Washington Editor

Regulators in the UK have concluded preliminarily that a so-called "cytokine storm" recently caused serious side effects in six Phase I patients, leading to restrictions for now on future first-in-man trials targeting the immune system.

The Medicines and Healthcare products Regulatory Agency (MHRA) released these early conclusions on Wednesday, just weeks after a study of an investigational monoclonal antibody called TGN1412 resulted in the hospitalization of six men who received the drug almost simultaneously. TGN1412, a compound from Wurzburg, Germany-based TeGenero AG, was in early development for rheumatoid arthritis.

The Phase I trial's protocol was approved by authorities in Germany and the UK, and it took place at a single hospital in London. Eight healthy volunteers were recruited, and six received the drug March 13; the other two received placebo. Later that day, all six who received TGN1412 had a serious adverse event - a life-threatening incident of cytokine-release syndrome, which occurs when the substance release by activated T cells produces a type of systemic inflammatory response.

The MHRA was notified a day later. (See BioWorld Today, March 16, 2006.)

Its investigation remains ongoing, and until that work is completed, the agency said it would take a precautionary approach for all further clinical trial applications involving initial human trials of any monoclonal antibody, regardless of the intended target, or other new molecules targeting the immune system and acting through a new mechanism. "Such trials will be not be authorized without having had additional expert opinion on whether the effects seen in the TGN1412 case may be repeated in relation to those substances," MHRA officials said in a statement.

When all investigations are complete, the agency will release more definitive findings and conclusions. Already, the MHRA blamed the side effects on "an unpredicted biological action of the drug in humans," and discounted manufacturing, formulation, dilution or administration errors. Outside observers already had reached those conclusions. (See BioWorld Today, March 30, 2006; March 31, 2006; and April 3, 2006.)

Notably, the resulting side effects were not foreseen by "apparently adequate" preclinical testing, the MHRA concluded. German authorities at the Paul Ehrlich Institute were in agreement, noting that the preclinical data did not raise major concerns, and that the animal model had been considered relevant.

But in hindsight, regulators in Germany said that because TGN1412 interfered with a master switch in the immune system in a new way, targeting a complex immune system process known as co-stimulation, there should have been a sequential inclusion of patients into this initial clinical study to avoid mass mishaps such as what happened. In Germany, such a rule is being implemented before approving similar protocols in the future.

No German patients were included in the study of TGN1412, a trial conducted under the watch of a contract research organization, Waltham, Mass.-based Parexel International Inc. It was to have included 32 patients, divided into four cohorts of eight. In each of those groups, six patients were to receive active doses of the test drug, and the other two were to receive placebo.

Of the six men admitted to the hospital, two had been released as of last week.

The MHRA's continuing investigation includes a panel of experts from the fields of immunology, toxicology and clinical trials. They will consider what could be necessary to better transition from preclinical to first-in-man studies, with an interim report due in three months.

Changes from the FDA could come about as a result of that final investigation.