Bisantrene is a small molecule anthracene-based chemotherapeutic that was originally developed by American Cyanamid (Lederle Laboratories) in the 1970s & 1980s with the goal of creating a less cardiotoxic/toxic anthracycline-like chemotherapeutic.
The drug was approved in France for relapsed or refractory (R/R) acute myeloid leukemia (AML) in 1990, however it was not commercialised and was lost to the clinical community for over 30 years due to various merger and acquisition transactions.
Bisantrene & cardio-protection
Bisantrene has been evaluated in over 46 clinical trials and 70 peer reviewed publications, with around 1.8k patients treated, demonstrating efficacy and a well characterised safety profile.
Anthracyclines have been the most administered category of chemotherapy agents for decades, however they can cause significant toxicity in the body. Lifetime limits of anthracyclines are enforced due to the risk of potentially fatal, congestive heart failure.
Studies have shown bisantrene reduces risk of cardiotoxicity and has higher tolerability than anthracyclines, while also demonstrating cardio-protection when used in conjunction with anthracyclines.
Race’s clinical program for bisantrene has been designed to build on the strong foundation of existing clinical data in AML, while also focusing on the drug’s anti-cancer and cardio-protective potential in the high unmet need area of breast cancer.
Bisantrene & FTO
Important scientific discoveries made over the last decade have identified dysregulation (loss of control) of RNA epigenetics (methylation) as a key driver in cancer development. One of the major players in this dynamic regulatory system is the Fatso or FaT and Obesity associated protein (FTO).
In 2011, FTO was identified as an m6A RNA demethylase and subsequent research has identified FTO to be a major global regulator of the m6A RNA epigenetic status in cells.
Other investigators have shown that changes in the expression of the FTO protein have a profound impact on both cancer development and metastasis.
Inhibiting FTO activity in cells has been found to kill or slow the growth of a wide range of cancers including leukaemia, breast, lung, ovarian, gastric, brain, melanoma, pancreatic, kidney and many more. Unsurprisingly, RNA epigenetic dysregulation has become one of the hottest areas of cancer research.
Recent studies by the City of Hope, identified bisantrene as the most potent enzymatic inhibitor of FTO (IC50 142nM) from a screen of more than 260,000 chemical compounds contained in the US National Institute of Health’s (NIH) National Cancer Institute’s (NCI) chemical library. The research also demonstrated in both cell and animal models, that bisantrene specifically killed FTO overexpressing cancers when used at concentrations far below that known to be toxic in humans.
Race has a worldwide license agreement with City of Hope that exclusively secures the rights to a City of Hope patent application and associated know-how to collaborate to elucidate the mechanism of action of bisantrene, and the role of FTO to develop a targeted approach with subsequent biomarker development.
Bisantrene’s historical pathway
Bisantrene was originally developed by Lederle Laboratories in the 1970s as a lower cardiotoxic alternative to the commonly used anthracycline chemotherapeutics. Lederle trialled bisantrene on a wide range of cancers in the 1980s (more than 50 clinical trials) and it showed particular promise in leukemias, breast cancer and ovarian cancer.
Bisantrene was studied in a large Phase 3 breast cancer trial in the late 1980s, where it showed anti-cancer activity though a response rate of 13% vs 28% for doxorubicin (p=0.004), with similar rates of overall survival at 2 years, without any congestive heart failure (0% bisantrene, 7% doxorubicin”). Unfortunately, due to the design of the clinical trial it was not possible to show drug equivalence and furthermore the bisantrene dose used was changed in the middle of the trial (from 260 mg/m2 to 320 mg/m2).
Further adding to these problems, Lederle’s parent company, American Cyanamid, suffered serious financial difficulties in the early 1990s economic recession, resulting in many non-core programs being dropped, sold or deprioritised. Given the original patent expired in 1998, interest in bisantrene appears to have been lost around this time and no further development of bisantrene was pursued by either Lederle or American Cyanamid. Employees of Lederle at the time bisantrene’s clinical development ended have told Race that Lederle’s management chose to prioritise the development of another Lederle chemotherapeutic mitoxantrone, instead.
In 1994 the financially distressed American Cyanamid was acquired by Wyeth.
Bisantrene was registered in France in 1990 for the treatment of Acute Myeloid Leukaemia (AML), however, this registration was later withdrawn voluntarily by the subsequent owners of bisantrene (Wyeth). At the time the economics of treatments for rare cancers was not as it is today and the value of keeping bisantrene registered in France for AML alone was minimal.
What happened to bisantrene is not uncommon in the pharmaceutical industry. Around 25% of all drugs that demonstrate good Phase 3 results end up not being approved for a range of non-clinical reasons. It is a rare drug that does not suffer many near death experience during its development – the most famous example of this is Pembrolizumab (Keytruda®) (a >US$25 billion a year sales blockbuster today).
The drugs we have today are the lucky survivors of a brutal battle that few candidates survive. Many good drugs were lost along the way and are candidates for rediscovery.
Clinical pipeline
Race is progressing a robust pipeline of clinical activities for bisantrene to maximise commercialisation and partnership opportunities to benefit cancer patients worldwide.
