Science

History and Science of Bisantrene

Bisantrene is a small molecule anti-cancer drug which has potential as both a low dose, highly targeted precision oncology agent and a high dose, less cardiotoxic chemotherapeutic.

History of Bisantrene

Bisantrene was originally developed by Lederle Pharmaceutical  in the 1970s as a lower cardiotoxic alternative to the anthracyclines. Lederle trialled Bisantrene on a wide range of cancers in the 1980s (more than 40 clinical trials) and it showed particular promise in leukemias, breast cancer and ovarian cancer. Bisantrene was studied in a large Phase III breast cancer trial in the late 1980s, where it performed as well as doxorubicin (the standard of care chemotherapeutic) but with significantly lower rates of damage to the heart (4% Bisantrene, 23% doxorubicin). Unfortunately, Lederle did not design the clinical trial to show drug equivalence and consequently Bisantrene was not able to be approved by the FDA.

Lederle’s parent company, American Cyanamid, suffered serious financial difficulties in the early 1990s, resulting in many non-core programs being dropped and deprioritised. Interest in bisantrene was lost at this time and no further development of Bisantrene was pursued by either Lederle and or American Cynamid. In 1994 the financially distressed American Cyanamid was acquired by Wyeth and Bisantrene was abandoned.

Bisantrene was registered in France  in 1998 for the treatment of Acute Myeloid Leukaemia (AML), however, this registration was later withdrawn voluntarily by the subsequent owners of Bisantrene (Wyeth).

It should be noted that what happened to Bisantrene is not uncommon in the pharmaceutical industry, where up to 25% of all drugs that show promising Phase III results end up not being approved due to non-clinical reasons. It is a rare drug that does not suffer many near death experience during its development – the most famous is Keytruda (>US$20 billion/year blockbuster), which was considered such a low priority by Merck that its development was shut down and it was placed on the out-license list. A term sheet (valuing the drug at next to nothing) was reportedly in place, but the disposal was pulled at the last minute when promising results from Bristol-Myers Squibb (BMS) motivated a reconsideration. This Forbes article describes the long and winding history of KeyTruda. The drugs we have today are the lucky survivors of a brutal battle that few candidates survive.

Precision Oncology

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 FaT and Obesity associated protein (FTO).

FTO was originally identified in the early 2000s from genome-wide genetic association studies as linked to weight gain. In 2011, FTO was identified as an m6A RNA demethylase and subsequent research has identified FTO to be a 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 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. It is difficult to find a cancer type where RNA epigenetic changes in general, and FTO specifically, are not playing an important role in the growth of the cancer. It is not surprising that 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 NIH National Cancer Institute’s 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.

The solid tumours, melanoma and clear cell Renal Cell Carcinoma (ccRCC) both overexpress FTO at high frequency. Race is currently pursuing pre-clinical studies in both cancers types to demonstrate if Bisantrene has utility before moving into proof-of concept Phase I/II clinical trials in one or both cancers. To read more about our FTO precision oncology strategy, please view our Three Pillars strategic update.

A Better Chemotherapeutic

At high doses Bisantrene behaves as an anthracycline-like chemotherapeutic, however, unlike the other anthracyclines, Bisantrene has a greatly reduced rates of cardiotoxicity (heart damage) in patients.

This unique property of Bisantrene may allow it to be used in patients who have reached their lifetime cardiotoxic limit of anthracyclines, or who cannot tolerate anthracyclines due to pre-existing heart conditions, age or other factors.

Under Pillars 2 and 3 of our Three Pillar strategy, we are investigating Bisantrene’s potential as a safer chemotherapeutic alternative in breast cancer and AML.

A comprehensive review of the science around Bisantrene was published in the International Journal of Cancer Research & Therapy.

The rediscovery of Bisantrene – a review of the literature

“Bisantrene has been shown to have greatly reduced cardiotoxicity compared to anthracyclines. This makes Bisantrene potentially well-suited for patients who have reached their cardiotoxic limit of anthracyclines or who have other health conditions that put them at extra risk.”

– Race Oncology CSO Dr Daniel Tillett

Intellectual Property

Race Oncology has a robust IP position on the use of Bisantrene as a cancer therapeutic. Race owns four granted patents on Bisantrene and has secured Orphan Drug designation which provided 7 years of post market approval exclusivity and Rare Paediatric Disease designation.

13 patents have recently been filed on the use of Bisantrene as a targeted agent of FTO.

Commercial Goals

The company is pursuing a Three Pillar Strategy that is aimed at creating valuable intellectual property to enhance partnering, licensing, or sale opportunities to a scaled pharmaceutical company.

Race Oncology has near term opportunities in seeking FDA approval for Bisantrene via the 505(b)(2) approval pathway in a number of AML indications. Additionally, the company has been designated as eligible for a Paediatric Priority Review Voucher (PRV) in paediatric AML as well as Orphan Drug Designation (ODD) for AML.

Timeline of Bisantrene

2020

Phase II Bisantrene AML trial results released showing a 40% clinical response rate in a very hard to treat, late stage, patient population. Bisantrene identified as a potent inhibitor of FTO, a key marker in cancer development and growth.

2019

Race Oncology announces updated commercialisation strategy (“5-Paths”) around treating AML, breast and ovarian cancers.

2016

Race Oncology lists on the ASX (RAC) with the mission to rescue Bisantrene and return it to the clinic via the Named Patient Program in Europe.

2011-2015

Bisantrene rediscovered, new patents filed and orphan drug designation obtained by Update Pharmaceuticals.

1990s

Bisantrene was approved for marketing in France for the treatment of AML. French registration withdrawn after American Cyanamid was acquired by American Home Products.

1980s

Tested in more than 40 Phase II clinical trials to assess its efficacy and safety in a wide range of cancers. The studies covered nearly 2,000 patients and revealed Bisantrene to possess low cardiotoxicity and useful therapeutic efficacy in several cancers, notably AML, breast and ovarian.

1970s

Bisantrene discovered in the United States by US Pharmaceutical company Lederle (a division of American Cyanamid).