BioWorld International Correspondent

MUNICH, Germany - German authorities are considering tightening regulations on human testing for new drug candidates following the hospitalization of six men involved in a Phase I trial for TeGenero AG, of Wuerzburg, Germany.

As of press time, the condition of four patients had improved, but two remained critical.

"I cannot imagine that this [event] will pass without consequences for the standards for clinical trials," Johannes Loewer, president of the Paul Ehrlich Institute in Langen, Germany, told German press. The Paul Ehrlich Institute assumed responsibility for approving human clinical trials in mid-2004 and had approved TeGenero’s trial. Loewer added that it is possible that additional preclinical tests will be required before human trials are approved, and he acknowledged that such procedures would add to the costs of developing new medications.

The first measure that the institute will consider is whether the testing of new compounds should begin with a single subject, rather than several simultaneous subjects.

Loewer said that mistakes by his institute in the approval of TGN1412 "were not identifiable at this time."

The antibody had been manufactured by Boehringer Ingelheim GmbH, of Ingelheim, Germany, which said that it could presently find no errors in its production. The company added that it would welcome "all measures that place protection of patients at the forefront."

Unlike antibody drugs such as Herceptin and Humira that dampen down an immune response, TGN1412 is an agonist, designed to boost production of T cells.

TeGenero calls TGN1412 a Super Monoclonal antibody, because in contrast to the natural immune response in which two signals are needed to prompt the production of T cells, the product is capable of activating the CD28 receptor directly. That bypasses the need to stimulate the T-cell antigen receptor (TCR).

While the company said on its website that property should have general use in cancer and autoimmune disorders, TGN1412 was being developed for B-cell chronic lymphocytic leukemia, B-CLL, a chronic disease which is closely linked to dysfunction of T lymphocytes.

The proposed mode of action suggests enhanced activation of T lymphocytes by treatment with TGN1412 "is expected to result in fewer infections and better control of the cancer," TeGenero’s website said.

The website also said that a pronounced T-cell activation and expansion mediated by CD28-SuperMAB in animal models is accompanied by the expression of anti-inflammatory cytokines, like interleukin-10, rather than by the toxic cytokine storm of pro-inflammatory mediators induced by other agents that address the TCR complex.

Accuracy Of Animal Models Questioned

The event is leading immunologists to question the use of animal models in testing drugs against highly specific targets in the human immune system. It also has been pointed out that although the role of CD28 in B-CLL may be understood, the breadth of its role in the healthy immune system is not.

In addition to investigations by the Medicines and Healthcare products Regulatory Agency (MHRA) in London, the state prosecutor’s office in Wuerzburg has begun an investigation. In German law, the opening of an investigation does not signal that criminal charges are under consideration; rather, it signals that the state has an interest in making an official determination of the facts of an incident.

The German Association of Research-Based Pharmaceutical Companies (known by its German acronym, VFA) said that cases like the TeGenero test are extremely rare. "Such serious side effects of a test have not been seen in Europe in the last 15 years," the organization said.

TeGenero was founded in 2000, and TGN1412 was its first product to reach clinical trials. The company, which has fewer than 20 employees, identifies and develops novel immunotherapeutic antibodies and aims to aid cancer-related deficiencies in the immune system and to treat autoimmune/inflammatory diseases. Investors include HBM BioVentures, of Zurich, Switzerland, and BioM AG, of Munich, Germany.

BioWorld International Correspondent Nuala Moran contributed to this article.