Ann: Race Appoints George Clinical for Phase 1 Trial of RC220, page-124

The available evidence quite clearly shows that greater dosing within the month generates the best response rates.



There is also a significant difference between frequent low-dose and high-dose regimens, indicating self-synergy with pleiotropic mechanisms.



The more I research Bisantrene, the more I understand that it has a very broad spectrum of activity. FTO inhibition is certainly the most potent that I know of (142nM), but this is closely followed by a1 adrenoceptors (145nM), where its inhibition has been linked to both anti-cancer and cardioprotective effects. The macrophage activity is very interesting, but this also needs to be viewed in the sense that Bisantrenes FTO inhibition can prevent macrophage polarization, but FTO inhibition in already formed macrophages can alter its activity. In truth, the more I understand, the more questions I have, hah. I really think we need to start appreciating Bisantrene as a RNA shotgun, with a focus on FTO inhibition and a very wide reach of activity to other systems.

So, to answer your question: It's really going to depend on what drug Bisantrene is paired with, but I suspect something like a 200-250 mg/m2 every other day for 10 days separated by a week and then repeated again. This would be 10 doses of Bisantrene in the month and be between 2000 mg/m2 and 2500 mg/m2, which is where there is strong efficacy. Similar dosing protocols has been completed in vivo and appears to be safe and tolerable, and the total dose per month is comparable to what patients have already received, so I presume it would translate to tolerability in humans. While these are my thoughts, they probably won't reflect what happens.

One of the fascinating things that I have read about Bisantrene is that more regular dosing of Bisantrene slows the terminal half-life, which would indicate that it is accumulating in the body.

I think you get it fine if you take the information at face value and ignore the recent discoveries for Bisantrene, but that's not really what I am talking about here.

Bisantrene is a first-in-class drug with separate mechanisms of action to Doxorubicin, but displayed comparable OS (I clearly stated above that it was non-significant). If you read above, you'll see that patients clearly respond better to greater total doses of Bisantrene in the month, which is likely due to the mechanisms of action. There are 1740 people across 62 clinical trials included in that analysis, so I'd say it's representative and reliable. RAC are focusing specifically on combining Bisantrene with Doxorubicin, which is advantageous because each drug has broad activity that appears to independent of each other.

Therefore, it is reasonable to assume the following:
1) For OS, Bisantrene is comparable to Doxorubicin
2) Bisantrene was not dosed optimally in this patient population.
3) The combination of separate mechanisms of action should increase the patient population likely to respond
4) The combination of drugs should synergise to more effectively treat each patient and prevent cardiotoxicity

Since Bisantrene is a first-in-class drug with unique mechanisms of cardioprotection and anti-cancer synergy, a phase III trial demonstrating comparable efficacy to Doxorubicin is relevant for someone like me looking to de-risk and understand their investment.

Interested to know your thoughts on these human-derived breast cancer samples and their response to either Bisantrene or Doxorubicin. Looks to me that a separate patient population responds to Bisantrene where they do not respond to Doxorubicin. This is what I believe to be happening in the P3 BC trial, and that is why it's essential to look at the data through an m6A mRNA modulating pleiotropic lense. It's repliacted again in another vitro study and in R/R AML patient populations where dosing reflects optimal.



54% sensitive vs 14%



50.7% CR rate vs 35% Response Rate