RAC (ASX) Ann: Race releases cardioprotection market potential data

Originally posted by Mason14: ↑

It's a little bit frustrating to have spent so much time away from this forum and discussing this stock to the best of my ability to come back to some absolute garbage and people forgetting the foundations of RAC. I think that people are going to have differing opinions and sometimes they might seem a bit odd, but that is ok - we're all in this together, guys. I can see that there are some standout people here that have followed on from my work and continued to provide excellent research and perspective. I love to see that. I'm not right all the time - there is no way that I can be. Though, as much as I can, I utilize the evidence to inform everything that I say.

That said, let's take some time to reflect on something else that is very important to consider.

We are all wondering what might happen when you combine Zantrene with an anthracycline, though the molecule itself has been identified as an anthracycline for approximately 40-years until the discovery of it's world-leading FTO inhibition qualities (1,2). Early research indicates that Zantrene had less-than-average anthracycline activity, failing to have as potent anthracycline activity as commonly approved compounds like doxorubicin, mitoxantrone, and others (3-5). Something worth noting is that the anthracene activity of Zantrene was worse than a drug named Ametantrone - a drug that made clinical trials, but was never approved due to poor efficacy (4,6; Figure 1). Ametantrone was noted as having a cardiotoxic profile like mitoxantrone, which is slightly better than doxorubicin (7). While anthracene activity was very bad, at high doses Zantrene still acted on common anthracene targets, including cardiotoxic targets (Topoisomerase II).

Figure 1: Cell survival following ametantrone (Yellow highlight) and Zantrene (Purple highlight) dosing. The further up the graph indicates the worse performance.

At this point, you have to ask yourself how a drug like Ametantrone never made it to commercialisation while Zantrene did, despite Ametantrone having a better preclinical efficacy than Zantrene. If you're thinking FTO and cardioprotection, you're probably right. Zantrene was functioning on heart muscle cells like Ametantrone wasn't and had a specific target of FTO like no other drug on the planet at the time.

As I have explained earlier, Zantrene has shown to be cardioprotective when used in combination with anthracyclines and carfilzomib as well as synergising with these compounds to better kill breast cancer cells (8-10). Another important point is the upregulation of FTO in Doxorubicin treated breast cancer cells as well as the synergy of FTO inhibition and Doxorubicin to kill BC cells (11). It's quite clear that the cardioprotection and anti-cancer synergy potential for Breast Cancer alone is substantial despite conservative assumptions used (12).

Looking specifically at a phase 3 breast cancer trial that has been completed with Zantrene in comparison with Doxorubicin and Mitoxantrone, we can start to see some real nuggets of information (13). Importantly, median survival was virtually the same for Doxorubicin and Zantrene (Figure 2). While this was the case, Zantrene demonstrated some considerable benefits over the other drug by having no cardiotoxic events despite 25 patients being exposed to, on average, 5440 mg/m2 of Zantrene (an anthracycline that targets Topoisomerase II - a known target for cardiotoxicity) (Figure 3).

Figure 2: Abstract of Phase 3 Zantrene trial

Figure 3: Cardiotoxic effects of Zantrene, Doxorubicin, and Mitoxantrone.

The lifetime limit of Doxorubicin is roughly 500 mg/m2, which I believe is an extreme upper limit and that the actual limit is much closer to 250 mg/m2. Being conservative, Zantrene dosing was roughly 10x (could be 20x) greater than the lifetime dose of Doxorubicin despite ony being 5 times greater than the dose of Dox during the clinical trial without any displaying any cardiotoxic events. I take a significant amount of confidence from this result. Clearly, Zantrene is a garbage anthracene, but it does influence the topoisomerase II target which leads to cardiotoxicity, though none was present. This tells me that the cardioprotective function of Zantrene was silencing the negative anthracene cardiotoxic function of topoisomerase II activity. Another positive is the great FTO inhibition of Zantrene did not seem to influence cardiac events.

