Pillar 1 - FTO (new thread), page-878

Why Bisantrene is not a very good anthracene
I encourage any potential, new, or current holders of RAC to read through all of this extremely carefully and unbiasedly. In my opinion, this is one of those posts that you cannot skim and have to read every single detail.

I was fortunate enough to have an extended coffee catch up with a bunch of fellow RAC holders yesterday and some things came to mind that I would like to share with you all. First of all, we as shareholders need to appreciate that Bisantrene is an FTO inhibitor first and anthracene-like drug second. That is a fact.

Competitors
Currently, there are 0 drugs approved by the FDA to inhibit FTO in cancer, which does make me ask the question of what else could be out there! It is important that before we do this, we first need to consider that Bisantrene is a clinically mature, phase II/III asset with a large amount of safety, tolerability, and efficacy data. Since it takes years and millions of dollars (and lots of risk) to move a novel compound from preclinical testing through the various phases of clinical research, Bisantrene can only really be compared to other clinically mature drugs. Fortunately for us, there are two very important studies that can help us to understand other comparable, potential FTO inhibitor drugs. The City of Hope evaluated 260,000 compounds from the National Cancer Institute library and the China Genoma Lab evaluated 1323 currently FDA-approved drugs. Importantly, the City of Hope paper was evaluating the use of FTO inhibitors in cancer (particularly AML), while the China study was trying to find an FTO inhibitor useful in metabolic disorders, which highlights the clinical versatility of FTO inhibitors and the attention they are getting from credentialed research institutes. I have attached a very brief summary of the articles below.



The take away from these studies tell us that Bisantrene is a 5-fold more potent inhibitor of FTO than the next most potent FTO inhibitor in a library of 260,000 compounds and 24.5-fold more potent than the most potent FTO inhibitor of current FDA approved drugs. Brequinar, as we know, failed as an anti-cancer agent and a transplant organ rejection drug, was immunosuppressive, and is impracticle to dose in humans. Therefore, in comparison to comparable clinically mature drugs, Bisantrene is by far the standout.

To my best knowledge, there are currently no preclinical compounds that can match Bisantrene in its FTO inhibitory properties. The first table are some preclinical models that have been released through publications.



The figure below is a graph taken from the City of hope comparing the properties of Bisantrene (CS1) to other identified FTO inhibitor compounds. The figure shows the IC50 (half maximal inhibitory concentration) of different compounds. The closer the lines are to the left of the figure, the better they are. Simply put, Bisantrene has a lower IC50 value (~83 nM) than other competitors.


An FTO Inhibitor

I firmly believe that if FTO was known in the 1980s-1990s, we would not have the opportunity we do right now with Bisantrene and hence, I feel extremely fortunate right now. Currently, we as shareholders can draw on quite a bit of data to determine the role Bisantrene plays as an anti-cancer agent. I would like to label that data into two different categories: 1) Current data; and 2) Circumstantial data.

Current data
The following table summarises very simply the data obtained from the City of Hope paper as well as the Chicago paper. The following conclusions can be drawn from this data:
- Bisantrene has been shown to function as an FTO inhibitor by two research institutes
- Bisantrene functions as an FTO inhibitor in AML, Breast, Glioblastoma, and Pancreatic cell models at low nM range
- Bisantrene functions as an FTO inhibitor in AML, Breast, and Arsenic-induced skin cancer animal models
- Regarding animal models, Bisantrene functions as an FTO inhibitor in patient derived xenograft model (human relapsed AML cells transplated into the mouse)
- Regarding animal models, Bisantrene functions as an FTO inhibitor in immunocompetent (BMT) animal models
- Two research institutes confirm the 5 mg/kg Bisantrene dose required to exert an FTO inhibitory effect (~7.5 mg/m2 in humans)
- By inhibiting FTO, Bisantrene has been shown to reduce cell survival, arrest the cell cycle, induce apoptosis, and abolish repopulation capacity in leukemia stem cells (the top of cellular heirarchy), synergise with hypomethylating agents, sensitize AML cells to T cell cytotoxicity, inhibit glycolysis, reduce growth and proliferation, and influence the expression of multiple genes.



Circumstantial data
A key strength of Bisantrene is the historic data that has been completed to date mostly in AML, but also Breast and Ovarian cancer. As I mentioned above, I think it is very important to look at this data with the knowledge that Bisantrene is a far better FTO inhibitor than anthracene-like drug.

To illustrate that Bisantrene is a poor anthracene, I will show you where Bisantrene is not acting like a usual anthracene. Common features of effective anthracyclines (like doxorubicin and epirubicin) are increased dose provides an increased anti-cancer response as well as increased cardiotoxicity - you could say that there is a positive relationship between dose and effect and cardiotoxicity. If you would like a very simple visual way to think about it, you could picture the graph below. If you have a lower dose, you have less effect and less cardiotoxicity and as you move the dose higher, you get more effect and more cardiotoxicity. The true relationship is not linear like what is shown below, but it may help you to visualise the relationship.



