The Medicines and Healthcare products Regulatory Agency (MHRA) in London is investigating the hospitalization of six men who took part in a Phase I trial of TGN1412, an immunomodulatory humanized agonistic anti-CD28 monoclonal antibody designed to treat chronic inflammatory conditions and leukemia.

The men were admitted Monday evening to the critical care unit of Northwick Park Hospital after an undisclosed inflammatory disorder emerged, affecting some organs. As of late Wednesday, two remained in critical condition, while the other four were in serious condition but showed some signs of improvement.

TGN1412 was developed by TeGenero AG, of Wurzburg, Germany, which hired the clinical research organization Parexel International Inc., of Waltham, Mass., to run the Phase I trial. The study began in the fourth quarter.

The MHRA requires clinical investigators to report all adverse events immediately to the agency. Parexel said it did just that, and the agency suspended its clinical trial authorization Tuesday, shortly after the hospitalizations.

"It is too early for us to talk about the cause of this incident," Stephen Hallworth, a spokesman for the MHRA, told BioWorld Today. "We have our inspectors down at the site. They’re down there, and they are starting investigations" to find out specifically what happened.

In preclinical studies, TGN1412 gave no indication of the severe reactions experienced by the volunteers. The trial enrolled eight young healthy men, two of whom received placebo, at Parexel’s clinical pharmacology unit located in Northwick Park Hospital. All six of those hospitalized received the drug. The trial was designed to evaluate tolerability.

The product is a fully humanized CD28-SuperMAB. TeGenero has highlighted TGN1412’s potential in enhancing cell-mediated antitumor immunity and induction of tumor-cell apoptosis, and the drug gained orphan medicinal product designation from the European Medicines Agency a year ago for B-cell chronic lymphocytic leukemia. It also was being evaluated in multiple sclerosis and rheumatoid arthritis.

A representative from TeGenero declined comment, but pointed BioWorld Today to a public statement posted on the company’s website. It quotes CEO Benedikte Hatz, and said, in part, that the "events were completely unexpected and do not reflect the results we obtained from initial laboratory studies." It continued, adding that Parexel "adhered to standard clinical research guidelines."

It is unclear as to how long the MHRA investigation will take, said Aisling Burnand, chief executive of the BioIndustry Association in London, who added that her organization hopes to receive an answer soon in order to allay public concerns.

"It’s incredibly, incredibly rare, if not unprecedented, for this sort of thing to have happened," she told BioWorld Today, emphasizing that the safety of monoclonal antibody drugs in general should not be in question. There currently are 17 monoclonal antibody drugs on the market worldwide, all of which passed thorough clinical safety studies.

Of those approved in the U.S., several were developed by South San Francisco-based Genentech Inc.: Rituxan, for non-Hodgkin’s lymphoma; Herceptin, for metastatic breast cancer; Xolair, for asthma; and Raptiva (co-developed with XOMA Ltd.) for psoriasis. The first monoclonal antibody approved was Orthoclone (Johnson & Johnson) in 1986 for allograft rejection, and one of the most recent approvals, in February 2004, went to Erbitux, ImClone Systems Inc.’s drug for colorectal cancer. The New York-based company recently received approval to expand the drug’s use into head and neck cancer. (See BioWorld Today, March 3, 2006.)

Still, immunologists do question the safety of the drugs, especially when Biogen Idec Inc., of Cambridge, Mass., and Elan Corp. plc, of Dublin, Ireland, were forced to suspend marketing in early 2005 of the antibody multiple sclerosis drug Tysabri only three months after receiving marketing clearance in the U.S., due to serious side effects of progressive multifocal leukoencephalopathy. The FDA expects to make a decision late this month as to whether to re-introduce Tysabri to the market. An advisory committee has advocated its return. (See BioWorld Today, March 9, 2006.)

Burnand said monoclonal antibodies, in general, have a good track record, as does the MHRA in regulating clinical trials. Whereas the FDA approved Tysabri based on only one-year data, instead of the two-year data normally required, because of its profound efficacy rates, TGN1412 entered its Phase I study meeting all the same parameters put upon every other drug ready for early clinical trials.

"Clearly, there are lessons to be learned from this," Burnand said. "They will be put into play and clearly adhered to, but we need to make sure we have all of the facts before we decide whether any system needs to change."

In the meantime, the six men who participated in the trial are being treated with therapies aimed at the immune system, said Ganesh Suntharalingam, clinical director of intensive care at Northwick.

The hospital is doing its best to treat the patients considering the "unique set of circumstances," he said. "We are also collaborating closely with colleagues in the UK and overseas to draw on the skills of other specialists."

Late in the day Wednesday, TeGenero issued this final statement: "There is no further human testing of TGN1412 being pursued."