For the past decade, Dutch immunologist Jacques (Sjaak) Neefjes has been on a mission to bring back a cancer drug that has been unavailable in Europe since 2004. “I am still amazed that a compound that could help thousands of people has been taken off the market,” says Neefjes. Why it was removed seems somewhat 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 in the last 20 years, Neefjes estimates that it could have helped 100,000 people.
But although the math sounds simple, the path of Neefjes’ research has been far from smooth. In his efforts to revive aclarubicin, he smuggled small quantities from China, found old samples in a Finnish freezer and financed part of his work through an inheritance from a Dutch MP who was murdered 10 years ago.
“It was a tough battle,” says Neefjes. And it’s not nearly over. Next, he needs to produce enough of the drug to conduct 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. These include drugs such as doxorubicin and daunorubicin, which are used in the UK and Europe. “Usually these drugs are only given four or five times to prevent heart problems,” says Neefjes. This may not be enough to put the cancer into remission, so researchers have looked for alternatives.
In 2013, Neefjes’ PhD student Baoxu Pang discovered that doxorubicin works in two different ways: it damages both DNA and it changes how genes are turned 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 The Netherlands in his bag. “In China you can get it with a prescription from a pharmacy,” says Neefjes.
From this small sample, Pang found that aclarubicin caused no DNA damage at all. This meant that it would not have the same cardiotoxic effects as other anthracyclines. That 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 produced aclarubicin on a commercial scale several decades ago. “She still had the bacteria needed to produce it in her freezer,” he says.
However, there was no funding to scale up production. “There is no patent on this compound, so industry is not interested in it.” said Cousins. Since the patent on aclarubicin has expired, there is no incentive for pharmaceutical companies to invest in it, as 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’ mother-in-law was the former Dutch Minister of Health Els Borst. In 2014, she was killed in her home because of her stance on euthanasia. Borst was a driving force behind the Dutch legislation allowing euthanasia under certain conditions. She has also been a strong patient advocate throughout her career. For Neefjes and his wife, Andra, it was a fitting tribute to use her legacy to support research to revive a forgotten cancer drug.
With the Borst heritage 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 an award of €2.5 million.
Meanwhile, Neefjes also entered into a collaboration with the clinician Junmin Li in Shanghai, who regularly used aclarubicin to treat AML. Li’s patient records revealed that aclarubicin improved the five-year survival rate of AML patients by 23% compared to other chemotherapy drugs. “Even the Chinese group was surprised to see the results,” says Neefjes. Li has yet to crunch the numbers on his own patient data.
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Still, these promising data are not enough to get aclarubicin back to Europe. The next step is clinical trials, and that could present entirely new obstacles, both for Neefjes and other aclarubicin researchers.
Jay Sarthy is an assistant professor at the University of Washington and pediatric oncologist at Seattle Children’s Hospital in the United States. He hopes to use aclarubicin to treat pediatric cancer. “Time and time again, I’ve seen kids have bad toxicities from chemotherapy regimens,” says Sarthy. “So a safer medicine like this needs to be investigated.”
In his research so far, Sarthy has found that aclarubicin, which has never been available in the United States, can work as a treatment for pediatric leukemias and lymphomas. “We immediately started preparing for a clinical trial.” But the lack of a patent means that drug companies are not interested in funding aclarubicin trials. “Support from charities has been critical,” says Sarthy.
Another challenge is finding enough people to participate in clinical trials, especially for AML.
“It’s a very crowded environment at the moment,” says Steven Knapper, a clinical haematologist at Cardiff University and the University Hospital of Wales.
AML is relatively rare, so any new drugs in development will compete for the same group of patients for clinical trials. “There is a trend toward newer treatments,” says Knapper. That is, drugs developed in recent years that target the root cause of AML, rather than relatively established chemotherapy drugs such as aclarubicin. There would need to be a demand for aclarubicin to make a trial feasible.
That claim seems to be on the way. “Having fewer side effects is so important,” says Veronica van Nederveen, chairwoman of the Dutch cancer patient advocacy organization Patiëntenstem.nu.
Van Nederveen, who herself 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 have a chemotherapy drug that has fewer and less severe side effects, I think people will line up for clinical trials.”
