A day after news broke about a clinical research tragedy in France, more details are beginning to emerge about what happened at Biotrial, the private research company in Rennes where the phase I study took place. An information sheet for prospective trial participants, posted yesterday at the French regional news site Breizh-info.com, provides an overview of the study's goal and procedures, while also offering a glimpse of what it's like to partake in a lengthy drug safety study.
According to the document, which is in French, participants in this particular study group were to receive €1900, including travel expenses; in return, they agreed to stay at Biotrial's facility in Rennes for 2 weeks, swallow a drug on 10 consecutive days, undergo extensive medical tests, and provide at least 40 blood samples.
Meanwhile, the Portuguese pharmaceutical company that sponsored the trial, Bial, confirmed in a statement issued last night that the drug tested in the study was an inhibitor of fatty acid amide hydrolase (FAAH), an enzyme that breaks down so-called endocannabinoids in the brain. FAAH inhibitors have been proposed as a possible treatment against chronic pain.
The study was halted on Monday, and all six patients who had taken the drug were hospitalized; one is brain-dead, four others have neurological symptoms of varying severity, while one is under observation but without symptoms, neurologist Gilles Edan of the University of Rennes Hospital Center said yesterday. MRI imaging has shown "deep, necrotic, and hemorrhagic lesions in the brain[s]" of the patients, Edan said.
Neither Biotrial nor Bial have confirmed the authenticity of the document on Breizh-info.com. But several details suggest it is indeed the information provided to healthy volunteers who were considering participating in the study before it started. The sheet describes a study of BIA 10-2474, a compound that Bial lists as being in phase I tests on its drug pipeline. Several potential therapeutic applications mentioned in the sheet match information provided by French health minister Marisol Touraine at a press conference yesterday.
The timing is consistent as well; according to the document, participants in this particular trial group had to stay at the Biotrial facility from 4 January through 18 January; the first of 10 daily doses of BIA 10-2474 was to be administered on the third day of their stay. (Touraine said yesterday that drug administration began on 7 January.) Breizh-info.com says the document was provided by someone who applied to be enrolled but was rejected.
According to the document, the trial enrolled nonsmoking men and women aged between 18 and 55 who had a body mass index between 19 and 30. The plan was to give patients BIA 10-2474 every day between the third and thirteenth day of their stay at the clinic, while they underwent an extensive battery of tests and sampling—including as many as nine blood collections on some days. On the first and last day of drug administration, patients' heart rates were to be monitored around the clock while all of their urine was collected for analysis. (Between day three and nine, however, all they apparently had to do was take BIA 10-2474 and provide a single blood sample.) They were due to be released on 18 January but had to come back for a final check-up and more sampling on 1 February.
FAAH breaks down a series of compounds in the body called endogenous cannabinoids, the best known of which is anandamide. These molecules activate cannabinoid receptors—the same ones that bind THC, the key component of cannabis. BIA 10-2474 is designed to inhibit FAAH, and thus slow the breakdown of endogenous cannabinoids, which might help fight pain. But Biotrial's information sheet lists a wide range of other possible therapeutic applications, including anxiety, motor problems in Parkinson's disease, multiple sclerosis, cancer, hypertension, and obesity.
Pfizer tested another FAAH inhibitor as a possible painkiller for patients with osteoarthritis of the knee, but reported in 2012 that it didn't work in a phase II study. The trial didn't reveal any serious side effects from that drug, however.
Why BIA 10-2474 would cause such severe damage is unclear. Bial says that the new drug had already been administered to 108 patients "without any moderate or serious adverse reaction." But phase I clinical trials usually start with single or lower doses; the six patients may have been the first to receive multiple doses.
It's possible that BIA 10-2474 drug has completely unexpected effects because it binds to another target besides FAAH, molecular pharmacologist Stephen Alexander of the University of Nottingham in the United Kingdom said in a statement distributed by the Science Media Center (SMC) today; such "off-target" interactions might only become dangerous with more extensive exposure. "Another option is a dosing accident, where patients were given far more than clinicians thought was in the dosage form," neuropharmacologist Ben Whalley of the University of Reading in the United Kingdom added, also in an SMC statement.
French authorities have already announced three investigations into the tragedy, with which Bial promised to cooperate. "Several BIAL representatives are currently at the site to monitor the situation with the research center and the hospital, ensuring the necessary cooperation with these entities, as well as with the relevant authorities," the statement says.