History and Science of Zantrene
Zantrene® (bisantrene dihydrochloride) is a small molecule anti-cancer drug which has clinical and preclinical efficacy as both a low dose, highly targeted precision oncology agent and cardio-protective chemotherapeutic. The recent identification that Zantrane is a highly potent FTO inhibitor has driven intense scientific and clinical interest in Zantrene as a rapidly translatable pharmaceutical able to target the exciting m6A RNA methylation pathway.
Zantrene® was originally developed by Lederle Laboratories in the 1970s as a lower cardiotoxic alternative to the commonly used anthracycline chemotherapeutics. Lederle trialled Zantrene 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.
Zantrene was studied in a large Phase 3 breast cancer trial in the late 1980s, where it performed as well as doxorubicin (a standard of care chemotherapeutic), but with significantly lower rates of serious damage to the heart (4% Zantrene, 23% doxorubicin). Unfortunately, due to the design of the clinical trial it was not possible to show drug equivalence and furthermore the Zantrene dose used was changed in the middle of the trial (from 260 mg/m2 to 320 mg/m2). These trial design failures made Zantrene unapprovable by the FDA without a new Phase 3 trial being run.
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 Zantrene appears to have been lost around this time and no further development of Zantrene was pursued by either Lederle or American Cyanamid. Employees of Lederle at the time Zantrene’s clinical development ended have told Race that Lederle’s management choose to prioritise the development of another Lederle chemotherapeutic mitoxantrone, instead.
In 1994 the financially distressed American Cyanamid was acquired by Wyeth.
Zantrene 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registered in France in 1990 for the treatment of Acute Myeloid Leukaemia (AML), however, this registration was later withdrawn voluntarily by the subsequent owners of Zantrene (Wyeth). At the time the economics of treatments for rare cancers was not as it is today and the value of keeping Zantrene registered in France for AML alone was minimal.
It should be noted that what happened to Zantrene 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). Keytruda was considered such a low priority by Merck that at one point its clinical development was shutdown and it was placed on its out-license drug list. A term sheet for the disposal of Keytruda (valuing the drug at next to nothing) was reportedly in place, but the disposal was pulled at the last minute when promising results released by Bristol-Myers Squibb (BMS) for their PD-1 inhibitor motivated a reconsideration. This Forbes article describes the long and torturous history of KeyTruda.
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.
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).
FTO was originally identified in the the 1990s in an natural mutant mouse and was found to cause a fused toe phenotype. The region lost in the mouse contained 5 gene, and the largest gene was given the name FTO (Fused Toe O). In the early 2000s, the FTO gene was identified from human genome-wide genetic association studies as being strongly linked to weight gain. 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 has 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. So widespread is FTO in cancer that 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. 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 NIH National Cancer Institute’s chemical library. The research also demonstrated in both cell and animal models, that Zantrene specifically killed FTO overexpressing cancers when used at concentrations far below that known to be toxic in humans. This work was confirmed by a separate lab at the University of Chicago in 2021.
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 Zantrene has utility before moving into proof-of concept Phase 1/2 clinical trials in one or both cancers. To read more about our FTO precision oncology strategy, please view our Three Pillars strategic update.
Race Oncology has announced a world-first cancer trial that is treating people with a rare subtype of the highly aggressive blood cancer Acute Myeloid Leukaemia (AML), known as extramedullary AML (EMD AML).
EMD AML is one of the most difficult cancers to treat with rapid progression. Race is running this clinical trial at The Calvary Mater Hospital in the hope of being able to offer patients a better and more effective treatment option with Zantrene.
At high doses Zantrene® behaves similar to chemotherapeutic, however, Zantrene has been found to cause less cardiotoxicity (heart damage) in cancer patients.
Recent discoveries by Race’s collaborators at the University of Newcastle has found that Zantrene is able to protect the heart muscle cells from anthracycline-induced damage while synergising with the anthracycline drugs to better kill the cancer. This cardio-protection effect was expanded to the other classes of chemotherapy when it was found that Zantrene was able to protect heart muscle cells from cell death caused by the proteasome inhibitor, carfilzomib while also synergising to better kill breast cancer cells.
Additional work in June 2022 has demonstrated that Zantrene is able to protect the hearts of mice from anthracycline damage without additional chemotoxicity and myelosuppression.
A comprehensive review of the clinical history of Zantrene® was published in the International Journal of Cancer Research & Therapy.
Race Oncology has a robust IP position on the use of Zantrene as a cancer therapeutic. Race owns six granted US patents on Zantrene, has secured FDA Orphan Drug designation which provided 7 years of post market approval exclusivity, as well as Rare Paediatric Disease designation.
13 patents have been filed by Race Oncology on the use of Zantrene as a targeted agent of FTO.
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 Zantrene via the FDA 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.