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The catastrophic outcome of a recent Phase I trial in Britain shocked the public and has prompted the United Kingdom to reexamine how it approves early human trials of
antibodies.
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The study began
-- and ended -- on March 13 when six healthy male volunteers at
London's Northwick Park hospital were injected with TGN1412, a humanized monoclonal antibody (MAb) developed by German firm TeGenero to treat autoimmune diseases and leukemia. The subjects rapidly experienced a massive autoimmune reaction called
"cytokine release syndrome", which put them in intensive care. Several needed prolonged organ support, but they all appeared recovered by early
April.
German pharma giant Boehringer Ingelheim manufactured the TGN1412 used under GMP conditions. The Phase I protocol was authorized by the United
Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) and conducted by clinical research organization Parexel at a custom-designed trials facility at Northwick Park. In a prepared statement, TeGenero said the compound had been extensively tested in animals
-- including primates -- with no sign of toxicity.
An interim report from MHRA said multiple causes are still being investigated, but that the most likely explanation is that the drug has a unique
"pharmacological effect" in humans.
Several pharmacology experts severely criticized the TGN1412 study and suggested MHRA should never have authorized it without
specialists' advice. "In hindsight, this was a disaster waiting to happen once this target and mode of action had been
chosen," commented clinical trials expert David Glover, former medical director of Cambridge Antibody
Technology.
Approximately 20 MAbs are already in widespread clinical use, and several are blockbusters. But Glover points out that most MAbs have a neutralizing action, whereas TGN1412 is an agonist. The drug possibly triggers release of the powerful immunostimulant cytokine interleukin-2 (IL-2) when it binds to the T-cell receptor CD28.
"That's a massive positive stimulus akin to putting your foot on the gas
pedal," said Glover. "Neutralizing antibodies are an intrinsically safer approach, more like gently easing off the
brakes."
TGN1412 is the first CD28-targeted product to reach the clinic and is also believed to be the first immunostimulant agonist to be tested in man. Moreover, it is a
"superagonist" that bypasses certain safeguards in the immune system and is therefore likelier to produced uncontrollable side effects. In addition, because of the immunological differences between species,
"Companies should be very wary about apparently reassuring signals from animal
data," said Glover.
Experts have also raised questions over the study protocol. Immunologist Gus Dalgleish of St.
George's Hospital in London and Glover, as well as former British Biotech clinical research chief Andrew Millar, suggested that patients should have been injected one at a time, instead of only a few minutes apart. That was also the recommendation of an editorial in the April 15 issue of The Lancet, which added that the trial disaster indicates that in Britain,
"urgent change is needed in the approval processes and regulation of Phase I trials of biological
agents."
Other safeguards could have mitigated the disaster, according to Glover. These include microdosing; the use of antibody fragments as the test compound, rather than a whole immunoglobulin; and testing the drug first on patients instead of healthy
volunteers.
As it waits for a final report on the incident, MHRA is taking interim steps. For now, any first-in-man trials of any MAb or other novel immune-targeting compound will not be allowed without additional expert
advice.
Weblink:
See the MHRA interim report and press release at
www.mhra.gov.uk.
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