When a new drug is synthesised it has to go through multiple testing phases taking place over years, the first of which take place in a laboratory and eventually move on to human trials, called clinical trials. Theralizumab (TGN1412) was an immunomodulatory drug that was manufactured to treat B cell chronic lymphocytic leukaemia and auto-immune diseases. Regulatory T cells are very important in the prevention of these auto-immune diseases as they can regulate or suppress other cells in the immune system. Regulatory T cells are activated by antigens which are controlled by signals via T cell receptors. TGN1412 was found to cause the expansion of T cells without any signals from T-cell receptors.
In March 2006 the phase I clinical trial began at Northwick Park Hospital, a hospital run by a company which carries out drug trials called Parexel. Eight healthy men volunteered for the study and were given £2,000 each, they were spilt into two groups and each group had its own room. One man from each room was given the placebo and the rest were administered a dose of TGN1412, a dose 500 times smaller than what was found safe in animal trials. Soon after being administered the drug the volunteers began to suffer from adverse reactions due to a large release of cytokines, small proteins that act as cell messengers to direct the immune system. This resulted in Cytokine release syndrome and the patients began to develop symptoms, starting with headaches and chills, quickly progressing to vomiting, severe pain, shortness of breath, swollen tissue and organ failure. The patients were transferred to the ICU where they were given large doses of steroids and some were put on life support machines. One patient, David Oakley’s, head swelled so much it looked like a ball with slits and his stomach was very swollen, this is how the trial came to be know as the elephant man drug trial.
After the trial the UK’s Medicines and Healthcare Products Regulatory Agency started an investigation into the trials methodology and manufacturing of the drug, they did not find any flaw in either and concluded that the severe reaction was due to an ‘unexpected biological effect’. However they found that Parexel didn’t keep appropriate medical records and were unable to provide 24 hour medical cover, they also concluded that one doctor who screened the volunteers had unsatisfactory training and experience for the role. Furthermore, the trial did not take place in a hospital which meant that it took doctors longer to diagnose and treat the volunteers than it should have and the first volunteer started showing symptoms of an adverse reaction prior to the infusion of the last volunteer but nothing was done to stop the infusion.