Mar 15, 2006
Critical Trials TGN1412
The BBC reports today that six men are on the critical list after becoming seriously ill while taking part in a clinical trial of a new drug for treating leukemia and arthritis: BBC Report.
The previously healthy young men were being paid (up to £150, $330 a day) to take part in the early stages of a trial of the novel drug TGN1412. However, within hours of their first injection, they reacted adversely (suffering multiple organ failure) and were put in intensive care. The two men receiving placebo in the trial are fine.
The compound in question is biopharmaceutical company TeGenero’s humanized CD28-SuperMAB (TGN1412) which is in trials for rheumatoid arthritis and B-CLL (B-cell chronic lymphocytic leukemia). Following standard toxicity studies it was entered into initial clinical trials. “The drug was developed in accordance with all regulatory and clinical guidelines and standards,” explained Dr Thomas Hanke, Chief Scientific Officer of TeGenero AG, in a statement, “In pre-clinical studies, TGN1412 has been shown to be safe and the reactions which occurred in these volunteers were completely unexpected.”
Adverse reactions to drugs in clinical trials are exceedingly rare, but then TGN1412 is not your everyday small molecule type drug. TeGenero developed this drug, a superagonistic monoclonal antibody, with the aim of balancing T cell (a type of white blood cell) activation by triggering receptors on another group of white blood cells known as T lymphocytes. Today’s events are likely to provide animal rights activists with new fodder to push for animal testing to be banned, they will undoubtedly cite this unforeseen problem as further evidence that animal tests cannot show how a drug might act in people.
Ganesh Suntharalingam of Northwick Park Hospital told the BBC that, “The drug, which is untested and therefore unused by doctors, has caused an inflammatory response which affects some organs of the body.” Why this should be so is unclear. The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has withdrawn authorisation for the trial (obviously) and doctors in other countries have been sent a warning not test it.
Sciencebase will keep you posted on events as we hear them, in particular we’ll try to bring you the results of the ongoing investigation as soon as we can. It may emerge that a clinical error is to blame rather than there being a biological problem with the drug itself, we will have to wait and see.
This very unfortunate incident comes just one day after widely acclaimed findings were revealed showing how the totally unrelated statins could reverse atherosclerosis. Such positive results that inspire public confidence in the pharmaceutical industry are almost as rare as the present negative result!
Richard Ley of the Association of the British Pharmaceutical Industry was reported as saying “This is an absolutely exceptional occurrence.” and “cannot remember anything comparable.”
The last of the six men who collapsed during the trial with multiple organ failure has been taken off the critical care list at Northwick Hospital, thankfully. He remains an in-patient, while the five others have been discharged.
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has tightened the regulations on future trials involving similar products to the monoclonal antibody TGN1412 given the seriously adverse reaction seen in this trial.
In its preliminary report, the MHRA said, it “has found no evidence to suggest that there was any problem with the manufacturing of the product which was given to the trial volunteers – it appears not to have been contaminated, or to have contained anything other than the correct ingredients. Neither have we found anything in the way the trial was run which contributed to the adverse reactions experienced by the volunteers – it was run according to the agreed protocol, and the correct dose of the product was given to the patients.”
The BBC today reports that “Two of the six men who took part in the TGN-1412 trial and suffered the consequences have been discharged from Northwick ParkHospital, although they will continue to be monitored closely as out-patients. One man remains critically ill while the other three are making progress, according to a Hospital spokesman.
Tegenero are keeping a very tight rein indeed on this trial. The only news since last week was reported by the BBC on Sunday to say that, “One of the two men left critically ill by a drugs trial almost two weeks ago is reported to be making good progress.”
There is still no hard report on what went wrong in the trial, whether or not the swollen monkey glands was a serious issue, or whether there were any error in administering the drug.
While two men remain in a coma and four are on the road to recovery (three of whom are now off organ support), it emerges that the drug caused temporarily swollen lymph nodes (glands) in the earlier animal testing phase of it’s development. However, the company developing the drug Tegenero says this was a different side-effect to that seen in the trial volunteers. More importantly, the side-effect was noted in regulatory submissions and the volunteers were warned that they might suffer swollen glands during the trial. However, this swelling, says Tegenero, was actually a sign that TGN1412 was working as it stimulated extra regulatory T-cell production.
The company claims no one could have predicted the seriously adverse effects that occurred in the volunteers.
Four of the men left critical ill in the Phase I clinical trial of TGN1412 have thankfully regained consciousness. Two remain in a critical condition under sedation.