Now, Bisantrene is very unusual, in that its effect does not increase as the dose increases and it does not convey cardiotoxicity. The phase III breast cancer trial that some have metioned recently is just one example of why Bisantrene is a poor anthracene. If you believe in the RAC story and are interested in Bisantrene as an FTO inhibitor I urge you to read through this carefully and think about what it means. The table below is a summary of the cardiac toxic effects of Bisantrene, doxorubicin, and mitoxantrone in patients from the phase III breast cancer trial. Importantly, patients included into this study were required to have completed at least one prior chemotherapeutic regimen (which we know increases cardiotoxicity). Overall, Bisantrene had 0 cardiac toxic effects, whereas doxorubicin had 9 (7%) and mitoxantrone had 2 (2%) during the study. Now, if we look specifically at the >7 courses section (highlighted), we begin to appreciate some truly fascinating data.



The study used doses of Bisantrene (260 mg/m2, which was increased to 320 mg/m2), doxorubicin (60 mg/m2), and mitoxantrone (14 mg/m2) to achieve an anti-cancer effect in breast cancer patients. If we do some simple mathematics and calculate the average total dose received by patients in the >7 courses group, it is as follows:

Bisantrene: 17 x 320 = 5,440 mg/m2
Doxorubicin: 10 x 60 = 600 mg/m2
Mitoxantrone: 11 x 14 = 154 mg/m2

The dose of Bisantrene used was 9-fold greater than doxorubicin and 35-fold greater than mitoxantrone, yet Bisantrene had 0 cardiac toxicity events in this trial. If we compare the data between the 1-7 courses and the >7 courses between doxorubicin and mitoxantrone, you can see that as the averaage number of courses increased from 5 to 10 for doxorubicin, the percentage of cardiac toxic effects increased from 2% to 17%, and mitoxantrone increased from 0% to 6%. To further illustrate the point, an average 5,440 mg/m2 dose of Bisantrene is safer than an average 300 mg/m2 dose of doxorubicin, which is 18-fold larger. With regards to safety, Bisantrene completely invalidates the side effects associated with anthracyclines.

Within the results section, the researchers noticed that increasing the dose of Bisantrene from 260 to 320 mg/m2 was not associated with improved response in patients. To put that into perspective, the dosage increase from 260 to 320 mg/m2 is the same total dose of Doxorubicin used in one cycle (60 mg/m2) and 4.2 times the dose of Mitoxantrone used, yet it conveyed no additional effect. Again, bisantrene invalidates the increased effect typically seen by increased dose of anthracyclines.



Therefore, with regards to safety and anti-cancer response, Bisantrene is not functioning as a typical anthracycline.

As mentioned previously, around 20% of breast cancer types overexpress FTO. With this in mind, we can now look at the results of the phase III breast cancer trial with fresh eyes. We know from the City of Hope and Chicago papers that regular dosing of bisantrene (the papers used every other day) shows the best response, however the PIII BC trial used 320 mg/m2 of Bisantrene once every 3 weeks, which means that could have been inhibiting FTO for about 3 days every 3 weeks. Therefore, the dosing regimen used in this trial is a key limitation for the function of Bisantrene as an FTO inhibitor. Nevertheless, we'll investigate what was found. Despite the response rates of Bisantrene (13%) being much lower than doxorubicin (28%), the median survival was stastically the same 290 and 315 days, respectively. The graphs below are showing the time to treatment failure and cumulative surival. I have highlighted the B's, which are patients who have been dosed with Bisantrene. What you will see is that at the very start of treatment, Bisantrene functions very poorly compared to doxo and mitox, however as percentage without failure and alive reaches around 25%, we start to see the B's moving to the right more aggressively and overtaking D's and M's. Remember, we are looking at this data through the eyes of Bisantrene as an FTO inhibitor and that typically, 20% of BC will overexpress FTO. Also remember that Bisantrene is only able to inhibit FTO for ~3 days every three weeks. Despite a dosing regimen that would not maximise the use of an FTO inhibitor, Bisantrene was able to achieve a similar survival rate to doxorubicin.







Unlike the breast cancer trials, the historic AML trials used Bisantrene in a way that could maximise it's FTO inhibitor properties. I have discussed this data before, but briefly, Bisantrene's average complete response rate is 52% in AML trials. What we know from the two independent papers is that ~7.5 mg/m2 of Bisantrene is required to inhibit FTO. The AML trials used an average of 250 mg/m2 per day over roughly 7 days, and with a half life of about 16 hours, that means Bisantrene would have been able to inhibit FTO for approximately 10-12 days. The studies that used a follow-up course would have been an additional 4-6 days.



My question to you is what happens when the upcomming phase II AML and breast cancer trials include 100% of patients that overexpress FTO?

Summary
There is a growing body of data that clearly supports Bisantrene as an FTO inhibitor in preclinical cell and animal models. Historic in-human trials show that Bisantrene does not function as a typical anthracycline in humans as increased doses do not convey a better anti-cancer respone or greater cardiotoxicity. Recent evidence uncovering Bisantrene as an FTO inhibitor enables a more detailed, nuanced explannation of historic data from the perspective of Bisantrene as an FTO inhibitor. With the discovery of the role of FTO in lipid-related metabolic diseases, particularly those which are risk factors for heart disease, it strengthens the connection made between Bisantrene and its role as an FTO inhibitor in historic trials. More specifically, FTO overexpression has been linked to the most common type of heart failure. In-human data that clearly demonstrates Bisantrenes role as an FTO inhibitor opens the doorway to a very large field of epigenetic transcriptomic therapy, of which their are currently no clinically mature competitors and/or known preclinical competitors. These fields include metabolic, neurological, and musculoskeletal diseases.