An interim investigation into the clinical trial which left six men in serious condition at a UK hospital has concluded that there were no problems with either the manufacturing or dosing of the drug tested, and that the trial was run according to the agreed protocol.
The Medicines and Healthcare products Regulatory Agency said that at this midway point in the probe, the evidence points to a side effect that was not seen in animal studies, including those involving non-human primates, but which emerged only when the drug was tested in man.
But the regulator is also looking at tightening up regulations on trials of the type of drug under testing in the study to see if such cases can be prevented in the future.
The MHRA said its findings are preliminary, and additional investigations need to be carried out. However, it added: “if these findings were to be confirmed, it would indicate that this product showed a pharmacological effect in man which was not seen in pre-clinical tests in animals at much higher doses.”
The preliminary conclusions are a relief to Parexel, the clinical research organisation that carried out the study at the Northwick Park Hospital in London, and also to Boehringer Ingelheim, which manufactured the drug for its developer, German biotech TeGenero Pharmaceuticals.
Restrictions have already been placed on testing drugs that act in the same way as the TGN1412, the antibody under test in the ill-fated trial, and as soon as the news of the side effects from the Parexel trial emerged, the MHRA put a hold on tests on similar products and warned other regulators around the world to do likewise.
TGN1412 is an anti-CD28 antibody, targeting a protein on immune cells that, it was thought, would stimulate regulatory T lymphocytes and dampen down the immune system, relieving autoimmune diseases and inflammatory conditions such as rheumatoid arthritis and multiple sclerosis. But one possibility is that it, in fact, triggered a massive over-stimulation of the immune system, which caused it to attack tissues and led to the multiple organ damage that hospitalised the six men in the Parexel study.
The drug “is a new class of monoclonal antibody which has a stimulatory mode of action affecting certain types of cell in the immune system,” said the MHRA in its interim report. The fact that the risk were not found in animal studies “raises important scientific and medical questions about the potential risks associated with this type of drug and how to make the transition from pre-clinical testing to trials in humans,” it went on.
The agency is setting up an international group of experts to look into the case, and this will “consider what necessary changes to clinical trials may be required,” according to MHRA chief executive Prof Kent Woods.
One aspect of the trial that has come under scrutiny is that patients were dosed with the antibody almost simultaneously, so all six men had received the drug before the first side effects emerged. Spacing out doses, even by a few hours, could have limited the number affected.
The advisory group will be chaired by Prof Gordon Duff, professor of molecular medicine at Sheffield University. It will look specifically at how trials should be designed and overseen for biological molecules with novel mechanisms of action, especially those targeted at the immune system, and those with highly species-specific action. An interim report is expected within three months.
Meanwhile, two UK industry groups – the Association of the British Pharmaceutical Industry (ABPI) and the Bio Industry Association (BIA) – have said they plan to set up an expert working group to provide industry input into the group’s deliberations on the way clinical trials are conducted.