CD28 monoclonal antibody trial goes tragically wrong

Janis Kelly

March 16, 2006

Mar 16, 2006

London, UK - All six men enrolled in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412 (CD28-SuperMAB, TeGenero AG) are in intensive care in a London hospital, and the study has been suspended by the UK Medicines and Healthcare Products Regulatory Agency. Two of the men are in critical condition; the other four are reported in serious but stable condition. According to the Associated Press, Dr Ganesh Suntharalingam, clinical director of intensive care at Northwick Park Hospital, said that the drug "has caused an inflammatory response that affects some organs of the body." Other press reports describe the problem as multiorgan failure accompanied by massive swelling.

TGN1412 was granted EU orphan-drug designation by the European Medicines Agency (EMEA) in March 2005 and was under development as a novel treatment for rheumatoid arthritis (RA), multiple sclerosis, and B chronic lymphocytic leukemia (B-CLL). The drug is described as a "superagonistic" T-cell stimulating antibody designed to convert "costimulatory" CD receptors into directly activated "stimulatory" CD receptors. This approach is thought to activate T cells regardless of their T-cell receptor specificity and was described by the company as "the first universal T-cell growth factor applicable for therapeutic purpose in the intact organism."

The phase 1 trial was being conducted by the Waltham, MA-based company Parexel International, in an independent medical research unit on the Northwick Park campus.

In a prepared statement, TeGenero chief scientific officer Dr Thomas Hanke said, "Our first concern right now is for the patients and families and that they get all treatment possible. We are confident in the excellent treatment at this hospital and have made ourselves available to answer any questions from the doctors about the drug. The drug being tested, TGN1412, is an innovative new treatment for the devastating illnesses of leukemia, rheumatoid arthritis, and multiple sclerosis. The investigation must proceed as quickly as possible into these shocking developments in the testing of a new medicine that showed no signs of any safety problems in previous testing. Our thoughts are with the patients and the families."

UK newspapers report agony of "human guinea pigs"

News of the trial disaster features on the front pages of most UK newspapers today, with lurid headlines describing the suffering of the volunteers who reacted to the experimental drug. One of the two volunteers who received placebo, Raste Kahna, said the six men given the drug began reacting within minutes. "They began tearing their shirts off complaining of fever, then some screamed that their heads felt like they were going to explode," he told the UK Sun newspaper. After that they started fainting and vomiting, and some were writhing in their bed and convulsing, he said.

Relatives visiting two of the victims were distraught at what they had seen, according to other reports. One of the men, 21-year-old Ryan Wilson, is reported to have suffered heart, lung, and kidney failure and was described as being unrecognizable, with a grossly swollen head and neck and dark purple skin. Another of the victims, a 28-year-old who remains unnamed, has a face "so puffed out that he looks like the Elephant man," his girlfriend, Myfanwy Marshall, told the London Times. "The doctors said he could die at any moment. His immune system is out of control, he needs a miracle."

Northwick Park hospital, where all the six volunteers are being treated, said this morning that there had been no change in the men's clinical condition overnight. The drug was given four days ago, on Monday, March 13 . One report suggested the patients were "having their blood filtered every hour in a bid to remove any possible toxins."

The trial in these eight volunteers was the first time that the experimental drug had been tested in humans. TeGenero said that "preclinical studies had shown the drug to be safe and the reactions that occurred in these volunteers were completely unexpected." But at a press conference last night, Hanke would not elaborate on what studies had been performed, saying only that the drug had been tested in mammals, but not in dogs or rats, the Times reported. "There has been no issue on the safety of the drug in animals. This is not relevant," he said. But the newspaper also quoted Marshall, who said, after visiting her boyfriend in the hospital, that the company had reportedly mentioned oversensitivity in monkeys and deaths in some of the animals that had been tested.

Richard Ley, spokesperson for the Association of the British Pharmaceutical Industry, commented to BBC News Online: "This is an absolutely exceptional circumstance. I cannot remember anything comparable."

- Zosia Chustecka



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