Ann: Race Appoints George Clinical for Phase 1 Trial of RC220, page-129

May I ask what exactly you are looking for?

Bisantrene and humans really haven't changed that much.

By my count, there are 65 clinical trials that aren't going anywhere, and 2 clinical trials completed recently in extremely unwell patients. If you consider EMD AML as a solid tumor (and there are many publications in the literature that have stated and proved the similarities), a 7-day 250 mg/m2 dosing regimen of Bisantrene has achieved a response in 7/9 solid tumor metastatic AML patients in the 2 most recent clinical trials. These are the only solid tumor patients that have ever received a 7-day course of high dose Bisantrene (if you exclude the EMD AML patients that achieved responses in the historic literature - they didn't screen EMD AML well back then, so it's unknown how many had EMD AML and I couldn't run that analysis).

Below is how Bisantrene compares to other treatment combinations for R/R EMD AML.



Now, we can look at this in isolation and go, well, is that it? 9 patients? Who cares! But the history of Bisantrene has many instances of high disease control rates (CR + PR + SD) in refractory and metastatic difficult to treat patients at dosing regimens that are not optimal.

Here are three excellent examples with once every three week dosing regimens. Of the 90 evaluable patients included into these phase 2 clinical trials, there were 9 partial responses (10%). If we were following an anthracycline model, we would consider this a failure, but Bisantrene is not an anthracycline. What this data shows is that there is a huge number of patients that responded to the drug, and what I am suggesting is the dosing regimen was not adequate for the drug to work effectively. Had these patients received a similar dose to the EMD AML patients included in the most recent P2 AML trials, what would the response rate have been?



Now, you could be shut-off from this because it happened so long ago, but when I see recent in vitro work completed by Oncolines, a preclinical program that has preceded multiple FDA approvals and confirmed multiple FDA labels, demonstrates Bisantrene is sensitive in almost 80% of cancer lines at clinically relevant doses, it is difficult not to get excited.



When you have done a full review of the literature, there are a lot of things that stick out. For me, there is a HUGE difference between the effects seen in vitro and what we can review in patients. However, this is not the case when a frequent, high-dose regimen is used. Even in AML, which has the best anti-cancer efficacy of any single agent therapy that I have found, Bisantrene is INEFFECTIVE at Q3W dosing. This paper isolated patients that had received P2 doses of 300 - 430 mg/m2 once every three weeks and only 1 / 19 (5%) responded. Quite literally, an increase from 5% CR to 50% CR with the correct dosing regimen.

Read the above section again and make sure it sinks in. Then read it once more.



Therefore, when I see the Bisantrene oncolines data and the in vitro work where Bisantrene is outperforming approved agents, and compare it to once every three week dosing where this is no efficacy and again to frequent high dosing where there is excellent efficacy, it's pretty bloody obvious that the drug was not used correctly.




Look very carefully at this data in hematological and metastatic solid-tumor-like-AML patients where the dose of Bisantrene reflects it's mechanism of action. It is exactly the same as what is happening in the in vitro models. So, when I look at the 60-70% disease control rates in metastatic solid tumor patients (above), I can't help but think that is a massive portion of patients that could have responded to Bisantrene had the drug been given appropriately.



Evaluating the P3 data from this perspective is why I am seeing things slightly differently to you.