RE: “If it wasn’t activating, would tolerability be an issue?”24 Nov 2022 10:59
(Internet connection back up! Meant ropey, not Tory, although I don't know - the serendipity of predictive text!)
OK, so I meant activation (cleavage of AVA6000 to release doxorubicin), not S&T.
Also, I don't think it can be truly said that activation is much nearer 100% than 0%. Activation is at a level that is likely to make AVA6000 efficacious, be that 10%, 50%, 80% or whatever.
Given that FAP will cleave AVA6000 to release doxorubicin, that can happen in the TME, where FAP is overexpressed compared to healthy adult tissues, or by FAP in other parts of the body. In the former case, as long as doxorubicin and its cytotoxic metabilites act only in the TME then all is well, but any leaking into the circulation will act like free doxorubicin with consequent side-effects from the killing of healthy cells. In the latter case, there will be local cytotoxicity, with possible leakage of doxorubicin and metabolites into the circulatory system. That the S&T is good to very good would indicate little of this stray doxorubicin is occurring.
Factors to consider that affect the 0%-100% inert-full activation range will include:
1. The infusion concentration and rate of administration (e.g. in mg of AVA6000 per minute) - i.e. concentrated over a shorter time or diluted over a longer time.
2. The capacity of FAP in the TME to cleave AVA6000 (e.g. in mg per minute) - i.e. FAP's natural rate of cleaving and how far into the tumour AVA6000 penetrates (a concentration profile in the cross-section of the tumour).
3. The half-life of AVA6000 in circulation before excretion - i.e. the number of passes of the tumour and the percentage of dosed AVA6000 at each pass.
3 will be found in the PK data.
2 will be hopefully be found in any biopsies (supporting findings from the animal studies).
There is great variability possible with 1 and could be decided based on how long it takes for dead tumour cells to be shed, exposing fresh FAP-rich targets, or, if AVA6000 pervades the whole tumour, a single bolus dose .
Sign In
Follow the stocks
