CardioprotectionZantrene is a rediscovered molecule with an...

Cardioprotection

Zantrene is a rediscovered molecule with an established clinical history and prior approval for Acute Myeloid Leukemia in France. A recent discovery of world leading FTO-inhibition highlights the most likely molecular pathway driving its clinical efficacy as a chemotherapy agent. Interestingly, FTO-inhibition was proven through research to not be the mechanism of action for cardioprotection, indicating another target for the drug. Recently, the Triangle Insight Group released a report highlighting the widespread use of anthracyclines in cancer treatment due to their clinical efficacy, despite concerns over cardiotoxicity, and reveals a significant unmet need for cardio-protective measures. Initial feedback from stakeholders suggests the potential for broad adoption of Zantrene as a cardio-protective agent in breast cancer therapy, with substantial commercial implications if anti-cancer benefits are also confirmed.

Preclinical Data

There have been three preclinical studies published to date evaluating the efficacy of Zantrene as a cardioprotective agent. The first two preclinical papers addressed similar questions, so they will be discussed together with the most recent research to follow.

1. Breakthrough Chemotherapy Heart Protection Discovery for Zantrene (22 Nov 2021) and Expanded Heart Protection Discovery for Zantrene (8 Dec 2021)

Zantrene was shown to shield heart cells from the damaging effects of doxorubicin and carfilzomib, common chemotherapy drugs. When heart cells were exposed to doxorubicin or carfilzomib, adding Zantrene significantly improved their survival, with the best results seen at higher doses of Zantrene, which are still within the safe range for human treatment.

For our math and biology aficionados, a 5,000 nm dose of Zantrene equates to roughly 2.065 mg, which, for an 80kg man of 1.75m equates to roughly 1.06 mg/m2. The dose provided in historic clinical trials ranged from 90 - 320 mg/m2.

Importantly, Zantrene has been shown to enhance the cancer-killing effects of doxorubicin, epirubicin, and carfilzomib. This synergistic effect occurs even at low levels of Zantrene and is effective against various breast cancer cell types, including those resistant to the drugs alone. Carfilzomib is mainly a multiple myeloma drug, so the synergism may open the door to this chemotherapy being used in solid tumors.

The data in the tables below showcases how the combination of Zantrene with three chemotherapy drugs increases their effectiveness in killing breast cancer cells. When used alone, the chemotherapy drugs reduce cell viability to varying degrees as their concentrations increase. However, when Zantrene is added, even in small amounts, it significantly enhances the cancer-killing effect, resulting in a greater decrease in the percentage of surviving cancer cells. The deeper shades of red in the table highlight this increased cell death, indicating a successful synergy between Zantrene and the chemotherapy drugs in targeting breast cancer cells.

2. Zantrene Protects Mouse Hearts from Chemotherapy Damage (30 June 2022)

In a landmark study with mice, Zantrene was found to significantly protect the heart from damage typically caused by the chemotherapy drug doxorubicin. Mice treated with doxorubicin showed reduced heart function, while those treated with Zantrene, either alone or in combination with doxorubicin, had much less damage to heart muscle. The protective effect of Zantrene was evident in both 1:1 and 1:2 molar ratio combinations with doxorubicin, indicating flexibility in dosing for achieving heart protection without compromising the anti-cancer effectiveness of the treatment.

Zantrene also enables the use of higher doses of chemotherapy without increasing overall toxicity or myelosuppression, which is the suppression of bone marrow activity leading to fewer blood cells. In mice, a mix of Zantrene and doxorubicin at 1:1 and 1:2 molar ratios resulted in 18% and 36% higher cytotoxic doses, respectively, without significant weight loss or changes in blood cell counts. This suggests that Zantrene can enhance the cancer-killing efficacy of doxorubicin while protecting against its toxic effects on the body and bone marrow.

Zantrene's preclinical efficacy marks a substantial advancement in oncology, offering dual benefits as a cardioprotective agent and a synergistic partner to conventional chemotherapy drugs. The concentration of Zantrene required to achieve a clinically relevant outcome for cardioprotection is well below the historical use of the drug. It has demonstrated potential in reducing the cardiotoxicity of agents like doxorubicin and carfilzomib, while simultaneously boosting their cancer-cell-killing effects, including in drug-resistant forms of breast cancer. Furthermore, Zantrene may allow for higher chemotherapy doses with minimal added toxicity, suggesting a new therapeutic strategy that could enhance patient survival and quality of life by enabling more aggressive treatment protocols without the usual increase in adverse side effects.

Historical Clinical Data

Personally, I find this to be the most valuable data that we have to date. The Triangle Insight Group did not reference this data throughout their report, which I believe to be the major flaw in their analysis - particularly when evaluating risk. Bisantrene has been used in over 40 clinical trials, with significantly less numbers of cardiac events. I will focus on some of the most interesting elements from certain clinical trials to discuss in this section.

