The TGN1412 Aftermath

In March 2006 the antibody TGN1412 was administered to six human volunteers with disasterous results. The immune systems of the volunteers over-activated causing a cytokine storm. Organ failure had developed, but the volunteers did recover. Now, the question has been asked: How can this happen in this era of animal testing?

With the cytokine storm over, the investigation began. The antibody used In the trial was tested and found to be pure. Protocol was followed, and all the regular safety precautions were in place. The laboratory that developed TGN1412 was investigated but it had followed procedure properly. So what went wrong? Part of the problem was with the pre-clinical laboratory tests. TGN1412 does not cause a large immune response in laboratory animals such as rats. However, animal cells do show an immune response if the cells express human proteins. The pre-clinical investigations should have used “humanized” cells and not cells that were purely non-human. This just stresses that humans and lab animals do differ, and efforts should be made to test drugs in human models, using human cells, DNA, proteins, etc.

An Expert Scientific Group has identified several flaws in the way new drugs are tested, especially those like TGN1412 which have a novel mechanism of action. They made several recommendations for future testing. They suggest that much more safety testing of the antibody was justified before human testing because a drug like TGN1412 has never been given to a human before. Accordingly, the doses used in the volunteers should have been lower. The trial itself was criticized. They suggest that the investigators should have given one dose to one volunteer and waited several hours before giving doses to other volunteers. In this way the toxicity would have been limited to one test subject. Adoption of the recommendations, and everything learned frm the disaster, will only serve to strengthen the safety of future trials.

Coming Up On Monday: You Won’t Forget This One

When Animal Testing Fails

Testing drugs in animals is essential. Nothing can replace the data obtained from a living, breathing system with all of its intricacies and capriciousness. I shudder to think what would happen if drugs were tested on humans in clinical trials without prior animal testing. Admittedly animal testing does not ensure safety. The birth defects caused by thalidomide were not detected in the early 1960s because the drug just happened not to cause teratogenesis in the rabbits used during preclinical tests. Another failure of animal testing occurred last year. This time, however, preclinical testing in volunteers detected the danger before the drug became available for widespread use.
TGN1412 is a antibody that was developed to treat leukemia. It was designed to increase the number of circulating T cells, which are deficient in B cell chronic lymphocytic leukemia. It may have also had a use in treating automimmune diseases such as arthritis. Tests in rats did not use TGN1412 but rather a similar antibody that had the same function. The tests showed that the antibody could be effective for arthritis, and that TGN1412 representeed a new class of drugs with a novel mechanism of action. Testing of TGN1412 itself in primates revealed that it could cause an increase in proteins that promote an immune response. Furthermore, the primates had a transient increase in the number of B cells and T cells. This inflammatory response was not considered a problem because it was dose-dependent; it was much more pronounced at higher doses. A dose that was one-500th of the dose that did not cause adverse effects in the primates was chosen for testing in humans.

On March 13, 2006,TGN1412 was intracvously-administered to healthy human volunteers. The volunteers were to receive one of four different doses of TGN1412 or a placebo. Within two hours, the six human guinea pigs reported pain, headache, low blood pressure, nausea, diarrhea and other symptoms. A cytokine storm had developed, which is a large increase in signaling of inflammatory cells. Their conditions deteriorated over the next 24 hours and they needed to be ventilated, given plasma, and put on dialysis. The inflammatory response subsided after two days, but by that time the volunteers had multi-organ failure. Within a month, the volunteers had recovered.
Coming Up On Friday: How We Can Improve Trials

Chew On This

The country of Yemen has virtually no cocaine or heroin users. This is not because of strong policing. Rather, the Yemen people have another drug that has very similar effects as cocaine. This drug is called khat, and it is derived from the Catha edulis plant. It is also known as chat, qat, or The Flower of Paradise. Up to 40% of cultivated land in Yemen is devoted to growing the plant. Khat is ingested by wrapping up to a pound of Leaves and twigs in banana leaves to form a bundle called a ma duuf. The bundle is stored in the cheeks and chewed, which extracts the jucie. The juice is either swallowed or spit out. Khat chewing has spread around the world, but it is especially common in several regions of Somalia and Yemen. An economist in Yemen blames khat for the country’s poverty: approximately 80% of the population chew khat four hours a day and socialize instead of working.

Khat contains vitamins and minerals along with cathinone, cathine, and norephedrine, which are responsible for the stimulant effects of the plant. Khat acts like amphetamine but is reportedly more euphoric and short-acting. Like amphetamine, khat causes a release of the neurotransmitters dopamine and norephinephrine (noradrenaline). Like amphetamine users, khat users experience alertness, excitement, greater concentration and creativity and well-being. Sexual libido is said to increase in both sexes. But habitual use can result in constipation, insomnia, psychosis, and anorexia. In Yemen, the sexual dysfunction of male khat users is thought to underlie the failure of many marriages.

Coming Up On Wednesday: An Inflammatory Storm