Wait for the ricochet

The conclusion that there was nothing wrong with the specifics of the TeGenero trial in which six healthy volunteers ended up in intensive care has repercussions for the wider biotech industry.

Development in three broad areas – biological molecules targeting any novel mechanism; any molecules targeting novel immune system mechanisms; and new agents with a highly species-specific action – will be subject to an extra level of scrutiny before being allowed to progress to first-in-man trials.

So far, this measure is in place for the three months that Gordon Duff, Professor of Molecular Medicine at Sheffield University, has been given to complete his expert report.

The UK BioIndustry Association is yet to survey its members and quantify the impact of the inevitable delays that will be experienced – often by development-stage companies with little spare cash.

But the fallout is not restricted to the UK sector. The trial was of a German product, being conducted by a US contract research organisation. It is an accident of globalisation that the trial took place in London – as the UK Medicines and Healthcare Products Regulatory Agency said when it announced the investigation, the findings “are likely to be of interest to regulators world wide”.

The TeGenero monoclonal antibody being tested, TGN1412, was designed to bypass the first stage of what is normally a two stage process, to directly stimulate production of a subset of T-cells. But as the MHRA said last week, the six volunteers suffered a cytokine storm, in which all classes of T-cells were activated, and not just the subset of Regulatory T-cells at which TGN1412 was aimed.

The files released by the MHRA show that the battery of primate testing and other animal testing carried out by TeGenero, as it prepared TGN1412 for the clinic, did not provoke any undesirable immune responses, and the initial dose in the human trial was at one 500th of the lowest dose in animal work.

No counterparts

That there was nothing in the animal studies to suggest the product might provoke a cytokine storm in man implies we are moving into realms where molecules are so precisely targeted at human biology, that there are no counterparts in animals on which they can be tested first.

It seems that even showing that the same CD28 receptor occurs in the test animals and in humans and that the drug molecule binds to both is not sufficient. It has to be shown that the molecule binds to both animal and human CD28 receptors in exactly the same way.

At the same time the CD28 receptor is expressed on most T-cells. Several immunologists have pointed out that given the widespread nature of CD28 it is likely to be very difficult to activate it selectively on a subset of T-cells. Furthermore, the precise role of CD28 in the healthy immune system is not precisely understood.

In its statement responding to the MHRA’s report on 5 April TeGenero said, “The preliminary findings of the investigation underline that we observed the highest standards in developing this drug, and that these symptoms were both unexpected and unforeseeable. The information released today shows there was no sign of risks in the preclinical tests of TGN1412.”

There is of course one simple thing that would have reduced the overall impact – and that is giving the drug one volunteer at a time rather than dosing all eight (two received placebo) virtually simultaneously. But that is hardly a satisfactory way of mitigating risk going forward. What happened to the six victims clearly was repeatable. This should mean it is possible to develop preclinical tests that will ensure the same does not happen with any other compound.

Now the biotech industry is anxious to have a say in the investigation. With its pharmaceutical industry counterpart, the ABPI, it is putting together an advisory panel to make sure industry expertise is factored into Duff’s investigation.

Paradoxically, groups running clinical trials in the UK reported an increase in interest from volunteers following the news of the fiasco. The MHRA must reach its conclusions, ensure the public understands the findings, and put any new measures in place swiftly, or their services may not be required.