A preliminary report compiled by the French National Agency for Medicines and Health Products Safety (ANSM) regarding the recent fatal clinical trial at a laboratory in Rennes has found that the high dosage administered to some participants is likely to have produced “off-target effects.” The report suggests not enough research into dosage efficacy was conducted prior to beginning the trial, and therefore says that more stringent guidelines on dosage selection be followed in future.
Taking place in January this year, the trial sought to investigate the effects of a painkiller called BIA 10-2474. A total of 90 participants were given various dosages of the drug, with the six who received the highest concentration of 50 milligrams ending up hospitalized. Of these, one died while the other five were left with severe brain damage.
BIA 10-2474 was designed to inhibit an enzyme called fatty acid amide hydrolase (FAAH), which breaks down a neurotransmitter called anandamide. As part of the body’s endocannabinoid system, anandamide helps to regulate a range of physiological processes including pain sensation, appetite and mood.
According to the ANSM report, previous research regarding the effect of BIA 10-2474 on animals had suggested that FAAH can be fully inhibited using a dosage around 40 times lower than that administered in the trial.
The ANSM has therefore called for the company behind the trial to provide more information regarding why this dosage was chosen. The report also questions the dosage increases used in the study. For instance, while the groups of participants receiving the lowest dosages were administered 2.5 and 5 milligrams respectively, the two highest-dosage groups were given 20 and 50 milligrams. Clearly, the jump in dosage between groups is not equal, which is why the ANSM has requested clarification on the scientific logic behind these figures.
In light of this, the report has also called for new procedures to be put in place ensuring that sufficient preclinical research is conducted to establish suitable dosage increases for all future clinical trials.
As a possible explanation for the harmful effects of high dosages BIA 10-2474, the report suggests that once all FAAH has been inhibited, leftover quantities of the drug act upon other enzymes, interrupting a range of biological processes. Additionally, previous research has shown that, in the absence of FAAH, anandamide is broken down by an alternative process known as the cyclo-oxygenases pathway, which may generate neurotoxic side-products.
The committee behind the report is due to meet again on March 24, when further evidence will be presented and reviewed.
