Such is the way with clinical trials of new drugs. It's a bit of...

Such is the way with clinical trials of new drugs.

It's a bit of a difficult thing to answer, honestly. You've said earlier intervention with various cancers, so I'll assume that you are talking about cancer stage (and we will also assume patient health is well enough to be treated with a chemotherapy).

Bisantrenes primary MoA for anti-cancer efficacy is the inhibition of FTO, which is the most sensitive in the world (to my best knowledge; below). Preclinical evaluation of Bisantrene in vitro and in vivo have consistently shown that it is most effective where FTO is overexpressed or where FTO is driving tumorigenesis.



You may have heard that Bisantrene is an anthracene - and it is - but it turns out that it is extremely poor. Like, so bad that a drug which was preclinically a better prospect displayed no efficacy in clinical trials. Below are two graphs taken from historic cytotoxicity preclinical research evaluating common anthracenes in their cell killing ability. Ametantrone (blue) outperforms Bisantrene (yellow) consistently in these preclinical models.




Here are the abstract of 2 clinical trials evaluating Ametantrone that show limited to no clinical efficacy which is in line with it’s poor preclinical activity, and the last screenshot is a table evaluating the clinical efficacy of Bisantrene in AML. Despite Bisantrene being far worse preclinically than Ametantrone, it showcases an average 51.6% complete response rate in blood cancers. Clearly, the clinical activity of Bisantrene does not correlate with its preclinically activity.





If you are new to the area of oncology, there are other drugs that are used in patients that overexpress or present with certain cancer characteristics, like anti-PD1 therapy, monoclonal antibodies, or TKI inhibitors. Essentially, these are drugs that fall into the area of targetted therapy or precision oncology, where the characteristics of a cancer type decide the treatment regimen. An example of a chemotherapy that is not precision oncology are our anthracyclines. Patients that present with cancer types that overexpress FTO or where FTO is driving tumorigenesis is where Bisantrene will have the most effect, which places Bisantrene into the area of precision oncology and not broad chemotherapy, such as it's anthracene cousins.

So, at this point, you should be aware that Bisantrene is a precision oncology therapy that specifically targets the FTO molecule, which is supported by historic clinical and preclinical data. While FTO was not known in the 80s and 90s, it is now, which is why when I evaluate the relationship between preclinical and clinical data for Ametantrone and Bisantrene, it highlights to me that a mechanism of action is driving the efficacy seen for Bisantrene. I only know of FTO, so it must be that.

Now, there are two key things that need to be addressed. Precision oncology medicines require precision tools to screen patients and identify those who would respond strongly to the drug, and the dosing regimen needs to be correct so that the target molecule is effectively inhibited for a duration of time that is sufficient to induce cytotoxicity. For Bisantrene, there is only one occasion that I have found where it has been used in a selective way, and that is from a phase 1 clinical trial. The researchers included 4 patients into their phase 1 clinical trial because their cancers were sensitive to Bisantrene in vitro. All 4 patients achieved clinical responses. This is the one example that we have that resembles a precision oncology methodology in patient selection, but unfortunately this study fell short on the dosing regimen, which may have influenced the strength of the responses observed.





I suspect that dosing for an FTO inhibitor is going to be far more regular than what has been done in historic clinical trials. For blood cancers, Bisantrene is typically given once per day over 5 days, whereas it is given once a month for solid tumors. The nature of FTO-derived m6A mRNA demethylation is that it is constantly happening within the cell, so a single dose of Bisantrene may not effectively inhibit the demethylation of m6A leading to the cancer surviving. I believe that this is why we see limited responses in patients with solid tumors and we see strong responses in AML - because Bisantrene is able to shut off m6A mRNA demethylation, essentially grinding cancer function to a halt.

The last point that I want to discuss to help me answer your question is the way chemotherapy increases FTO expression and produces stronger cancer cells like leukemia stem cells (LSCs). Cancer cells are like us - they want to survive. When something tries to kill them and they survive, they get stronger. Think about one sheep in a herd having an extra thick layer of fur to fight off extreme cold long enough to live and multiply. I think there are 10 or more drugs that have been shown to synergise with an FTO knockdown model or an FTO inhibitor. Suggesting that exposure to these chemotherapies leads to intracellular epitranscriptomic changes to overcome their cytotoxicity. By inhibiting FTO, Bisantrene is essentially able to prevent this safe-guarding survival process and allow the cancer killing effects of these compounds to take effect. Studies have shown that FTO inhibition with Bisantrene influences the LSCs directly, which as stated by the City of Hope "is necessary to achieve a cure".





Ok. So, now that you have all of that, I can say the following.

I think that Bisantrene will be most effective in a specific group of patients with stage 3 or 4 cancers that overexpress the m6A mRNA epitranscriptomic protein FTO, and it may be that the best responses are seen in patients that have failed one or more lines of therapy, as this will increase cancer dependency on FTO. It could very well be that a synergy of Bisantrene with other forms of chemotherapy (either broad or specific) could function to overcome chemoresistance and fight earlier stages of cancer as well as late stage cancers. That said, I believe our target population will not necessarily be front-line patients, and if they are, certainly not the first that we treat along our journey.