@HeyLineCan you please re-read my latest post in this thread. I address the dosing of Bisantrene directly. If that explanation doesn't make sense to you, I'm happy to find another way to explain it.
The lead in dose of Bisantrene is to test the changes in m6A levels. Because Bisantrene inhibits FTO function, you won't see a reduction in FTO levels, and instead you'll see changes in m6A levels. Testing m6A during the lead in phase will generate pre- and post-bisantrene m6A levels, proving Bisantrene increases m6A levels via inhibition of the FTO protein. These changes in m6A levels can then be correlated with those who do and don't respond to treatment in the combination study.
Bisantrene works well at low doses inhibiting the FTO protein, but the dose of Bisantrene will need to be the maximally tolerated in combination with anthracyclines for humans. This is because the concentration required for cardioprotection is higher than what is required for FTO inhibition. We are lucky anti cancer synergy is met first and dosing thereafter is for increasing cardioprotection. I believe the dosing regimen for Bisantrene in combination with anthracyclines will be 200-250 mg/m2 possibly over 1-3 days, which easily achieves in-human concentrations of 3000 nM that have proven to provide consistent cardioprotection across 4 major drug classes. Based on 1980s partitioning studies in dogs and monkeys, we know the heart is one of the highest deposition sites for Bisantrene.
Bisantrene will not need a separate low dose regimen to prove FTO inhibition. The lead in dose for Bisantrene as a single agent provides m6A level changes, which can then be correlated to patients. For example, those with lower m6A levels will have higher levels of FTO, and if their m6A levels increase after Bisantrene dosing, we know Bisantrene is decreasing demethylase action through the inhibition of FTO. This correlated with clinical responses highlights the therapeutic synergy, as FTO inhibition is shown to synergise with anthracyclines. Responses in patients with high FTO status is a massive market. The significantly more interesting associations well be the clinical responses of patients that already have moderate or high m6A levels (normal or low FTO expression) which increase after Bisantrene dosing. If the synergy between FTO inhibition and anthracene activity drives meaningful responses irrespective of FTO expression or m6A levels, then we have an inconceivably large market. Lastly, there are likely large datasets available that have investigated single agent anthracenes in similar patient populations, which can be compared to for combination synergy.
Lastly, the VO2PEAK data can be generated roughly 4-6 months after treatment initiation. Since there are anthracene naive popupations to refer to, we can have usable CPACS data, inclusive of m6A level and cardiac function data, in a clinical instant. Moreover, RAC have been in constant communication with the FDA due to the Orphan Drug Designation, so it is guaranteed that the CPACS trial has been influenced by the FDA in favor of data that would drive breakthrough therapy designation and approvals.
