A clinical drug trial that went horribly wrong - putting six men in a London hospital – raises a raft of new questions about drug testing.
The men, volunteers in a trial for a new antibody-based drug for leukemia, were admitted to intensive care March 13. A week later, at lunchtime on 20 March, the hospital said that four of the men are continuing to respond to treatment and are making a steady recovery. Artificial organ support has been removed from these four. The two other men remain in a critical condition, though there are very early signs of improvement. But the medical team remains cautious, saying it is too early to comment on prognosis.
“This is shocking because it is unprecedented,” said Simon Best, chairman of the UK BioIndustry Association. “If you think about the number of Phase I trials that are carried out, both with bio and small molecule drugs, you’ve never heard of anything having such a terrible impact.”
The news has implications also for the recently established UK Clinical Research Collaboration. This has £74 million funding from the government to create a single gateway to the largest pool of patients in the world, in the UK’s National Health Service, with the aim of making the country the best location worldwide to conduct clinical trials.
Just two months ago, the Health Secretary, Patricia Hewitt published a new research strategy for the NHS, Best Research for Best Health, in which she said health research, “Plays a key role in the knowledge economy of our country through its contribution to international competitiveness and economic growth.”
The drug being tested, TGN1412, a fully humanised monoclonal antibody targeting the CD28 antigen, has EU Orphan Drug status in the treatment of B-cell chronic lymphocytic leukaemia, (B-CLL), a rare, chronic form of the disease. It is being developed also for treating autoimmune diseases including rheumatoid arthritis and cancer by TeGenero AG, a 15-strong biotech start up based in Wurzburg, Germany.
The Phase I safety trial was being carried out for TeGenero by the US contract research company Parexel International in a private unit attached to the Northwick Park Hospital in London, where the men were taken to be treated.
After the men became ill on Monday the UK Medicines and Healthcare Products Agency immediately suspended the trial, and began a full review of the data submitted with the application for clinical trial authorisation. Professor Kent Woods, chief executive of the MHRA said, “Our immediate priority has been to ensure that no further patients are harmed. We will now undertake an exhaustive investigation to determine the cause and ensure all appropriate actions are taken.”
The Metropolitan Police are involved in the investigation as it is necessary to rule out foul play.
Best said the ramifications for the biotech industry in general depend on the outcome of the MHRA’s investigation. “The MHRA needs to get in there and dig deep and quickly to find out if it is a specific or a general problem. It could be a problem with dosing, it could be contamination: they can’t take anything for granted, they’ve got to look at the science, and every possible thing that could explain it.”
The pathology of B-CLL is closely linked to a pronounced dysfunction of patients’ T lymphocytes. According to TeGenero, TGN1412 was expected to activate T lymphocytes, reducing the number of infections that patients suffer and keeping the cancer under control.
When the company announced the EU Orphan Drug designation just over a year ago, Thomas Hanke, chief scientific officer, said, “Due to its novel mode of action, TGN1412 has the potential to provide a significant benefit to patients suffering from B-CLL, as demonstrated in recent preclinical studies.”
Hanke himself was at the Northwick Park Hospital in London yesterday, where the sick men are being treated, but in statement put out by the company he said, “The drug was developed in accordance with all regulatory and clinical guidelines and standards. In preclinical studies, TGN1412 has been shown to be safe and the reactions that occurred in these volunteers were completely unexpected.”
Camilo Colaco, chief scientific officer of the specialist immunology company Immunobiology Ltd in Cambridge, said he did not believe the adverse reaction caused by TGN1412 would affect the standing of antibody drugs in general.
“This is nothing to do with antibodies; in my opinion the problem is probably the target.”
TeGenero says that TGN1412-mediated T-cell activation and expansion in animal models is accompanied by the expression of anti-inflammatory cytokines, such as IL-10, rather than by the toxic cytokine storm of pro-inflammatory mediators induced by other agents that address the T cell receptor complex.
However, reports of the symptoms suffered by the volunteers at Northwick Park Hospital, including swelling, inability to breathe and organ failure, suggest they did experience a cytokine storm.
Colaco believes this may expose the shortcomings of preclinical testing on mice and other animals “The more we learn about the immune system, the more we realise that the mouse is not a good model for humans.”
“This mismatch may be a particular problem with CD28, where there is little, or no, cross reactivity between a human antibody and the mouse immune system.”
Science|Business spoke to a representative of TeGenero to request an interview on these issues, but the call was not returned at the time of going to press.
Best agreed there are unlikely to be implications for the wider antibody market, pointing out there is wide range of antibody drugs on the market, treating thousands of people.
After more than 20 years in development, antibody-based drugs are now a great success story for the biotech industry. In 2005 Humira, for treating rheumatoid arthritis became the first fully human monoclonal antibody discovered in Europe to attain blockbuster status. More than a dozen are on the market and total sales of antibody drugs now stand at over $10 billion per annum.
As to whether the terrible events will have implications for the UK’s standing as place for carrying out clinical trials Best said, “Don’t forget these are Phase I safety trials; new drugs may have adverse effects and that’s why you do these trials. A lot depends on whether the investigation shows there are general, as opposed to specific issues.”
Receive the Funding Newswire each Tuesday, our Policy Bulletin each Thursday, and news about bridging Europe’s east-west innovation gap twice a month in The Widening. 
A unique international forum for public research organisations and companies to connect their external engagement with strategic interests around their R&D system.