1. Treatment of relapsed or refractory acute leukemia in childhood with bisantrene combined with high dose aracytine (1994)

This study aimed to evaluate the effectiveness and safety of bisantrene combined with aracytine in treating children with refractory and relapsed acute leukemia. Of the 26 children, the treatment showed a 46% overall response rate, with specific remission rates observed across acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), and undifferentiated leukemia (AUL). Despite the high level of prior treatment and poor prognosis in most patients, the combination therapy achieved complete remission in several cases. To truly allow the reader to understand the health of these children, I’ll quote this directly from the paper:

“Most patients had been highly pretreated. All patients had previously received one (17 pts) to two (6 pts), or three (3 pts) different anthracyclines. Fourteen patients had received daunorubicin with a mean cumulative dose of 245 mg/m² (160 to 400), 12 pts had received zorubicine, 860 mg/m² (380 to 1300), 8 had received mitoxantrone, 58 mg/m² (30 to 70), and 1 (pt 17) had received doxorubicin, 120 mg/m². Four patients (pts 1, 11, 15, 22) had been treated with amsacrine, 450 mg/m² (300 to 450). Twenty-three had received aracytine with a mean cumulative dose of 9860 mg/m². Aracytine had been used in various schedules: standard dose (100 mg/m²/d in continuous infusion in 16 pts), low dose (25 to 30 mg/m² twice a day subcutaneously) in 13 pts, and HD Ara-C (1 to 2 mg/m² twice a day) in two pts.”

Clearly, these are very sick kids who have had an extremely high cumulative dose of cardiotoxic agents, primarily with anthracyclines.

The main adverse effect was infection, with serious episodes in 42% of the patients, while primary and secondary cardiac toxicity was notably absent, and liver and kidney toxicities were temporary. These findings highlight the functional capacity of bisantrene to synergise with aracytine as well as provide cardioprotection in heavily pretreated AML and ALL patients.

2. Randomized Trial of Doxorubicin, Bisantrene, and Mitoxantrone in Advanced Breast Cancer: A Southwest Oncology Group Study

In a study comparing the efficacy and toxicity of three chemotherapy agents in 411 women with metastatic breast cancer, doxorubicin showed a higher response rate and longer median time to treatment failure compared to bisantrene and mitoxantrone, but it also led to more severe side effects, including leukopenia, nausea, vomiting, mucositis, alopecia, and notably higher cardiotoxicity. As I have discussed, the FTO-inhibitory properties of Zantrene require a very specific population group to provide the drug for a true evaluation of its efficacy, though we can take a look at the cardiotoxicity properties of this trial.

The table below is a summary of congestive heart failure events for Bisantrene, doxorubicin, and mitoxantrone. Overall, Bisantrene had 0 cardiac toxic effects, while doxorubicin had 9 (7%) and mitoxantrone had 2 (2%) during the study. Bisantrene did not record CHF events at 1-7 or >7 courses. Remember, the clinically effective dose of Zantrene for cardioprotection was shown to be 1.06 mg/m2 (5000 nM) - 7 courses of Zantrene in this study is approximately 2,240 mg/m2.

Another interesting table worth consideration is evaluating cardiotoxicity by left ventricular ejection fraction (LVEF) grade found below. As recently stated by our new member to the Scientific Advisory Board, Erin Howden, LVEF is an insensitive prognostic marker for detecting and evaluating cardiotoxicity and long-term heart failure risk. With this in mind, the following is discussed speculatively. The table shows that moderate to severe LVEF grades increase as the dose of Zantrene increases, with 0 cases in courses 1-3, 3 in courses 4-7, and 13 in >7 courses. While understanding the limitations of LVEF, I speculate that this could this be an early indication of the low dose requirement of Zantrene to provide a cardioprotective benefit.

In conclusion, the clinical data underlines bisantrene's potential as a cardioprotective chemotherapy agent. Furthermore, in comparative studies with adult metastatic breast cancer patients, bisantrene demonstrated lower cardiac events and cardiotoxicity than doxorubicin and mitoxantrone, reinforcing its suitability for patients with a high risk of heart damage. These findings along with the plethora of similar clinical data suggest bisantrene's efficacy in treating cancer while offering a safety profile that may reduce the risk of long-term cardiac complications.

3. Two French women treated with Bisantrene

A long-term survival case report highlighted the journey of two French women who achieved complete remissions following a dosing protocol with Bisantrene who were alive at the time of the study at the age of 47. I’ve included the treatment timeline for both women below. Both women were exposed to anthracyclines among other chemotherapeutic agents and while they each achieved a complete remission, they both relapsed. The highlight for me here is that the use of Zantrene either alone or in combination with other drugs was able to treat relapsed cancer patients, which enabled them to live long into their years without any reported cases of cardiac events.

Summary

The preclinical and clinical profiles of Zantrene establish its dual function as an effective chemotherapy and cardioprotective agent. The published clinical data for Zantrene including particularly that which has been discussed here allows investors to appreciate the risk profile as specific clinical validation of the drug is set to begin. It is my contention that this body of evidence presents a compelling case for the integration of bisantrene into broader oncological use, with a heightened emphasis on preserving cardiac health alongside effective cancer treatment.

Note: I want more data