I don't really understand the PFE decision. Based on IDO's role, it's not expected to have single agent activity, so it's bizarre to see them drop this drug after <20 patients and without even trying a combo. Regardless of whether or not IDO is a good target, I don't think this trial is an indictment as it seems strangely limited in scope. PFE clearly got spooked by something. My suspicion is given their trailing status, they had a very high internal bar for what this drug had to do to make it seem worthwhile.
>I was sceptical about Inoximod MOA early and still am<
A couple of excerpts below from a recent review paper. I'm relatively convinced that indoximod is not an IDO inhibitor. This doesn't validate the IDO inhibitors out there, but does suggest one would make a mistake by extrapolating heavily based on the indoximod data.
"By far, the IDO probe most employed in the preclinical liter- ature is the simple racemic compound 1-methyl-D,L-tryptophan (1MT) with a reported Ki for IDO1 of 34 mmol/L (65, 66). The L isomer acts as a weak substrate for IDO1 and is ascribed the weak inhibitory activity observed with the racemate, as the D isomer neither binds nor inhibits the purified IDO1 enzyme (4)." - note, indoximod is the D isomer of 1MT
"A number of studies have addressed the mechanism of action of indoximod. However, in considering an evaluation of human pharmacokinetics where clinical responses have been noted (69), only one study has provided an explanative mechanism consis- tent with blood serum levels achieved in clinical trials (70). Specifically, this study revealed that indoximod can resuscitate cellular mTORC1 activity inhibited by tryptophan depletion with an IC50 of approximately 70 nmol/L (70). Thus, indoximod acts as a high-potency tryptophan mimetic in reversing mTORC1 inhibition and the accompanying autophagy that is induced by tryptophan depletion in cells." |
