RE: Full Case Study Document AVA61038 Feb 2025 12:18
@bootnk, I think you might be misunderstanding maximum tolerated dose (MTD) and maximum lifetime cumulative dose (MLCD).
MTD is defined during Phase 1 as the dose below the dose where toxic side-effects become unacceptable due to dose-limiting toxicity (DLT). It is true that this was not found for AVA6000 but that was only because the drug was showing sufficient efficacy so they stopped looking for a MTD - it was a matter of finding the sweet spot between adequate efficacy and overly high contributions to the MLCD (see below).
MLCD is defined for doxorubicin (aka Adriamycin®) as 450-550 mg/m² but is dependent upon the condition of the patient and can be lower for sick patients with bad hearts (if risked being given at all) and can go higher for very fit patients with no heart issues. MLCD is calculated for AVA6000 as the amount of free, released doxorubicin in the plasma. That sounds awkward as it would need to be calculated for each dosing. Hopefully they can use a surrogate measure such as heart condition, but we'll see.
When a drug is authorised for use in the clinic, the dosing regimen - both the dose level and the dosing frequency - and the indications it can be used for - SGC, TNBC, etc - are defined according to what was used in the clinical trials. Doctors will not be able to prescribe unlimited high doses nor for other indications unless they want to do it 'off-label' as their own personal responsibility. The company - Avacta, etc. - is only responsible, and thus liable for litigation, for the authorised prescribing.
For information, the factor for converting doxorubicin in AVA6000 to free doxorubicin is 54/80 (80 mg/m² of AVA6000 contains the equivalent of 54 mg/m² bound doxorubicin) but it should be noted that not all the doxorubicin bound in AVA6000 will be cleaved by FAP. The amount cleaved will only be known by measuring the amount in the plasma (unless Avacta have evolved some fancy other technique) but the point is that enough is cleaved within the tumour microenvironment (TME) to produce a highly concentrated dose exactly where it's needed.
It should also be noted that AVA6000 is not a straight substitute for doxorubicin use in every case as it requires FAP to be present in order to work whereas doxorubicin, as used in the clinic for decades, does not. Of course, there are also large numbers of patients who can't be given straight doxorubicin due to age, heart condition, etc. who could be given AVA6000. No way am I going to attempt any guess at the total addressable market (TAM) for AVA6000 or any other drug candidate. I leave that sort of thing to any farmer wanting to make an offer for AVA6000 or a larger part of the company.
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