Animal models may not by suitable for determining drug safety in humans in certain genetically engineed compounds.
By Patricia Reaney
Sun Mar 19, 1:50 PM ET
LONDON (Reuters) - Differences between a cell signaling protein in humans and animals may explain the unexpectedly severe reaction in six young men given a new drug in a clinical trial in Britain, an expert said on Sunday.
The previously healthy men were the first humans to receive the drug, designed to treat leukemia and chronic inflammation disorders. Shortly after they were given the treatment last week, they suffered massive inflammation and excruciating pain.
Two are still critically ill, one is on organ support, and the other three are recovering.
Doctors are baffled about what went wrong in the trial of the antibody drug TGN1412, made by the privately-owned German company TeGenero AG, which had previously been tested in laboratories and on rabbits and monkey.
TGN1412 belongs to a class of drugs known as monoclonal antibodies, which specifically bind to target molecules. TGN1412 targets an immune system protein called CD28.
Dr David Glover, a drug industry consultant with extensive experience of antibody treatments, said the protein the drug targets may not be the same in all species.
"I suspect the antibody was designed to work against human CD28 and because it was designed to work best in humans its performance in different animals may fall short of what you might have expected in humans," Glover said in an interview.
"That is why the animal testing may have falsely provided reassuring results. It could be one of the explanations."
Dr Thomas Hanke, the chief scientific officer at TeGenero said in a statement last week that tests on animals had not produced drug related adverse advents, nor drug-related deaths.
CD28 is a protein on the surface of some white blood cells that plays a part in activating them for an immune response. Hanke said TGN1412 was designed to activate its target protein -- rather than blocking it as many antibody drugs do.
In the British trial, the administration of the drug was followed by a massive inflammation reaction.
The trial was being run by U.S. drug research company Parexel International Corp. on behalf of TeGenero AG.
Ray Nobel, a medical ethicist who sits on a committee at University College London, said Phase 1 trials, in which new compounds are tested on healthy volunteers, are a fundamental part of the ethical process.
Glover said no one should lose sight of the benefits of antibody drugs. He said the focus should not be on antibody treatments in general, or stopping clinical trials.
The breast cancer drug Herceptin, made by the Swiss pharmaceutical Roche, is an antibody treatment. It attaches itself to the HER2 receptor on the cancer cells and blocks them from receiving growth signal.
Eighteen antibody products have been approved for sale and their combined worldwide sales reached $14 billion last year.
However Glover said trials of drugs targeting the protein CD28 should be reviewed.
"Should we stop doing trials that are directed against the target CD28? I think the answer is yes, until more is known about what it going on," he said.
The Medicines Healthcare products Regulatory Agency (MHRA) is conducting and enquiry into what went wrong. Results are expected in weeks.
