update

Bial cannot rule out link between BIA 10-2474 and lung lesions in study dogs

By Gareth Macdonald contact

- Last updated on GMT

Bial facility in Portugal
Bial facility in Portugal

Related tags: Pharmacology, Toxicology, Clinical trial

Bial says BIA 10-2474 met safety and tolerability requirements for human trials, but the firm cannot rule the drug out as the cause of lesions in dogs in a preclinical study.

Last night French newspaper Le Figaro​ reported that several dogs died during a toxicology study of BIA 10-2474, the candidate painkiller linked to the death of a human volunteer in a Phase I study halted in France last month​.

Bial – the Portuguese drugmaker developing BIA 10-2474 – told us the dogs were put down as a result of pulmonary lesions and “didn’t die of similar conditions or adverse effects verified in the volunteers​.”

The firm told us "this project of investigation was initiated in 2005, and studies with this compound began in 2009 with preclinical in vitro and in vivo pharmacological and toxicological evaluation.

"The results obtained in these preclinical studies have shown a safety and tolerability profile that allowed, in June 2015, the approval of the phase I clinical trial in humans with healthy volunteers by the French Regulatory Authorities and by the French Ethics Committee​."

Bial told us it cannot rule out the possibility that BIA 10-2474 was the cause of the pulmonary lesions in the dogs.

"We cannot say neither that it was nor that it was not​" the firm said, reitering that "the cause of the death of the two animals was not related to the adverse effects verified on the volunteers on the phase I clinical trial​."

François Peaucelle, director of French CRO Biotrial which ran the halted Phase I human study, told TV channel BFMTV​ preclinical data for BIA 10-2474 indicated it was safe to take into trials. 

Peaucelle said: “The conclusions of this [preclinical] study were sufficiently clear and clean to rule out any particular ambiguity about proceeding with human tests​.”

Preclinical toxicology​ 

BIA 10-2474 is a fatty acid amide hydrolase (FAAH) inhibitor. Inhibition of the enzyme results in the accumulation of fatty acid amides, one of which – anandamide – is thought to damp down neurones involved in the transmission of pain.

According to information released​ by Bial last month “animal toxicology studies of repeated daily dosing of BIA 10-2474 for up to 13 weeks in mice, dogs and monkeys and up to 26 weeks in rats have been conducted​.”

In dogs BIA 10-2474 had no major effects on arterial blood pressure (BP), heart rat, and on the PR, the QRS, the QT, and the QTc intervals. No arrhythmia or other changes in the morphology of the electrocardiogram which could be attributed to BIA 10-2474 were observed."

"Treatment with BIA 10-2474 produced no signs of toxicity in mice, rats, dogs and monkeys up to the no observed adverse effect level (NOAEL).”

Biotrial tweeted the following last night:

 

Biotrial study

The phase I study of BIA 10-2474 was halted last month​ after six male patients who had been given the highest does of the drug fell ill.

One of the men was declared brain dead and four others were hospitalised with neurological injuries. A sixth volunteer was sent to hospital as a precaution, but later discharged.

Related topics: Regulatory & Safety, Regulations

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