At the AGM/Corporate update, slide 20 (pdf of slides) entitled "Target Modulation Measured in Clinic" showed alteration in mRNA levels for MYC, BCL2, CCR1, IL1RN, and GPR183 before ZEN-3694 dosing and after 4h or 24h. This shows the effect of a single dose (the lowest starting dose) of ZEN-3694 on the mRNA levels found in blood after the patients in the single agent ZEN-3694 trial received their first dose of drug. I presume they took blood samples from patients as 0, 4 and 24 hours after dosing to analyze the mRNA. We can see that ZEN-3694 lowered the mRNA expression level of all five targets after 4h. For some targets, like MYC and BCL2, the mRNA level remained suppressed at 24h as well; whereas for CCR1, IL1RN and GPR183 the mRNA levels started to return to their baseline levels.
This data, or at least the layout, looked very familiar to me. I looked at their recent AACR poster and in it is a panel "ZEN-3694 Phase I Trial in mCRPC: PD marker modulation in ex-vivo treated human whole blood." A very similar figure is shown there, which shows the effect of various doses of ZEN-3694 on the mRNA expression of MYC, BCL2 and four other undisclosed targets in whole-blood treated ex-vivo for four hours. For this, they took blood from patients not treated yet with ZEN-3694 and then added the various levels of the drug to the blood sample. One can see a clear dose-response suppression of 5 of these mRNA targets, and a sixth one that is also undisclosed was increased by the drug.
Exact same color scheme for the five suppressed targets between the AGM graph and the AACR graph; the sixth target that was on the AACR poster doesn't appear to present on the AGM graph. So we can assume that the other 3 undisclosed targets in the AACR poster were CCR1, IL1RN and GPR183. We can also assume that in the patients treated with higher doses of ZEN-3694 that these effects on suppressing MYC, BCL2, CCR1, IL1RN and GPR183 would be even greater.
They seem to be on their way to establishing a non-invasive means of drug efficacy; a ZEN-3694 signature. All they need is a baseline blood sample and a blood sample taken after ZEN-3694 dosing and they can use the mRNA profile of a panel of genes to determine if the patient is responding to the drug. It had already been shown in the literature that MYC and BCL2 were suppressed by pan-BET inhibitors. Now, it seems that Zenith has 1) established a more comprehensive panel of genes that comprise a ZEN-3694 signature; and 2) shown that they can monitor modulation of this signature with mRNA analysis from a blood sample taken from a treated patient.
Very cool!
BearDownAZ
