|Moderated By: Miljenko Zuanic -- (Moderated) -- Started: 4/18/2012 2:37:26 PM Revision History|
To continue from BV tread:
>>Non-toxicity is company “illusion”
Well the side-effect profile in monotherapy was substantially better than any of the other small-molecule VEGF drugs.
>>indicate serious problems with PK/PD
If I recall correctly, their initial dosing in their Phase I proved much too high, indicating they did get some sort of surprise concerning their PK/PD modeling. But once they dropped the dose the drug seems to work well.
Well, I am not sure about “better” safety profile versus other specific (not Sutent) VEGF inhibitors. There is no direct comparison, so TIVO-1 will give idea about safety profile relative to Nexavar, as well as general safety profile. Latest (also safety PI) JofCO article on PII suggest that there is some problematic off-target side effects (liver).
Regards the PK/PD profile and data, I am afraid that even 1.5 mg dose is too high (at the borderline MTD). At the sign of the any toxicity FDA may ask them to consider (further explore) 1.0 mg dose. 2.0 and 1.5 mg was (actually) ~1/3 of NOAEL in monkey, so liver recirculation was unexpected. This may not be a problem, but great variability between subjects and absorbtion/clearing rate due to subject condition may be a big problem for oncologist (dose titration is not very applicable for cancer condition).
Regards the TIVO-1 and Nexavar better than expected PFS (9 versus 6 months), it is intriguing that at the same time Tivozanib PFS decline from ~15 to 13 months. Why? “Selective” selection of the subjects?
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