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Six hospitalized in Bial clinical trial in France

By John Brosky and Cormac Sheridan, Staff Writers

PARIS – One volunteer for a phase I trial of novel compound BIA 10-2474, designed to target pain relief by acting on cannabinoid receptors, has been pronounced brain dead, while five others were hospitalized with identical neurological symptoms at the University Hospital Center of Rennes in France.

The volunteers were among 90 enrolled since July 9, 2015, in a first-in-man trial conducted by Biotrial Research SAS testing BIA 10-2474, a compound developed by Bial-Portela & Ca. SA, of São Mamede do Coronado, Portugal.

The six volunteers, all men ages 28 to 49, began a protocol for multiple doses of the compound on Jan 7.

The trial protocol divided the other volunteers into cohorts receiving a single unit dose, one where the compound was taken with a meal, and one with placebo.

On Jan 10, the first of the six men taking multiple doses was hospitalized, and the others followed progressively, according to a chronology of events presented by French Minister of Health Marisol Touraine during a press conference Friday afternoon.

Biotrial halted the study on Jan. 11, and the French Ministry immediately recalled all volunteers enrolled in the trial for medical exams and personalized follow-ups.

"This is exceptionally serious," Touraine said, adding that to her knowledge there has never been an event of this magnitude for a clinical trial.

The French National Agency for Medication Safety (ANSM) was on site at Biotrial conducting an investigation ahead of the press conference; Touraine said she had also launched an on-site investigation at Biotrial by the Inspector General for Social Affairs.

Independent of the Health Ministry, the Office of the Procurer of Paris said it would investigate the incident for potential charges of involuntary injury through its public health enforcement section, also enlisting an intervention by the Gendarmerie in Rennes and the specialized Ministry of Justice Office for the Environment and Public Health.

Biotrial filed with ANSM on April 30, 2015. On June 26, 2015, it received approval of protocols and authorization to conduct the clinical trial for Bial.

A prospective volunteer forwarded to the French media a copy of the documents received from Biotrial that detail the goals for the study. The primary objective is stated to be an evaluation of tolerance for administering the drug orally. It describes BIA 10-2474 as a "product in development for the treatment of different medical conditions from anxiety to Parkinson's disease, but also for the treatment of chronic pain of sclerosis, cancer, hypertension or the treatment of obesity." The trial was to be concluded on Feb. 1.

Each volunteer was paid €1,900 (US$2,080) for participating.

ANSWERS NEEDED

A very basic question that will have to be addressed by the investigation that Touraine's ministry will undertake is whether the adverse events experienced by the six volunteers arose from the drug or from some form of contamination. It is difficult, however, to see how contamination of an oral drug would lead to brain death.

Another big question is whether the patients were dosed in parallel rather than sequentially. Cases like this were not supposed to occur following the introduction of new guidelines in the wake of the Tegenero trial of TGN1412 in London, in 2006, in which six volunteers experienced cytokine storm after receiving a CD28-targeting “superagonist.” That episode supposedly set new safety standards for trials of previously untested drugs. It is not clear whether those were followed in Rennes. 

Whatever the outcome of the investigation, it is clear at this point that the preclinical toxicity testing undertaken by Bial was tragically inadequate. The animal models it used were unable to predict the disastrous effects that the trial volunteers experienced in Rennes.

The pharmacology of cannabinoid receptors – a specialized class of G protein-coupled receptors – has been an active area of research for more than two decades, which makes the present case all the more mystifying. Of the two main types of cannabinoid receptor, CB1 receptors are mainly expressed in the neurons of the central nervous system and the peripheral nervous system, while CB2 receptors are expressed in immune cells in peripheral tissues, in the gastrointestinal system and in glial cells within the brain. Activation of both receptor types reduces the experience of pain in animal models. 

Bial has yet to disclose the precise mechanism of BIA10-2474, so it is unclear at this point whether the molecule was disastrously overactive or had a dangerous off-target effect. Either way, the trial in Rennes exposes poor standards in Bial's drug discovery and development processes and will further undermine public confidence in the safety of clinical trials conducted in Europe. 

 

See the next edition of BioWorld Today for more on this story.