The next generation of cancer therapy: how Deflexifol could replace a generations-old cancer drug to offer fresh hope to cancer patients
Australian biotech company FivepHusion has developed a breakthrough drug that brings two cancer-killing drugs together for improved tolerability, higher dosing potential and enhanced anti-cancer activity. With AusHealth’s support, a phase II trial could make Deflexifol the first drug therapy for paediatric ependymoma and redefine standard care for millions of other cancer patients. More amazing, it could be approved within just four years…
For more than 60 years, one of the most widely used cancer drugs in the world has remained fundamentally unchanged.
5-fluorouracil – known simply as 5-FU – was first launched in 1962, well before colour TV came to Australia. Today, it is still the standard treatment for a wide range of solid tumours, including colorectal, gastric, pancreatic, head and neck and some breast cancers.
In the 1990s, a second drug, leucovorin (LV), was added to clinical practice after oncologists discovered it dramatically boosted 5-FU’s cancer-killing power. Together, the drugs were synergistic and the science was clear: in the fight against cancer, one plus one could equal three.
There was a problem, however. When administered at the same time, 5-FU and leucovorin formed crystals that blocked the central venous catheters used to deliver chemotherapy. These catheters are surgically implanted and essential for patients receiving frequent treatment.
To this day, to overcome the risk of blockage of a patient’s catheter, oncologists are forced to give the drugs sequentially. This however is a poor compromise: when the drugs are no longer optimally co-exposed in the body, the synergy is largely lost.
“Instead of ‘one plus one equals three’, treatment has become closer to ‘one plus one equals only one’, with little benefit provided by the leucovorin,” says Dr Christian Toouli.
Dr Toouli is the CEO and Managing Director of FivepHusion, which was founded by oncologists to solve this decades-old conundrum in the treatment of cancer.
Working with researchers at the University of Wollongong, the team discovered a way these two drugs could finally be delivered together, safely, the way they were always intended to be.
The breakthrough came through co-formulation rather than reinvention. Researchers tailored a sugar-based cyclodextrin excipient molecule already used in many medicines to stabilise 5-FU and leucovorin in the same solution.
The result is Deflexifol, a single, co-formulation of the two drugs that can be administered safely without precipitation or catheter blockages.
“In many ways it’s a very elegant solution,” says Dr Toouli. “But what’s particularly exciting is that we significantly decrease the risk in development because we’re optimising drugs that are proven and already given to millions of patients around the world.”
FivepHusion has now completed three clinical trials – two in adults and one in children – investigating Deflexifol’s safety, tolerability, and activity.
The results have been impressive.
In adult patients with advanced solid tumours – many of whom had already failed multiple lines of chemotherapy, including 5-FU and leucovorin given sequentially – Deflexifol demonstrated:
- Improved tolerability, with fewer and less severe side effects
- Higher maximum tolerated doses, up to 40% higher than standard therapy
- Evidence of renewed anti-cancer activity, even in tumours previously considered resistant.
“Excitingly, we observed in our clinical trials that patients gained benefits from being given Deflexifol. Tumours stopped growing and, in some cases, shrunk in size. It’s very unusual that a cancer that has become resistant to a particular drug will then respond to it again.”
In one trial involving end-stage cancer patients, up to 69% experienced disease control – meaning tumour growth slowed or stopped – and in some cases tumours shrank. It was especially notable in patients who typically had only months to live.
What’s happening biologically is elegant and compelling.
5-FU works by blocking an enzyme called thymidylate synthase (TS), which cancer cells need to replicate DNA and divide. On its own, 5-FU binds weakly and intermittently to TS. Leucovorin reshapes the enzyme so that when 5-FU binds, it sticks, leading to far superior TS inhibition.
But this only works if both drugs are present at the same time over a sustained period of time. With standard treatment, that overlap is estimated to be as little as seven percent of the dosing window. With Deflexifol, co-exposure can be sustained for up to two days (100 percent of a typical treatment) – restoring the synergy oncologists discovered in the 1990s but were never able to capitalise on.
A new option for children with no approved treatments
One of the most exciting potential applications of Deflexifol is in paediatric ependymoma, the third most common brain cancer in children.
Ependymoma is typically diagnosed in very young children – under four years of age – and currently has no approved drug therapies anywhere in the world. Surgery and radiotherapy are the mainstays of care, but both carry significant risks, especially in the treatment of developing brains.
Independent research in the United States had already shown that 5-FU alone could benefit some children with recurrent ependymoma.
“This is really exciting, because of course Deflexifol takes the 5-FU and optimises it with leucovorin, making it a better cancer-killing combination that is also safer and more tolerable. But we needed to prove that in kids,” Dr Toouli explains.
In collaboration with the Australian & New Zealand Children’s Haematology/Oncology Group (ANZCHOG), the team completed a national Phase I trial in children with brain cancer last year, demonstrating that Deflexifol is both safe and tolerable.
Thanks to a commitment of $1.2 million of funding from children’s charities Kids with Cancer Foundation (NSW) and the Robert Connor Dawes Foundation (VIC,) a phase II trial is now set to begin.
Dr Toouli is excited at the prospects. “What we’re hoping and expecting to see based on the US data is that Deflexifol should provide benefits to these patients. We then have a route for taking that data and moving toward getting the drug approved.
“If successful, Deflexifol could become the first approved drug treatment for paediatric ependymoma worldwide.”
From a drug-development perspective, Deflexifol is unusually ‘de-risked’.
Both active drugs used in the co-formulation are already approved, widely used and well understood. This has allowed regulators, including the US FDA, to agree that Deflexifol can be developed through an accelerated pathway, potentially requiring only one Phase III trial for use in metastatic colorectal cancer, FivepHusion’s drug development focus for adults.
FivepHusion is also pursuing sovereign manufacturing in Australia, partnering with Pfizer’s Melbourne facility to produce Deflexifol for clinical trials and, ultimately, global markets.
The company is funded by AusHealth to cover additional costs of the phase II trial in children, as well as costs of FDA engagement to confirm the Deflexifol regulatory and development pathways for treatment of paediatric ependymoma.
According to AusHealth CEO Dr Justin Coombs, this ambitious project is ideally placed to replace and expand the use of a decades-old standard of care with a safer, more effective, next-generation therapy.
“This project could not only benefit millions of cancer patients each year,” says Dr Coombs, “it could also revolutionise brain cancer treatment for children in Australia and around the world.
“The goal is clear and urgent, and the project is incredibly exciting. We’re delighted to be part of it.”
More information: