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Men sickened in British drug trial had "storms"

Six British men who became seriously ill while testing an experimental drug had an immune system overreaction known as a cytokine storm, the doctors who cared for them reported on Monday.

All six men have recovered and the incident appears to have been an unforeseeable consequence of taking the drug, designed to treat chronic inflammatory conditions and leukemia, Dr. Ganesh Suntharalingam and colleagues at Northwick Park Hospital in northwest London said.

Their case can help doctors understand what happens when the immune system overreacts in such a way -- which may well occur again in future clinical trials, the doctors wrote in the New England Journal of Medicine.

The men became ill shortly after they were given infusions in a phase 1 safety trial of TGN1412, made by German biotechnology firm TeGenero AG.

The drug is a monoclonal antibody, a targeted immune system protein engineered to affect immune system cells known as CD28 cells. The men were paid volunteers in a study being run by U.S. drug research company Parexel International Corp. on behalf of TeGenero, which has since filed for insolvency.

Eight men took part in the trial. Six got the drug and two got a dummy infusion.

Within 90 minutes, the six men who got the drug reported headaches, shivers, nausea, diarrhea and lower back pain. "At 12 hours one of the patients became severely unwell," Suntharalingam said.

When one patient became so ill he had to be put on a ventilator, the doctors decided to put the other five into intensive care just in case. Some of the men became very disturbed and then their blood pressures all plunged and their organs began to fail.

The doctors described a dramatic two weeks during which the previously healthy men developed symptoms that looked like a serious infection known as sepsis, with difficulty breathing.

STRUGGLE WITH THE UNKNOWN

The doctors struggled to keep the men going as they tried to figure out what had gone wrong. They gave the patients steroids and a drug designed to tone down the immune system response, but stopped that drug after they discovered the men in fact had lost immune system cells.

They had transfusions of blood products after their blood started to clot abnormally. Tissue started to die and peeled off at the ends of their fingers.

It took weeks to stabilize the patients and to lead them to slow recovery.

Tests of their blood shows they had a cytokine storm -- a sudden over-release of immune system inflammatory chemicals. The over-response of the immune system can kill, and has been described in patients with avian influenza.

This did not happen in animals, in part perhaps because lab animals are often kept in super-clean environments and their immune systems have never been challenged, Dr. Arlene Sharpe of Harvard Medical School and Dr. Abul Abbas of the University of California, San Francisco, said in a commentary.

"Regulatory authorities, who tested TGN1412 from the same batch as the infused drug, found no errors in its manufacture, formulation, or administration and found no contamination," the researchers added.

They said scientists running clinical trials should be aware of the danger and should learn how to handle such cases.

"There are clearly going to be more trials of new drugs in field of molecular biology," Suntharalingam said.

"As long as we continue to manipulate biology in new ways, we probably cannot prevent all such events from occurring. We must do what we can to minimize risk, but the future health of the world population demands that we not let adverse events put an end to medical progress," Journal Editor Dr. Jeffrey M. Drazen added in a commentary.