Experimental drug that injured UK volunteers resumes in human trialsBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h1831 (Published 02 April 2015) Cite this as: BMJ 2015;350:h1831
A phase II trial of an experimental drug that made headlines nine years ago when it caused horrific injuries to volunteers in a London trial is about to begin in Russia to evaluate it as a potential treatment for rheumatoid arthritis.
The drug, known as TGN1412, attained brief worldwide notoriety when six paid volunteers, all young men, were admitted to hospital for intensive care soon after being given what was believed to be a minute dose by a contract research organisation in Northwick Park Hospital, London.1 The men experienced a cytokine storm, an extreme autoimmune reaction leading to multiple organ failure. One lost his fingertips and toes to necrosis. Another was described by hospital staff as looking like “the elephant man” after his head ballooned. All had lasting injuries.
But the drug is set for a “potentially triumphant return,” an editorial in the British Journal of Clinical Pharmacology has argued. “TGN1412 was a chilling example,” wrote an editor, Adam Cohen, of how “a sophisticated product could be destroyed by inadequate development.”2
The injured men were compensated after a legal battle, and the drug’s developer, TeGenero, founded by researchers from the University of Würzburg, Bavaria, went bankrupt. But the disastrous trial continued to be studied at Würzburg and in the United Kingdom.
In late 2006, before investigators could establish what had gone wrong, the commercial rights to TGN1412 were acquired by a Russian investor. The drug was renamed TAB08 and was developed further by the Russian biotechnology company TheraMAB.
Soon after, researchers at Würzburg and in Britain gained new insights into the drug’s effects on T cells. The drug’s developers had hoped that it would preferentially activate regulatory T cells, suppressing autoimmune inflammation. They had initially tested it on cynomolgus monkeys (a species of macaque), in whose T cells the drug’s target CD28 receptor closely resembles the human version. Their starting dose in the human trial had been just 0.2% of the final dose tested on the monkeys.
But they overlooked subtle differences in the human immune system that cause other, pro-inflammatory immune cells to also carry CD28 receptors accessible to the drug. The error was compounded by TeGenero’s failure to calculate a starting dose on the basis of receptor occupancy. Normally, when potential agonists are tested on important body systems, the initial dose is calculated so that a maximum of 10% of available receptors might potentially be occupied. When this calculation was belatedly made after the event, it showed that the dose used had been enough to occupy 90% of all CD28 receptors in the human body.
This knowledge led Russian researchers to begin a phase I trial with a dose 0.1% of that given in London, then to titrate upwards. At 5% of the London dose, they concluded, regulatory but not inflammatory T cells were activated.3 A phase II trial will begin this June in Russia, TheraMAB’s chief executive, Dmitry Tyrsin, told Reuters, and the company is seeking approval to extend the trial to the United States later this year. Trials in patients with lupus and psoriasis are also planned.
“This is good news for the whole industry,” Tyrsin said. “It shows that if you plan preclinical development in the right step-wise way, then you can safely develop potentially risky drugs.”
Cite this as: BMJ 2015;350:h1831