Well, I could do that, but there are many opportunities for education. I'm also keen for a good debate on RAC and Bisantrene, so why not have a little practice.
The study used Ara-C in combination with Losartan for AML. I think they messed up this figure, though, and it should be interpreted that Losartan was given for the entire study duration and not Ara-C.
A typical human dose of Losartan is 50-100 mg/d. Losartan bioavailability is poor at 33%, which means if 100 mg/d is taken, approximately 33 mg is available in the blood stream. Volume of distribution for Losartan is roughly 34L, which means typical dosing of 50 - 100 mg/d achieves a peak plasma concentration (cMAX) of 0.44 to 1.1 uM.
https://sci-hub.se/https://link.springer.com/article/10.2165/00003088-200544080-00003
How does this compare to the IC50 of the drug for an anti-cancer effect you ask? The cMAX achieved in humans for Losartan is roughly 300 times lower than what is required to decrease cancer cell viability, and that's only the half-maximal inhibitory concentration. Due to the drug's poor bioavailability, administering such an enormous dose to patients would likely lead to toxicities and/or contraindications. In contrast, Bisantrene has IC50s below 0.5 μM in 79% of 143 Oncolines cancer cell lines, making it 600 times more potent than Losartan. The cardioprotection mechanism of action has an IC50 value around 2 μM, which is still 150 times lower than Losartan. Essentially, Bisantrene is an AMG GTR, while Losartan is an electric scooter.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056058/pdf/EXCLI-20-506.pdfMoreover, Bisantrene has already successfully been used in a heavily pretreated pediatric R/R AML patient population with high-dose Ara-C, achieving a 50% ORR. A subgroup analysis of those who had received prior Ara-C, and are more likely to be resistant to the drug, shows Bisantrene achieves a complete response rate of 57%. This is important because studies have shown that inhibiting FTO resensitizes Ara-C resistant AML cells to Ara-C. Additionally, despite the high risk of cardiac events for children heavily pretreated with anthracyclines, there were no cardiac events in this population group.
My interpretation of these findings is that Bisantrene is an m6A mRNA modulating shotgun with pleiotropic activity that further synergised with Ara-C to better kill cancer while protecting the heart from further cardiotoxicity. This may be the first in-human study of a CPACS drug, and they didn't even know.
In vivo models not translating to in-human effects shouldn't be unfamiliar to BGN, given his first-hand, recent financial experiences. If any of you don't believe me, go read IMU's Investor Presentation for CF33 and look specifically at how they phrase the efficacy of CF33 compared to other parent viruses. At first glance, this looks promising. However, sticking with the car analogies, a parent virus is like a shell on the production line waiting for parts to make it a car, while CF33 is a car with wheels, an engine, and seat belts. It's common knowledge that a complete car will outperform something on the production line because it hasn't been specialized yet. Some people might interpret these findings and invest accordingly, while others might not. There are many other examples of poor in vivo models explaining why CF33 is failing, but this is fine for now.
Following through to this point leads me to highlight that Bisantrene has an enormous amount of clinical data supporting it, which is viewed positively by the FDA that want to find effective treatments and organizations looking to profit from novel therapies. There are multiple examples of Bisantrene performing unusually well in the clinic when combined with chemotherapy classed as cardiotoxic, providing confidence that we will see meaningful CPACS in combination with Dox. Confirmation of cardioprotection in humans is very exciting and is likely the key catalyst to commercialization, as the evidence supporting Bisantrene's anti-cancer effects is already very strong. The pleiotropic activity of Bisantrene means focusing on a single anti-cancer mechanism of action is very difficult, indicating that the overall effect of the drug in humans (ORR, CR, PR, SD, PFS) is essential to understand its efficacy alone and in combination. It also highlights that it is impossible to view Bisantrene singularly in function as either one thing or another. Bisantrene is a pleiotropic m6A mRNA modulating agent that hits FTO potently but has a wide range of other effects. Viewing cardioprotection or anti-cancer in isolation means not understanding the drug or biology—if you drop a magnet into a drawer of bolts, screws, and nuts, it's going to stick to all sorts of stuff. A simple analogy to explain something very complex.
There has never been a drug that provides cardioprotection while effectively killing cancer. If cardioprotection is confirmed in humans, all the clinical investigations of Bisantrene are viewed very differently.
(20min delay)