A phase II trial of an experimental drug that made headlines when it left human volunteers fighting for their lives is about to begin in Russia — as a potential treatment for rheumatoid arthritis.
The drug, then known as TGN1412, had caused six male volunteers in London to experience a ‘cytokine storm’ with devastating consequences. Fortunately they all survived but not without suffering long-term injuries.
The drug had previously been tested on cynomolgus monkeys but the researchers had overlooked subtle differences in the human immune system, according to an editorial by Adam Cohen from the Centre for Human Drug Research in the Netherlands.
This error was then compounded by a failure to calculate a starting dose on the basis of receptor occupancy.
Calculations made after the trial revealed that the starting dose was sufficient to cause approximately 90% of all CD28 receptors in the human body to be occupied by TGN1412 antibodies, Cohen wrote in the British Journal of Clinical Pharmacology.
Despite this outcome, and the subsequent bankruptcy of the company involved in the trial, a Russian investor purchased the rights to antibody TGN1412, which was then renamed TAB08.
After much more research (read Cohen editorial for more details) the Russian biotech company TheraMAB eventually conducted trials in humans using doses at 0.1% of the dose used in the London study.
No serious side effects were observed, and the results of the new trial were published in April of last year in the European Journal of Immunology.
The researchers are now conducting a follow-up study in patients with rheumatoid arthritis [ClinicalTrials.Gov registration number: NCT01990157].
The company’s ultimate goal is to develop the antibody into a drug that will down-regulate the inflammatory response in rheumatoid arthritis by selectively activating regulatory T cells, says Cohen and his co-author Marcel Kenter from The Netherlands Organisation for Health Research and Development.
“The extraordinary drug development route of TGN1412 demonstrates that innovative and potentially risky drugs can be tested safely in humans if researchers have sufficiently detailed insight into the mechanism of action and if informative preclinical studies and biomarkers are available for accurately predicting the effect in humans, thus providing a rational approach for determining a safe starting dose,” they concluded.