I'm unsure what your motivators are for researching this company or its science, but I am constantly searching for information to better understand what this drug might do in the clinic. We have been blessed with some excellent clinical opportunities for Bisantrene, and I for one am extremely excited for the upcoming CPACS trial. I think this plays out as the ultimate differentiator for FTO inhibitors.
It's impossible to know whether Bisantrene is going to provide
cardioprotection while also
synergising with doxorubicin to more effectively treat cancer, but there are some things that I have found that highlight just how plausible a significant outcome can be.
Comparable Cardioprotection of Bisantrene to FDA Approved DexrazoxaneDexrazoxane is the only FDA approved drug for cardioprotection against doxorubicin-induced cardiotoxicity. It has shown excellent efficacy for cardioprotection in multiple phase III clinical trials, however the FDA state that Dexrazoxane impairs the efficacy of Doxorubicin to treat cancer.
- In Vitro ComparisonIt is impossible to truly compare the cardioprotection of Bisantrene to Dexrazoxane without a direct head-to-head comparison in preclinical and clinical models. However, I have done my best to find all of the available preclinical data for Dexrazoxane to inform my comparison. Dexrazoxane has consistently improved heart cardiomyocyte viability in the presence of doxorubicin, though the following paper provided the optimum comparison to the cardioprotective effects of Bisantrene.
Table 1 below contains a comparison of the in vitro dox-treated HCM viability when Bisantrene or Dexrazoxane is used at various concentrations. Importantly, there are some differences between the methodologies used that cast doubt on a direct comparison, such as different HCM, growth media, culture conditions, and methods for assessing cell viability. The researchers treated HCM with 0.5 µM of doxorubicin with increasing concentrations of Dexrazoxane (5 - 100 µM) to assess cell viability. A 100 µM dose of Dexrazoxane improved HCM viability from 17% to 53%. Increasing doses of Bisantrene improved HCM viability from 20% to 60% at 5 µM concentration.
Table 1: In vitro comparison of Bisantrene to Dexrazoxane. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947016/pdf/41598_2023_Article_29964.pdfFTO inhibition/knockdown has been shown to synergize with doxorubicin and other cardiotoxic drugs to more effectively kill HCMs (Figure 1). So, while the Bis-Dox model used double the dose of doxorubicin, there is also a high likelihood of FTO-inhibition-associated cardiotoxicity synergy, indicating that Bisantrene overcame greater (possibly significantly so) cardiotoxicity than Dexrazoxane. Thus, the key takeaway is that Bisantrene demonstrates comparable cardioprotection to Dexrazoxane in vitro.
Figure 1: HCM viability in DOX and DOX-drug combinations
Other in vitro cardiotoxicity studies that I found interesting involved the generation of reactive oxygen species (ROS). Dexrazoxane was shown to decrease doxorubicin-induced increases in ROS production, while Bisantrene decreased ROS production in heart submitochondria and sarcoplasmic reticulum. Bisantrene is clearly behaving differently than its anthracycline peers, but there is no direct comparison to make here as Bisantrene was not tested with doxorubicin.
- In Vivo ComparisonThere are many in vivo studies investigating the cardioprotection of Bisantrene and Dexrazoxane, but there are few comparable models. Much of what RAC has conducted is yet to be announced, and I assume this will be revealed when the high-impact cardioprotection publication is released. The comparable models I found included left ventricle fractional shortening and body weight. Fractional shortening measures the percentage change in the diameter of the left ventricle between the contracted (systole) and relaxed (diastole) states. It is an indicator of the contractile function of the heart. Like Dexrazoxane, Bisantrene improves LVFS in dox-treated mice (Figure 2). The addition of Bisantrene to doxorubicin treatment did not significantly alter body weight (Figure 3). There really isn't much to say here other than Bisantrene appears completely comparable to Dexrazoxane in these models of cardioprotection and toxicity.
Figure 2: Left Ventricle Fractional Shortening in Mice
Figure 3: Body weight of Mice
Preclinical Evidence Supporting the Clinical Synergy of Bisantrene with DoxorubicinThe anthracycline-focused CPACS revenue data is enough to make anyone excited, where 1% of the TAM equals billions of dollars a year in revenue. The simplicity of that model opens the door to criticism, but instead of attacking the model, I have decided to try and arm myself with information that will help me understand the likelihood of success in the upcoming combination trial.
