long term benefit is a possibility.

I'd wager the MACE rate will benefit substantially from roxa in comparison to epo - and a good shot even against placebo because the iron cycle is probably significantly important to coag etc (and roxa seems to normalize that). But the rest is very much an unknown - except to the DSMB which will have seen at least trends by now.