23 Jul New clues why the Phase I drug trial of Biotrial France has gone horribly wrong
In January last year a Phase I trial on BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor, produced by the Portuguese drug maker Bial and tested in healthy volunteers by the French contract research company Biotrial in Rennes, led to the death of 1 volunteer and produced mild-to-severe neurological symptoms in 4 others.
At the 2016 PharMed CRO Forum in Montreal, François Peaucelle, Executive Director of Biotrial France spoke about the study protocol and the Biotrial crisis management, impacts and lessons to take. However no clue for the reason of this tragic incident was provided.
A new study shows that the compound BIA 10-2474 has effects on many other enzymes in addition to the one it was supposed to inhibit. The results suggest that BIA 10-2474 may disrupt how neurons in the cerebral cortex metabolize lipids, the research team reports in Science.
The researchers used activity-based protein profiling, a technique, which allowed them to screen the molecule’s activity against a very large group of enzymes in living human cells. They found that at higher concentrations, the Bial drug disrupted the activity of several lipases, enzymes that break down fatty acids; the Pfizer drug, by contrast, did not. Previous studies have linked one of the off-target enzymes PNPLA6 to defects in the gene encoding for PNPLA6 to rare neurological disorders.
These “off-target” effects might explain why the drug caused serious side effects, going to irreversible brain damage. Bial could have known about the risk if it had thoroughly screened for off-target effects in human cells; that’s what Pfizer did with its FAAH inhibitor, says the chemical biologist Mario van der Stelt from the Leiden University.
Jürg Gertsch, a biochemist at the University of Bern, says it’s “unbelievable” that Bial did not do a more extensive study of the drug’s effects before giving it to humans. The new study indicates that in addition to FAAH, the BIA 10-2474 compound targeted several different lipases and substantially altered lipid metabolism in cultured neurons.
The neuropharmacologist Daniele Piomelli from the University of California, Irvine, says the doses given to the volunteers in the group where the accident occurred were also unnecessarily high, because full inhibition of FAAH occurred at a much lower level. This even raised questions what was the real objective of the study.
This is the second such incident with serious consequences since the 2006 TGN1412 Phase I trial of TeGenero. In both cases the trial started with an initial dose, 500 and resp. 1000 times smaller than what was found safe in animal studies, In the wake of the Biotrial case, the European Medicines Agency started developing stricter rules for “first-in-human” studies.