Drug trial fiasco induced immune system overload in patients

The doctors who treated six British men in a trial of a drug in March which went horribly wrong, say they believe the men suffered an immune system overreaction known as a cytokine storm.

The men were testing an experimental drug in a phase 1 safety trial; the drug was designed to treat chronic inflammatory conditions such as rheumatoid arthritis, multiple sclerosis and some forms of leukemia.

The drug is a monoclonal antibody, an immune system protein engineered to target immune system cells known as T-cells that directly stimulate the immune system.

In a healthy person the T-cells dampen the function of other parts of the immune system by preventing the body from attacking itself and when this safeguard fails, it can lead to autoimmune diseases.

TGN1412 was designed to deal with such a response.

Although all the men have since recovered it has not been without certain ramifications regarding their long term health; one already has the early signs of lymphatic cancer.

Ryan Wilson age 21 was the most seriously injured volunteer and had to have parts of his fingers and toes amputated because he developed gangrene.

Of eight healthy men, six were given the drug TGN1412 and two a placebo; within a short space of time the six men who received the drug developed headaches, shivers, nausea, diarrhea and lower back pain; within twelve hours one of the patients became severely ill and some of the men became very disturbed, their blood pressures all plunged and their organs began to fail.

All were fortunately transferred to an intensive care unit where they received intensive cardiopulmonary treatment, including dialysis, high-dose Medrol, a corticosteroid used to reduce inflammation and an anti-interleukin-2 receptor antibody.

Two of the patients developed cardiovascular shock and acute respiratory distress syndrome, which required eight to 16 days of organ support.

Dr. Ganesh Suntharalingam and colleagues at Northwick Park Hospital in northwest London who treated the men have written a report of the incident and along with comments from other medical experts, and hope the information provided will contribute to the debate over identifying potentially dangerous drugs and stop such an event from happening again.

The report is published in the New England Journal of Medicine.

The doctors say the incident appears to have been an unforeseeable consequence of taking the drug, but believe the case may help doctors understand what happens when the immune system overreacts in such a way, which could occur again in future clinical trials.

The ensuing two weeks were pretty dramatic as the previously healthy men developed symptoms that resembled sepsis, a very serious infection.

They experienced difficulty breathing and in the fight to keep the men alive the patients were given transfusions of blood products after their blood started to clot abnormally and tissue started to die and peeled off at the ends of their fingers.

It eventually took the doctors two weeks to stabilize the patients and to lead them to recovery, but some remained in hospital for months.

Blood tests showed they had a cytokine storm, a sudden over-release of immune system inflammatory chemicals and such an over-response can be a killer.

This had not happened in the animal trials, possibly say some experts because lab animals are often kept in super-clean environments and their immune systems have never been challenged.

Researchers say regulatory authorities, who tested TGN1412 from the same batch as the infused drug, found no errors in its manufacture, formulation, or administration and found no contamination.

They advise that scientists running clinical trials should be aware of the possible dangers and equip themselves to handle such cases.

The volunteers were each paid about US$ 3,500 for taking part in the trial.

Four of the men have already received compensation payments of about US$25,000 from TeGenero.

The others are waiting for the results of medical tests before making specific compensation claims.

Lead report author Dr. Ganesh Suntharalingam says the patients were given the drug at 10-minute intervals, and perhaps there needs to be more time between doses.

He says the men were lucky that the trial took place at a fully equipped medical center, and were able to get to intensive care very quickly when they needed to.

Other experts are now questioning the medical ethics of phase 1 trials where high risks are taken for money and believe more animal experiments with experimental drugs need to be done before drugs are tried on patients.

Others are concerned that the fiasco will be detrimental to the use of such new drugs which have the potential to benefit many people.

TGN1412 is made by German biotechnology firm TeGenero AG and the trial was run by U.S. drug research company Parexel International on behalf of the company and has since filed for insolvency.