PARIS – French regulators are investigating a phase I trial of small-molecule candidate BIA 10-2474 after one volunteer was pronounced brain dead and five others hospitalized with identical neurological symptoms at the University Hospital Center of Rennes in France, in what appears to be the worst clinical disaster since 2006's phase I study of monoclonal antibody TGN1412 put six healthy volunteers into intensive care.

The affected volunteers were among 90 enrolled since July 9, 2015, in the planned 128-subject first-in-man trial conducted by clinical research organization (CRO) Biotrial Research SAS testing the compound developed by Bial-Portela & Ca. SA, of São Mamede do Coronado, Portugal. BIA 10-2474 is designed to target pain relief by acting on cannabinoid receptors.

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 in a clinical trial.

Pierre-Gilles Edan, head of the neurology unit at the University Hospital Center of Rennes, said that four of the five other patients have presented with neurological disorders of varying degrees, though it was too early for a definitive diagnosis. He said the hospital's neurology team hovers between "hope and worry" for those patients.

The French National Agency for Medication Safety (ANSM) was on site at Biotrial conducting an investigation ahead of the press conference; Minister Touraine said she had also launched an on-site investigation at the CRO 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, 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 fashion rather than sequentially. Cases like this were not supposed to occur following the introduction of new guidelines in the wake of the Tegenero AG trial of TGN1412 in London in 2006, in which six volunteers experienced cytokine storm after receiving a CD28-targeting "superagonist." While an investigation by U.K. regulators determined that the adverse events with TGN1412 were due to an unexpected biological effect rather than any errors in manufacturing or administration, it did raise concerns that all the trial volunteers were injected with gaps of only 10 minutes. (See BioWorld Today, March 16, 2006, and May 26, 2006.)

The TGN1412 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 appears to 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.

In a press release Friday, Bial disclosed the mechanism of action of BIA 10-2474, which it said inhibits fatty acid amide hydrolase, or FAAH, an enzyme that hydrolyzes endocannabinoid anandamide and is believed to have promising analgesic effects. Bial maintained that development of the compound had proceeded "in accordance with all the good international practices guidelines, with the completion of tests and preclinical trials, particularly in the area of toxicology."

The firm added that BIA 10-2474 previously had been administered to 108 patients with no moderate or serious adverse reactions reported.

Whether and how last week's clinical disaster will affect Bial's prospects remains to be seen. Following the fiasco with TGN1412, Tegenero, of Wurzburg, Germany, despite having been cleared of any wrongdoing, was unable to raise any additional investments and had to close up shop. (See BioWorld Today, July 6, 2006.)

As a larger firm, Bial is better positioned to withstand the negative press. Founded in 1924, it is currently Portugal's largest pharma company. In addition to a marketed product – eslicarbazepine acetate is approved in both the U.S. and Europe as adjunctive therapy in adults with partial-onset seizures – Bial has other clinical and registration-stage programs in epilepsy, Parkinson's disease and pulmonary arterial hypertension.

The company said it will work with authorities to determine the causes of the adverse events in the BIA 10-2474 study.

Managing Editor Jennifer Boggs contributed to this story.