For the past decade, the Dutch immunologist Jacques (Sjaak) Neefjes has been on a mission to bring back a cancer drug that hasn’t been available in Europe since 2004. “I’m still flabbergasted that a compound that could have helped thousands of people was taken off the market,” says Neefjes. Why it was removed seems something of a mystery, but as far as he can tell, it was simply a lack of demand.
His latest research shows that this drug, aclarubicin, can improve the survival of people with acute myeloid leukemia (AML) much better than other forms of chemotherapy. If it had been available in Europe for the past 20 years, Neefjes estimates that it could have helped 100,000 people.
But while the maths sounds simple, the path of Neefjes’s research has been far from smooth. In his attempts to revive aclarubicin, he has smuggled small amounts from China, found old samples in a Finnish freezer, and funded part of his work using an inheritance from a Dutch MP who was murdered 10 years ago.
“It has been a tough battle,” says Neefjes. And it’s nowhere near over. Next, he has to produce enough of the drug to run clinical trials for AML patients in Europe.
AML is a blood cancer in which bone marrow rapidly produces abnormal cells instead of healthy blood cells. Chemotherapy is a common treatment, but the side-effects of some of these drugs are quite harsh. In particular, a group of chemotherapy drugs called anthracyclines can cause heart damage. This includes drugs such as doxorubicin and daunorubicin which are used in the UK and Europe. “Usually these drugs are given only four or five times to prevent heart problems,” says Neefjes. That might not be enough to bring the cancer into remission, so researchers have been looking for alternatives.
In 2013, Neefjes’s PhD student Baoxu Pang discovered that doxorubicin works in two different ways: it both damages DNA and it changes how genes are switched on and off. The gene switch was mainly responsible for killing cancer cells while the cardiotoxic side-effects were linked to DNA damage.
Aclarubicin is also an anthracycline, and has been used in China and Japan as a cancer treatment. On a trip to China, Pang obtained a small amount of aclarubicin and took it back to the Netherlands in his suitcase. “In China you can just get it at a pharmacy with a prescription,” says Neefjes.
From this small sample Pang found that aclarubicin didn’t cause DNA damage at all. That meant that it wouldn’t have the same cardiotoxic effects as other anthracyclines. This alone would be a good reason to bring aclarubicin back to Europe, but they needed more evidence – and more aclarubicin.
Neefjes found a researcher in Finland who had once produced aclarubicin on a commercial scale, several decades ago. “She still had the bacteria that were needed to produce it in her freezer,” he says.
However, there was no funding to scale up production.“There’s no patent on this compound, so industry isn’t interested in it.” says Neefjes. Since the patent on aclarubicin has expired, there is no incentive for pharmaceutical companies to invest in it, since any competitors are also free to produce the drug. That leaves small grants, charity and independent funding – and for Neefjes, some of his initial funding came from a tragic and unexpected source.
Neefjes’s mother-in-law was the former Dutch health minister Els Borst. In 2014, she was murdered in her home because of her stance on euthanasia. Borst was a driving force behind the Dutch legislation that permits euthanasia under certain conditions. She was also a strong patient advocate throughout her career. For Neefjes and his wife, Andra, using her inheritance to support research into reviving a forgotten cancer drug was a fitting tribute.
With the Borst inheritance and the bacteria from Finland, Neefjes was able to produce more aclarubicin in India for his research in the Netherlands. Another boost for the project came in 2020, when Neefjes won the prestigious Dutch Spinoza prize for his research, with a €2.5m award.
Meanwhile, Neefjes also struck up a collaboration with clinician Junmin Li in Shanghai, who had been routinely using aclarubicin to treat AML. Li’s patient records revealed that aclarubicin improved the five-year survival rate of AML patients by 23% compared with other chemotherapy drugs. “Even the Chinese group was surprised to see the results,” says Neefjes. Li hadn’t crunched the numbers yet on his own patient data.
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Still, this promising data is not enough to get aclarubicin back to Europe. The next step is clinical trials, and that could pose entirely new hurdles, both for Neefjes and other aclarubicin researchers.
Jay Sarthy is an assistant professor at the University of Washington and paediatric oncologist at Seattle children’s hospital in the United States. He is hoping to use aclarubicin to treat paediatric cancer. “I’ve seen time and again that children have bad toxicities from chemotherapy regimens,” Sarthy says. “So a safer medicine like this must be explored.”
In his research so far, Sarthy has found that aclarubicin, which has never been available in the United States, could work as a treatment for paediatric leukaemias and lymphomas. “We immediately started preparing for a clinical trial.” But the lack of a patent means that drug companies aren’t interested in financing aclarubicin trials. “Support from charities has been critical,” Sarthy says.
Another challenge is finding enough people to participate in clinical trials, especially for AML.
“It’s a really crowded environment at the moment,” says Steven Knapper, a clinical haematologist at the University of Cardiff and the University Hospital of Wales.
AML is relatively rare, so any new drugs in development will vie for the same group of patients for clinical trials. “There is a tendency to move towards newer treatments,” says Knapper. That is, drugs developed in the past few years that target the root cause of AML, rather than relatively established chemotherapy drugs such as aclarubicin. There would need to be demand for aclarubicin to make a trial feasible.
That demand seems to be on the way. “Having fewer side-effects is so important,” says Veronica van Nederveen, chair of the Dutch cancer patient advocacy organisation Patiëntenstem.nu.
Van Nederveen, who herself has had chemotherapy to treat breast cancer, notes that the cardiotoxic effect of drugs such as doxorubicin can even leave some people needing a heart transplant. “If you’ve got a chemotherapy drug that has fewer and less severe side-effects, I think people will be lining up for clinical trials.”