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 an highly potent FTO inhibitor has driven intense scientific and clinical interest in Zantrene as a rapidly translatable pharmaceutical agent able to target the exciting m6A RNA methylation pathway.
History of Zantrene
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 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). The 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. 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registered in France in 1990 for the treatment of Acute Myeloid Leukaemia (AML), however, this registration was later withdrawn voluntarily by the subsequent owners of Zantrene (Wyeth).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, where up to 25% of all drugs that show good Phase III 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 Keytruda® (a >US$20 billion/year blockbuster today), which was considered such a low priority by Merck at one point that its development was shut down and it was placed on its out-license 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 from 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 and many good drugs are lost along the way.
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 associatedprotein (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.
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 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 Heart-protective Chemotherapeutic
At high doses Zantrene® behaves as an anthracycline-like chemotherapeutic, however, unlike the other anthracyclines, Zantrene has been found to cause less cardiotoxicity (heart damage) in cancer patients.
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 recently 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 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.
History of Zantrene®
Zantrene found in preclinical studies to protect the heart muscle from anthracycline-induced damage while synergising with these widely used chemotherapeutics to better kill cancer cells. Updated ‘Three Pillar’ clinical strategy revealed focusing on the FTO and cardioprotection opportunities.
Phase II Zantrene AML trial results released showing a 40% clinical response rate in a very hard to treat, late stage, patient population. Zantrene identified as a potent inhibitor of FTO, a key marker in cancer development and growth. New ‘Three Pillar’ strategy announced building on the FTO discovery with preclinical and clinical programs focused on breast, melanoma, kidney cancer and AML.
Race Oncology announces an updated ‘5-path’ commercialisation strategy treating AML, breast and ovarian cancers.
Race Oncology acquires Update Pharma’s IP and lists on the ASX with the mission to rescue Zantrene and return it to the clinic.
Zantrene rediscovered by Update Pharma, new patents and trademarks filed and orphan drug designation obtained.
Zantrene was approved for marketing in France for the treatment of AML. Zantrene abandoned due to trial design issues with the Phase 3 Breast Cancer Trial.
Tested in more than 50 Phase II clinical trials to assess its efficacy and safety in a wide range of cancers. The studies covered more than 1500 patients and revealed Zantrene to possess low cardiotoxicity and useful chemotherapeutic efficacy in several cancers, notably AML, breast and ovarian.
Zantrene discovered in by Lederle Laboratories, a division of American Cyanamid after a extensive search to find an anthracycline chemotherapeutic without cardiotoxicity.
Targeting Zantrene® towards better cancer outcomes