Peter, “all we know about the Phase III was that safety was consistent with the Phase II”,
that was CEO words.
Drawing conclusion about drug safety (for now let put aside efficacy) based on comparison with similar drug performance in controlled trials (placebo or active) and not comparing subjects baseline characteristics, placebo adjusted SAE profile, even placebo subjects performance, can be tricky. For instance Axitinib was safer than Sorafenib in PIII, Pazopanib has liver toxicity problem,…
Second, it is drug related SAE (not all AE), treatment failure due to toxicity (reduction/discontinuation),… that count in therapeutic index and medical benefit. It is true that Tivozanib has lower incidence of SAE (fatigue, stomatitis, diarrhea, hand-foot syndrome, and proteinuria) in PII RCC trial.
In safety PI DLT (2.0 mg) were: proteinuria, hypertension, and ataxia, with significant ALT/AST and GGT level increase, while 1.5 mg had also those toxicity, but with bit lower level. Nonetheless, in PII RCC trials suddenly we have very low ALT/AST toxicity, but increase in GGT. IF drug absorption exhibit liver re-circulation (as visible from Tmax/Cmax measure, feed condition) elevated ALT/AST should be expected. That was not the case. Why? I think that JCO article (PII RCC data) does not show TRUE picture about drug toxicity.
So, IF PIII show the same type ‘consistency” in drug toxicity profile (as CEO claim, very low off-target toxicity), I am not sure what I will believe? |
