Dangers and Risks of Drug Development

During the lecture today (Tuesday) we discussed the development of drugs to target viruses, in particular smallpox. We learnt about toxicity and efficacy curves, the horizontal distance between the two curves at varying doses determining the therapeutic index. The danger and toxicity of certain drugs is well demonstrated by the failure of TGN1412 in the first phase of clinical trials.

This was a huge scandal in the UK. In its first human clinical trials, in March 2006, it caused catastrophic systemic organ failure in the subjects, despite being administered at a supposed sub-clinical dose of 0.1 mg per kg, some 500 times lower than the dose found safe in animals. All six volunteers were hospitalized, with four suffering from multiple organ dysfunction, and one volunteer showed signs of developing cancer. The responsible company TeGenero Immuno Therapeutics, entered into insolvency as a result.

Each of the men were paid over $3000 to participate in the trial, and six were administrated with 1/500th of the dose deemed safe in animals, the other two receiving a placebo (lucky)

TGN1412 is the name of an immunomodulatory drug which was withdrawn from development, originally intended for the treatment of B cell chronic lymphocytic leukemia and rheumatoid arthritis. It is a humanised monoclonal antibody that not only binds to, but is a strong agonist for, the CD28 receptor of the immune system's T cells. The in vitro (in test tube) and in vivo data from animal studies suggested that administration would lead to preferential activation of regulatory T cells, leading to a net effect of T cell down regulation.

Instead the TGN1412 instead caused the release of a cytotoxic storm only hours after adminstration, akin to the effects of the complement cascade in severe allergic reaction. None of the patients died, although they have been warned that they now face "a lifetime of contracting cancers and all the various auto-immune diseases from lupus to MS, from Rheumatoid arthritis (what it was supposed to treat) to ME".

This however could have happened to almost any researcher or drug development. There has been a lot of criticism about the failure to predict this action, with a scientist in hindsight claiming "You don't need to be a rocket scientist to work out what will happen if you non-specifically activate every T cell in the body". The MHRA (Medicines and Healthcare Products Regulatory Agency) however, stated that they found no deficiencies in TeGenero's preclinical work; there was no evidence of undisclosed studies.

Each of the men were paid over $3000 to participate in the trial, and six were administrated with 1/500th of the dose deemed safe in animals, the other two receiving a placebo (lucky)

Think twice before doing clinical studies.....Josh

Matthew Goodyear

http://en.wikipedia.org/wiki/TGN1412