UK Drug Trial Disaster Was Predictable Based on Severe Side Effects During 2005 Study Involving Similar Drug

When eight healthy young men volunteered to enter a drug trial of an investigational medication six were given the drug and two were given a placebo. All six who received the drug had violent, life threatening reactions and remain ill; two are in critical condition. 

While none of the victims ever imagined what would happen, it now appears more and more likely that the manufacturer and medical experts associated with the trial should have anticipated the very problem that occurred since a similar drug had produced equally
horrendous adverse reactions less than a year ago.
 

The present drug, known as TGN1412, is made by the German pharmaceutical company TeGenero AG and is designed as a cure for chronic lymphocytic leukemia as well as a treatment for rheumatoid arthritis and multiple sclerosis.
 

The catastrophic results, which are unprecedented in British drug trials, have raised many serious medical and ethical issues. It is already regarded as a scandal for a number of reasons.
 

The “first stage” clinical trial was simply designed (as all early trials are) to prove the safety, quality, and efficacy of a drug.
 

In the case of TGN1412, however, even the incredibly small doses administered to the six test subjects may have caused permanent, or even fatal, injuries to the otherwise healthy young men involved.
 

After taking the drug, the men all experienced excruciating pain. At the same time their necks reportedly swelled to several times their normal size making them appear to be grotesquely deformed like the “Elephant Man.”
 

Immediately, questions were raised as to the reason why such an experimental drug was given to healthy young men instead of terminally ill cancer patients who had already failed to respond to all available treatments and medications.
 

Using the healthy young men as “guinea pigs” has outraged many experts in the UK. One top cancer expert has even accused the firms involved of risking volunteers’ lives to find a cancer cure. (An American company, Parexel International Corp., was conducting the trial for TeGenero.)
 

The unnamed expert, who has been quoted in the British press, stated: They were going for the holy grail of not just containing cancer like some other drugs, but killing it. The risk was that they could have also killed the volunteers.”
 

He also said that the “company developing this drug would have known that there was a risk and that it could get out of hand because of the way it has been developed.” 

Treating the men has been hampered by the fact that doctors still are at a loss to explain exactly what went wrong.
 

Scotland Yard has assigned officers from its elite Specialist Crime Directorate to the case raising the possibility that charges may be brought for negligence or even manslaughter, if any of the men die. The possibility of civil actions by the volunteers or their families is also a possibility.
 

Questions also surround the approval of the test by British health authorities and ethics commission. Reports coming out of the UK state that the volunteers were told there had not been any significant adverse effects in prior (animal) tests. Documents in the possession of the Daily Mail appear to confirm that fact.
 

In addition, TeGenero had apparently claimed that there had been “no drug-related adverse effects” during those prior animal trials.
 

It now appears that, during the animal trials, TGN1412 caused monkeys’ necks to swell and that this reaction was considered serious enough by TeGenero officials to order the monitoring of the human volunteers’ immune systems in order to react immediately in the event of any swelling.
 

It also appears that earlier concerns had been raised by an article in Clinical Immunology wherein medical researchers warned of the possibility that human cells would be adversely affected by the drug.
 

Another possibility being considered is that differences between a human and animal cell signaling protein may explain the violent reactions in the volunteers.
 

TGN1412 is a monoclonal antibody designed to bind itself to specifically targeted molecules of an immune system protein known as CD28.
One expert in antibody research believes that this unexpected problem should cause any trials of drugs targeting the CD28 protein to be carefully reviewed and even halted until more data is obtained that might explain what went wrong with TGN1412 this week. 

Now, however, an article in DrugResearcher.com has added a new twist to the story. 

According to that report, a test in 2005 of another monoclonal antibody known as MDX-010 produced a sever toxic reaction in 12 of 20 subjects. That drug too was designed to target immune system protein receptors and block the CTLA4 and CD28 engagement. 

The sever reactions that included enteritis, hypophysitis, and meningitis were the subject of a study entitled “Tumor regression in patients with metastatic renal cancer treated with a monoclonal antibody to CTLA4 (MDX-010),” and was presented at a meeting of the American Society of Clinical Oncology in May 2005. 

Angus Dalgleish, a professor of cancer at St George’s hospital medical school, south London, told The Sunday Times: “The previous studies which caused similar severe side effects were in patients already suffering from cancer, but [the researchers] should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways.” 

While health officials in the UK attempted too justify last week’s trial by claiming there was “nothing to suggest that this product would be hazardous to man at the doses to be used in the clinical trial.”
 

Parexel, the American firm running the human trials for TeGenero, said in a statement: “We believe that best practices were followed and the appropriate policies and procedures were adhered to.” 

“Best practices,” however, may not be the issue if it is determined that a red flag was already waiving due to the multiple similar severe toxic reactions produced by precisely the same type of monoclonal antibody. If that is the case, and there is no reason to believe that it isn’t, there is much explaining to do with respect to the haste with which this trial was approved and the protocols used. 

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