| To: tuck who wrote (3142) | 9/9/2017 3:04:42 PM | | From: tuck | | | | IDO/PD1 combo battle part 2: Here is the data for Epacadostat/Keytruda in melanoma:
Progression-Free Survival Data from ECHO-202 Trial of Incyte’s Epacadostat in Combination with KEYTRUDA® (pembrolizumab) Underscore Durability of Response in Patients with Advanced Melanoma
Again, to preserve formatting, just the permalink. Without knowing baseline characteristics of the ECHO patients, not sure how things stand. Here's a presentation with baseline characteristics for Indoximod/Keytruda combo. Apparently, the dose here was 1200mg/kg, whereas they are taking half that dose into P3, which is interesting, because the SAE profile looks OK, and no worse than Epacadostat . . .
Interim Analysis of the Phase 2 Clinical Trial of the IDO Pathway Inhibitor Indoximod in Combination With Pembrolizumab for Patients With Advanced Melanoma
Both open label. Again, with out ECHO baseline data, hard to compare well, but based on what we have, I give the edge to Indoximod. Better looking safety, better CR rate, similar ORR, slightly better mPFS. No wonder NLNK had more than a one day tear.
ECHO data more mature? CR rate is down from previous look.
Always interested in other opinions.
Cheers, Tuck |
| | Incyte (INCY) | Stock Discussion ForumsShare | RecommendKeepReplyMark as Last ReadRead Replies (1) |
|
| To: tuck who wrote (3149) | 9/9/2017 4:09:26 PM | | From: tuck | | | | IDO/PD1 . . . Here's is INCY's presentation, which dose give demographic data. This was a dose escalation trial, whereas, NLNK's was at single dose. So apparent disadvantage of Epacadostat I noted in the prior post may be due to that.
Incyte ESMO presentation
I can't quite read through the patient baseline characteristics. It seems ECHO had a slightly higher % of M1c patients: 55 versus 50. Further, every patient was M stage (stage IV), whereas in the NewLink trial, 13% were stage III. ECHO also had substantially fewer treatment naive patients.
So now, having seen all the available data, I would call this approximately even. NLNK had better numbers, but population was less sick.
Cheers, Tuck |
| | Incyte (INCY) | Stock Discussion ForumsShare | RecommendKeepReplyMark as Last ReadRead Replies (1) |
|
| To: tuck who wrote (3153) | 1/4/2018 1:08:22 PM | | From: Miljenko Zuanic | | | | I do not think that it is kynurenine level (as biomarker) that describe path for cancer IDO-1 activity, it was biopsy of resected brain tumors. So, my guess is that regardless long t1/2 and high dose (in addition to preclinical model), PFE candidate did not penetrate tymor mass...results was inactivity.
In general, this guy from SA favorise NLNK Inoximod:
seekingalpha.com
but, I was sceptical about Inoximod MOA early and still am. Wish, PGS can stop by and drop few words on topic (I do not like conversation @ twitter).
PS: IF INCY drop further (due to luck of data at JPM), I am considering position. |
| | Incyte (INCY) | Stock Discussion ForumsShare | RecommendKeepReplyMark as Last ReadRead Replies (1) |
|
| 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." |
| | Incyte (INCY) | Stock Discussion ForumsShare | RecommendKeepReplyMark as Last ReadRead Replies (3) |
|
| 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? |
| | Incyte (INCY) | Stock Discussion ForumsShare | RecommendKeepReplyMark as Last Read |
|
| 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. |
| | Incyte (INCY) | Stock Discussion ForumsShare | RecommendKeepReplyMark as Last Read |
|
| |
