Replies to post #178280 on Biotech Values

[biomaven0]

>>ISIS

Highly implausible

At first I thought this might be a small number issue (7 vs 1 or 14 vs 2), but turns out the background rate of VTE (>25% on enox) is much higher than I had realized, so it's more likely this is not a statistical fluke.

The dose-response curve could be very different for this type of drug in a condition like this than for more typical drugs. So a non-linear dose response of some sort is not beyond the bounds of possibility. (Note we are dealing with two different dose response curves here - first the impact of the drug on Factor 11 levels, and second the impact of Factor 11 levels on VTE incidence. That makes a nonlinear overall dose response more plausible to me).

Peter

[iwfal]

ISIS -

Highly implausible, IMO; hence, the results in one of the two ISIS-FXIRx trial arms were presumably a fluke.

The p value makes it clear that unless there were "protocol issues" the result isn't a fluke. It is the sine qua non purpose of a p value to provide a measure of how flukey it could be. (Note that unrepeatable "protocol issues" are inherently more likely in single site trials)

The concern IMO should be the text in the italics since it wasn't a large number of sites and, more importantly, almost all were in EE. I'd want to see the data from the two non-EE sites (in Canada).

[iwfal]

ISIS

Highly implausible, IMO; hence, the results in one of the two ISIS-FXIRx trial arms were presumably a fluke.

FYI - the only published animal model dose response data set I can find for FXIRx with useable fidelity* also shows important non-linearity. That said, it is animal model data (with all the caveats) and the animal numbers are small. Nonetheless the non-linearity is strong enough to look both real and potent even with small numbers.

Also, there is literature pre-dating ISIS's work that speculates a key MOA of FXI is allowing positive feedback on clot size - i.e. in the presence of FXI the bigger the clot the larger/faster it grows (obviously at some point there must be a counter factor - but I haven't bumped into speculation on what that is). And inhibition of FXI would thus mitigate/prevent that positive feedback. Feedback loops result in very non-linear behavior.

*There are other dose response data sets - but they consist of 2 or 3 doses (i.e. too few) and thus cannot allow a non-linearity to be seen.

Restatement of my position so no one misinterprets the above:

1) I think there is a very good chance that in fact the VTE rate for FXIRx is much lower than Enox - but not necessarily 7x better or 3x better or ... . (I have little opinion about bleeds other than a good chance it to be comparable to Enox or better)

2) Nota bene: I think it is inherently problematic to compare the efficacy of two different drugs with *very* different time constants (relative to the needed treatment duration).

[iwfal]

ISIS - FXIRX competitor. Another drug (ichorcumab) with potential to be very good anti coagulant but with minimal excess bleeding risk. And at the macro/mechanical level the same explanation is given: Thrombosis risk is about clot growth, bleeding is about micro clotting (I.e. Capillaries or totality of other small bleeds). FXIRx and ichorcumab both shut down the former while not effecting the latter.

http://www.tcpinnovations.com/drugbaron/ichorcumab-the-blood-of-the-gods/

HT @michael_gilman