TeGenero Drug Too Perilous to Test on Healthy People
By: Administrative Account | Source: Bloomberg
May 2, 2006 6:10AM EST

May 2 (Bloomberg) -- An experimental drug that left six men with multiple-organ failure this year in London shouldn't have been tried first on healthy volunteers because it supercharged the immune system in a new way that wasn't fully understood, said researchers who reviewed the trial. Parexel International Corp., the Waltham, Massachusetts- based company that conducted the experiment, should have tried the medicine first in ill patients with no other treatment options, the researchers said. Testing lower doses one person at a time also would have cut the risk of the therapy. TeGenero AG, a six-year-old biotech company based in Wuerzburg, Germany, developed the product, a laboratory-produced antibody designed to treat arthritis, leukemia and multiple sclerosis. It acts on a biological switch in the body's immune system that no drug had previously targeted, TeGenero said. ``I would be very reluctant to use healthy volunteers for an antibody trial such as this,'' said Patrick Round, senior vice president of development at competing Cambridge Antibody Technology Group Plc. England-based Cambridge discovered Humira, an antibody drug for arthritis that is sold by Abbott Laboratories of Abbott Park, Illinois. The six test subjects were hospitalized for several weeks after severe reactions to injections of the TeGenero medicine at a Parexel facility in north London on March 13. Five of the volunteers have since been released, a hospital spokesman said today. The sixth may have to stay in the hospital for as long as six months, and is certain to lose the tips of three fingers, according to Ann Alexander, his London-based attorney. ``They all have major immune system issues and the prognosis for that is completely unclear,'' she said in an interview April 20. Worldwide Attention Clinical drug testing companies like Parexel often are hired by pharmaceutical makers to recruit healthy volunteers for the first human studies of a drug's safety and potency. The Parexel experiment attracted worldwide notice when it went awry in March. The test is being probed by the British Medicines and Healthcare Products Regulatory Agency. Parexel spokeswoman Jennifer Baird didn't respond to questions e-mailed to her on April 21. Wuerzburg authorities are still investigating if there is a basis for a charge of bodily harm resulting from negligence, spokesman Erik Ohlenschlager said April 27. TeGenero's drug, called TGN1412, was developed either to weaken or strengthen the immune system, depending on the dosage and the disease being targeted, according to research articles written by company scientists. `Atomic Bomb' Antibodies are part of the immune system's response to infections. Drugmakers have created laboratory-produced versions of the substances to mute overactive immune systems involved in diseases like rheumatoid arthritis. The lab-made antibodies counter inflammation at the heart of these diseases. Researchers familiar with the manner in which the TeGenero drug interacts with the immune system said they weren't surprised by the side effects that surfaced in the London study. ``Add an antibody and it's like dropping an atomic bomb'' into the body, Axel Ullrich, a molecular biologist at the Max- Planck-Institute for Biochemistry in Martinsried, Germany, said in an interview. Ullrich helped develop Genentech Inc.'s Herceptin cancer drug, a powerful antibody-based medicine. Scientists who have reviewed the London study say the medicine's novel nature should have led researchers to follow a more cautious approach. ``We really have to think about dosing the first group in intervals, and not all at the same time, in a first-in-man study,'' Christian Schneider, head of the antibody division at Germany's Paul Ehrlich Institute, the government's medicines regulator agency in Langen, Germany. High-Risk Drug As a result of the TeGenero study the institute will no longer allow antibody drugs that stimulate the immune system to be tested on more than one patient at a time in a first-in-human trial, spokeswoman Susanne Stoecker said. In addition, researchers said healthy volunteers shouldn't be exposed to a high-risk drug. Sick patients with few treatment options who might benefit from a drug are more appropriate subjects for a novel treatment. ``We can't expect patients to deal with the side effects of these drugs if they don't have some chance of a benefit,'' Dirk Jaeger, head of the medical oncology unit at Germany's University of Heidelberg, said in an interview. The Parexel consent form also didn't sufficiently inform the participants of TGN1412's possible dangers or depict the treatment as a new type of drug that can disrupt the body's immune system, three medical ethicists said in a Bloomberg News story April 10. Parexel Shares Following an interim report by the London-based Medicines and Healthcare Products Regulatory Agency, TeGenero said results indicate the side effects resulted from the drug itself, not from improper dosing or manufacturing. The controversy hasn't hurt Parexel's shares. They've risen 44 percent this year, including more than 5 percent since the volunteers were hospitalized. The company's revenue rose 2.9 percent last fiscal year, and April 27, the company said third- quarter net income rose 46 percent, almost three times as fast as sales. Parexel also raised its forecast for the fiscal year and for calendar 2006. The shares fell 4 cents, or 0.1 percent, to $29.47 yesterday in New York. The side effects might have been avoided if researchers used doses lower than are now often used in studies that test a drug for the first time in people, scientists say. Low-dose human tests have the potential to weed out dangerous products early, even those that appeared safe when tried in animals, according to Janice Reichert, senior research fellow at the Tufts Center for the Study of Drug Development in Boston, Massachusetts. `Concerns' TGN1412 had been tested in animals at doses ``500 times higher than the dose used in the trial,'' TeGenero said in an April 21 statement. ``Regulators in both the U.K. and Germany agreed that this should have provided a more than adequate safety margin.'' Schneider, of Germany's Ehrlich Institute regulatory agency, said ``there were concerns'' about the drug before the test. ``But the animal data didn't give us reason to expect anything bad,'' he said, noting that animal tests have a predictive value of 70 percent to 80 percent. The medicine's inflammatory side effect may be because it works in a unique way. The drug stimulates the immune system and overrides some of the body's safety circuits adding to its potency, company researchers had reported. The antibody leads to a ``strong activation'' of certain white blood cells in the immune system, according to a 2005 article in Annals of the Rheumatic Diseases by TeGenero's Chief Scientific Officer, Thomas Hanke and the co-chairman of the company's supervisory board, Thomas Huenig. Rousing the Defenders There are 18 antibody-based therapies on the market, 16 of them targeting cancer or an illness of the immune system such as multiple sclerosis or rheumatoid arthritis, according to data gathered by the Tufts drug study center. The drugs generated about $13 billion in worldwide sales last year, according to Bloomberg compiled data. They include Abbott's Humira arthritis treatment, and Herceptin and Avastin, cancer drugs produced by Genentech, the South San Francisco biotechnology company. Most these drugs work by switching off or muting the body's disease-defending immune system, not by rousing it as TeGenero's drug does, said Round of the Cambridge, England-based Cambridge Antibody. In the TGN1412 test, one part of the antibody may have undergone a process called ``crosslinking,'' when it binds to another one, multiplying the drug's effect, a report said in the April 13 issue of the British journal Nature, which cited scientists who work on antibodies. The amplification of the immune system may have led to massive inflammation that caused the volunteers' organs to shut down within hours after taking the drug, said Bernd Muehlbauer, head of the Institute of Clinical Pharmacology in Bremen, Germany and member of the ethics board in the German Bundesland Bremen, which appraises clinical trials in Bremen. ``This was not business as usual,'' Muehlbauer said.

To contact the reporter on this story: Eva von Schaper in Munich at evonschaper@bloomberg.net Last Updated: May 2, 2006 04:07 EDT