To: Miljenko Zuanic who wrote (3154) | 1/4/2018 2:39:23 PM | From: former_pgs | | | 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." |
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To: former_pgs who wrote (3155) | 1/4/2018 7:13:53 PM | From: Miljenko Zuanic | | | Thanks, we agree Indo is not an INDO-1 inhibitor.
<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.>
Can this explain synergy with IO path and added activity, seen for other INDO-1 inhibitor? Should re-activation of the mTORC1 bring "survival" benefit to cancer cells? |
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From: scaram(o)uche | 1/7/2018 7:32:20 PM | | | | Celgene buying fedratinib for what?????
PGS and friends discussing it at twitter, no need to digest here. "Incremental" has become CELG-important, a shame. |
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To: former_pgs who wrote (3155) | 1/9/2018 1:59:18 PM | From: Miljenko Zuanic | | | At JPM, INCY was cautious on IDO1, so...PFE exiting IDO-target may (after hearing their and BMY presentation) sound as diversification from BMY-overlapping programs. IF PFE can afford (at least) 40% premium to current BMY MC, they would go after it.
Sorry to pollute INCY tread with PFE/BMY thoughts! |
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To: Miljenko Zuanic who wrote (3158) | 1/9/2018 2:47:15 PM | From: scaram(o)uche | | | >> At JPM, INCY was cautious on IDO1 <<
With all of the commentary about duration and deepening of the response, and with the slide showing data vs. historical for PD-1 alone? Emphasizing that nivo/epa results were as strong as pembro/epa? I got the opposite feel, that they were very strong re. IDO1. |
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To: former_pgs who wrote (3155) | 1/9/2018 3:29:40 PM | From: scaram(o)uche | | | These findings are important translationally, because they suggest broader clinical uses for D-1MT against cancers that overexpress any tryptophan catabolic enzyme (IDO1, IDO2 or TDO).
ncbi.nlm.nih.gov
>> does suggest one would make a mistake by extrapolating heavily based on the indoximod data <<
Yeah, but a mistake in which direction?? Isn't downstream inhibition of IDO1, IDO2 and TDO better than IDO1 alone??
The Incyte rationale for IOD1 selective agents is given here, third paragraph.....
ncbi.nlm.nih.gov
So they would say "no". |
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To: scaram(o)uche who wrote (3159) | 1/9/2018 3:42:07 PM | From: Miljenko Zuanic | | | Indeed, P2 Epa-PD1 chombo data v PD1 mono (multiple indications) are very strong, still Mr. Market expect much translating P2 data to P3. That was INCY position. If they do not believe in chombo they will never license MGA012 (let MRK and BMY promote "marginal" IDO1 data), or for any other in-house combination. They know that they can not depend on partners if they want full and fair benefit from their own drugs, Epa included. |
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