Firstly, Table 2 highlights the sensitivity and resistance of patient tumor samples to Bisantrene, Adriamycin (doxorubicin), and Mitoxantrone, where Bisantrene (28% and 23.2%) is found to be significantly more sensitive than both doxorubicin (2.4%) and Mitoxantrone (4.8%) at clinically relevant doses. The preclinical study was completed in 1983, and while discussing the results, the author states: "Even more intriguing was the finding that in vitro a tumor may be resistant to one of these agents and sensitive to another" and "The possibility that mitoxantrone and bisantrene are at least as active as adriamycin and that there is lack of co-resistance between these agents for the individual tumor suggests some very interesting clinical studies in tumor types such as breast, ovarian and small cell of the lung." If the researchers of that era knew what we know now, the sensitivity of Bisantrene to tumor samples resistant to Dox and Mitox would be easily understood and clinical investigations with dosing regimens appropriate to its primary mechanism of action.
The important consideration investors need to make is that 76% of the patient tumor samples had been previously treated with either cytotoxic chemotherapy (66%) or doxorubicin (10%). Common chemotherapeutics of that era are antimetabolites and alkylating agents, where FTO has repeatedly been shown to drive chemoresistance, which also extends to doxorubicin-treated resistant breast cancer cells. Since FTO inhibition/knockdown has been shown to overcome therapy-acquired resistance, it is highly likely that the patients included in this study would have benefited from the combination of Bisantrene and doxorubicin or Mitoxantrone. Moreover, since all studies are single-agent, the Bis-Anthracycline combination efficacy is unknown. This highlights the unique patient population Bisantrene is targeting for resistant solid tumor types and that Bisantrene in combination with doxorubicin should have a broad therapeutic target population relative to doxorubicin on its own.
Table 2: Sensitivity and Resistance of Bisantrene in comparison with Doxorubicin and Mitoxantrone in patient tumor samples
Historic patient-derived in vitro data on Bisantrene is very encouraging, highlighting its unique properties compared to its peers 40 years ago. Recent preclinical advances further demonstrate Bisantrene's significant synergy with doxorubicin in 86% of 143 cancer cell lines. While preclinical evidence often fails to translate into clinical efficacy, the quality of the methodology used can mitigate this issue. High-quality preclinical methods are generally more predictive of clinical outcomes. To assess the quality of the Oncolines cancer cell study, I reviewed peer-reviewed publications utilizing their cell models. One notable study investigated various approved kinase inhibitors across 134 different Oncolines cancer cell lines. This study's key finding was that the Oncolines cell lines accurately identified patient stratification markers as described in FDA labels, confirming the specific cancer types each kinase inhibitor was approved for. This high degree of confirmation underscores the reliability of the Oncolines cell models, particularly when evaluating the synergism seen in the Bis+Dox combination. It is up to each investor to establish their own risk model, but if the likelihood of improved efficacy from the combination is 86%, then that is very attractive indeed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516332/Summary and ValueWhile this information does not represent my full CPACS clinical risk analysis for Bisantrene with doxorubicin, it provides substantial support for the combination in solid tumor patients. Bisantrene is a very unusual molecule with many secrets that are (hopefully) soon to be known. At this stage, Bisantrene has comparable cardioprotection to the FDA-approved agent, Dexrazoxane, and preclinical models highlight that Bisantrene synergizes with doxorubicin to more effectively kill a broad range of cancer types. Moreover, the cancer cell models used are highly predictive of in-human responses, indicating the combination of Bisantrene and Doxorubicin may indeed prove CPACS.
The following valuation highlights just how enormous this opportunity is. At an 86% improved cell-killing rate, the combination of Bisantrene with doxorubicin should improve stated average response rates from 34% to 52%. Assuming Bisantrene captures 5 geographical markets including the US, EU, AUS, and 10% of China & Japan (10% assumed to be the wealthier majority), this indicates that Bisantrene could generate almost $50 billion per year in sales. Because there are no clinical competitors and the likelihood of a commercial competitor reaching approval within two years is low, Bisantrene will be able to capture the absolute maximum of this addressable market. Obviously, this analysis is not entirely accurate as doxorubicin does not represent the entire anthracycline market, but if Bisantrene is approved for use in combination with doxorubicin, it is not far off from being used in combination with other anthracyclines. It is up to each investor to do their own calculations, but we all need to remember that this is only 1 of 16 approved drug classes where FTO is shown to drive chemoresistance.
Ultimately, the puzzle pieces are coming together nicely for Bisantrene. A molecule that was lost and rediscovered, even now assumed to be valueless, might very well play one of the biggest hands ever in biotech history.
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