France Tragedy: Molecule Likely Caused "Off Target" Effect
By Ed Miseta, Chief Editor, Clinical Leader
While many questions still surround the clinical tragedy in France, which resulted in the death of one patient and the hospitalization of four others, it seems certain at this point that the molecule administered to the patients is to blame, and not the CRO that conducted the study. Calling the reaction of the molecule on the brain “astonishing and unprecedented”, a report on the tragedy concludes there were no manufacturing issues and no genetic weaknesses common among the victims.
On January 17th one patient died and four others were critically ill, two with what may be permanent brain damage, at the Rennes University Hospital. They were undergoing a clinical trial conducted by Biotrial, a clinical research organization. The molecule being tested, BIA 10-2474, was developed by the Portuguese firm Bial and was intended to act on the cannabinoid receptor. The drug’s purpose is to block the action of brain enzyme FAAH (fatty acid amide hydrolase), which destroys cannabinoid produced by the body. It is now believed to have had an “off target” effect, activating other receptors of the nervous system.
In an article appearing on lemonde.fr, translated here, Dominique Martin, head of the National Drug Safety Agency and Health Products (ANSM), notes the intensity of side effects is generally correlated to the dose of a drug administered. However, in this instance, that was not the case. There were no warning signs from the first patients who were dosed with the medicine. Martin states, “it is as if a dam had burst.”
But according to a report released this week by experts appointed by ANSM, there is also an alternate possibility. A substance derived from the degradation of BIA 10-2474 may have been involved. That substance could have proved toxic to the nervous system of the afflicted patients. According to Martin, “both explanations are consistent with the neurological recognized by doctors. The fact that nothing like this has been observed in animals that received much higher doses, remains however, a mystery."
Similar molecules have been under development at pharma companies such as Pfizer, BMS, and J&J, but no serious side effects were ever reported. Two of the studies had been halted due to lack of efficacy.
The dosage amounts administered to patients have also been called into question. The last participant was administered 50 milligrams, which is ten times more than the dosage expected to completely inhibit FAAH. The report notes this dosage amount should be discussed further.
Additionally, the report is asking Bial, the clinical firm involved in the study, for additional information on their preclinical tests. The drug was reportedly tested on four animal species rather than two, which is usually the case. It also notes the deaths of two dogs and six primates during those tests, while not unusual, could have been better documented. The molecule was also tested on rats and mice, in addition to dogs and primates.
Although the molecule is being blamed for the adverse effects on patients, Biotrial is not completely off the hook. It has already been determined that the lab administered the dose to five additional patients the day after the first patient was hospitalized. Le Figaro has also reported that in addition to the animals that died during preclinical testing, others were left with serious side effects, similar to those seen in the human patients. Catherine Hill, a biostatistician who previously served on the ANSM's scientific advisory board, has been quoted as saying it was "a big mistake" to begin giving the six volunteers the drug on the same day. She notes a delay should have incorporated, and the lack of it created an "unreasonable protocol." The protocol also appears to be contrary to recommendations contained in the Duff Report, written after a trial in 2006 left several patients hospitalized.
A final meeting of the experts is expected to be held on March 24th, at which time more conclusions could be expected. ANSM has forwarded all the scientific documents in its possession to other health agencies, including the FDA and EMA.