Tuck, I am familiar with John T analysis, done similar one 18 months ago when I took position on VKTX. I took position because of the lipids reduction level (from elevated, LDLc, Apo-b and Lipo-a) observed in initial P1b trial. Dose reduction (actually choice) to 5 and 10 mg did induce to me concern that there is a problem with liver tox. P1a data (presented by John T) by itself do not explain choice/reasons to go with lover doses...so, is there additional problem related to liver tox?????
VKTX chose HeHF subjects with elevated LDLc, some fats in liver,.... but mostly "normal" liver function...no elevated (no elevated at significance, as sign of the inflammation/fibrosis) ALT and/or APT enzymes.
"Among patients with elevated baseline ALT levels, those receiving VK2809 also demonstrated reduction relative to placebo." ...12 w may be too short period for meaningful observation, ..... placebo had small increase and drug flat level??? Point is that this were not subjects with serious ALT elevation at baseline, that was the case in 3196 trial.
As I noted early and repeated, this were subjects with primary hypercholesterolemia with >10% liver fat, and focus was on "lipids lowering effects"! Here, one have to ask simple question: "what bio-chemistry explanation" is for elevated markers of the liver dysfunction, in NASH or HF subjects? Simple answer would be "dysfunctional enzymatic activity"! VK2809 is pro-drug, and require certain liver enzyme to convert 2809 into active moiety. The same enzyme is involved in conversion of the VK2809 into potential "toxic metabolite" (unrelated to thyroid beta receptor activity, ...pointed and explained to me by BiotechJim). This is low probability, but experience from other compounds teach chemist to be cautious. It is like "continuous slow poison".....and what IF it is cumulative????
So, my first two point of observation stay....VKTX twisted the story! On third one, I can not be relieved before I see full safety data and primate tox results (liver tox data). It is not on-target toxicity, it is not off-target toxicity,...it is metabolite concern! So, when CEO brag about further dose reduction (IF needed), how can I be blind and say...all is OK????
This VK2809 P2 data are in right direction, lets hope they will hold in further studies. Interim tox issue is solved, long term concern stay.
Next step on VK2511 will tell me how serious this company is. |