It is safe to say that this valuation has made me extremely excited. For the first time in this stocks history, an independent organisation has reviewed RAC and found it to be worth as much as $32 per share for 4% of the potential population of a single indication that is 5% of the global population. Theoretically and hypothetically, a geographical lock on US-only for Zantrene use in breast cancer for $2B would be a great option for us, with the door wide open for other geographical areas (where the majority of anthraycline use is). There are countless cardiotoxic drugs in the market and about 30+ cancers that are linked to aberrant FTO expression. Common sense is required when an offer of <$2B comes knocking. Two blue water markets is a once in a lifetime opportunity. When the drug is used properly, I think we will alter the course of oncolgy forever.

Happy easter - let's all take some time to think about what we are adding to this forum

1. National Cancer Institute (1991) Final Report to the Food and Drug Administration: Bisantrene. Bisantrene IND. Bethesda, MD: National Cancer Institute. (Document available under request)
2. https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(20)30216-6
3. https://pubmed.ncbi.nlm.nih.gov/6678863/
4. https://pubmed.ncbi.nlm.nih.gov/6850582/
5. https://aacrjournals.org/cancerres/article/45/10/4915/489250/Comparative-Molecular-Pharmacology-in-Leukemic6. https://pubmed.ncbi.nlm.nih.gov/3987756/
7. https://pubmed.ncbi.nlm.nih.gov/6875860/
8. https://cdn-api.markitdigital.com/apiman-gateway/CommSec/commsec-node-api/1.0/event/document/1410-02463955-1DOHC0VF6VO6KDECS48J2FT4LV/pdf?access_token=0007GQMyvJ5ZEDBJBvS1WEPbtUVe
9. https://cdn-api.markitdigital.com/apiman-gateway/CommSec/commsec-node-api/1.0/event/document/1410-02455256-57J4JVIN605MULB4PJ4MR8S21V/pdf?access_token=0007GQMyvJ5ZEDBJBvS1WEPbtUVe
10. https://cdn-api.markitdigital.com/apiman-gateway/CommSec/commsec-node-api/1.0/event/document/1410-02536753-6KK2JIQ1LPCU9JRFF7PB3HFSMH/pdf?access_token=0007GQMyvJ5ZEDBJBvS1WEPbtUVe
11. https://pubmed.ncbi.nlm.nih.gov/34076564/
12. https://cdn-api.markitdigital.com/apiman-gateway/CommSec/commsec-node-api/1.0/event/document/1410-02651127-6QKEMPUNC2NUDGE2G7085G30SL/pdf?access_token=0007GQMyvJ5ZEDBJBvS1WEPbtUVe
13. https://pubmed.ncbi.nlm.nih.gov/1875415/

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great reminder @Mason14 to consider the fundamentals, science and commercial opportunity.

Why is Zantrene a superior anti-cancer and cardio-protective drugs but a crap anthracycline?

Bisantrene is a modified version of Doxorubicin without the anthracycline ring, which gives Dox most of its killing power. This is supplemented by FTO inhibition boosting Zantrene to be formidable cancer killer.

The reason why Zantrene is a first in class and best in class FTO inhibitor is ability to bind strongly to the catalytic pocket. Whilst other FTO inhibitors bind to non-catalytic sites so are less effective at demethylation. I believe this is because Zantrene is negatively charged making it a magnet to cancer at the c-terminal domain, thus superior to other FTO inhibitors. We know that FTO overexpression is relevant to the progression of 30+ cancers. It we will know this year how close it will be to 100 cancers.

Cardio protection is independent from FTO inhibition, and my view is it relates to iron metabolism, ROS and oxidated stress, all interlinked. In effect, the hydrogen bonds on Zantrene prevent the Fenton reaction (via iron chelation) and thus protects against cardiotoxicity. This issue translates across multiple cancer drugs, such as 5-FU and Trastuzumab. It will be interesting to see the results of the expanded heart safety program which is reviewing Zantrene across a panel of cardiotoxic drugs.

Why is this even useful to me as an investor. Well DYOR, and not simply rely on the reports and valuations paid by Race. The science needs to work, to have any chance of commercial success. Also, understanding how big these elephants really are to know the risk v reward opportunity.

I expect some big announcements and changes to Race over the next 12 months as it transitions from building science -> Clinical data -> Commercialisation. Best of luck.