Everything in compliance with fatal drug test in London
The clinical study, which caused six he althy men in London to become life-threatening in mid-March, was properly conducted in all respects. During the review, the British regulatory authority MHRA and the Paul-Ehrlich-Institut found no evidence of errors in manufacturing, incorrect dosage or contamination of the substances used (1). A commission of experts is now to examine the scientific background of the unexpected side effects.
On March 13, eight he althy volunteers received a dose of the monoclonal antibody TGN1412 from the Würzburg company TeGenero as part of the usual approval process for a new drug. Only a short time later, the volunteers developed a so-called "cytokine storm", in which a massive release of these messenger substances triggers a violent inflammatory reaction throughout the body with fever, cramps, shortness of breath and high blood pressure. Two of those affected became life-threatening and were in a coma.
In the meantime, five of the sick are back at home, albeit under further medical observation. According to a lawyer representing four of the subjects, they still suffer from constant headaches and dizzy spells. The sixth patient was at least able to leave the intensive care unit and is on the mend, according to the treating Northwick Park Hospital.
The new active ingredient should activate T cells of the immune system directly - but only those representatives that have a balancing effect. The researchers wanted to use this to treat diseases that are due to an overreaction of the immune system, such as multiple sclerosis, rheumatoid arthritis, but also leukemia. TGN1412 differed from comparable monoclonal antibodies, some of which have already been approved, in that it does not need another partner to activate the target cells, but can act alone by binding to a key receptor, the CD28 molecule, on the surface of the T cells.
However, why the test subjects' T cells reacted with the massive release of cytokines and thus showed exactly the opposite of the expected effect, remains completely unclear. Corresponding tests with a 500-fold dose in cynomolgus monkeys, which have the same receptor with an identical binding site for the antibody, had not shown any evidence of such an effect.
However, there had been problems and even deaths from massive cytokine release and subsequent organ failure during therapy with monoclonal antibodies. A 71-year-old leukemia patient died in 1999 after receiving the cancer drug rituximab (2). The manufacturing company Roche Pharmaceuticals admitted at the time that there had been eight more deaths.
