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Apr
13

BIA 10-2474 saga continues – who knew what and when – and nobody comes out a winner

Apologies, recovering from some bug and my head is a bit fuzzier than usual so I hope this all makes sense. A day that started surreal and just kept going.

Straight out of the gate this morning I had an email from a journalist Damien Mascret from Le Figaro. I had never been in contact with this French newspaper before so to get an email was a complete surprise. The contents were odd. He sent me the copy of a Fax received anonymously regarding BIA 10-2474, (the compound that was in a clinical trial tragedy earlier in the year) and asked me to interpret it. It contained some sketched molecules and no explanation. I had a quick Skype call with Chris Southan who probably knows more about the lineage of these molecules than anyone in the world based on patents etc. So I theorized a bit and sent Damien links to the exhaustive digging from Chris Southan and posts herein. (Perhaps as this unfolds it will become clearer as to what it means.)

And then I thought nothing more until I looked at Le Figaro online tonight…Its the headline or at least it was at the time of writing.

I have tried to Google translate the article (see bottom of page), its probably not perfect but from what I can gather – bottom line the French medicines agency ANSM allegedly swept aside knowledge that there was an issue with the compound from preclinical studies and then Biotrial allegedly ignored side effects (neurological) seen in the clinic. Le Figaro have a massive scoop in getting to the bottom of this tragedy. Or is it really the bottom yet? I am hoping for a better translation of the article at some point but coming back to the fax that Le Figaro received really does make you question whats going on. Why is a national newspaper able to find out whats going on when it appears  the official commission cannot? Why are people in this day and age still faxing documents – is it really anonymous? This is certainly not some whodunit  but as this unfolds no one is coming out smelling of roses, not Bial, not Biotrial, not ANSM and especially not the official commission that supposedly is digging into this or at least has come to no conclusion, infact this would appear to now be contradicted.

I am pretty sure one day a book will be written about this.

 

***Google translate of Le Figaro article – this may not be a perfect translation***

Clinical trial: the document that overwhelms and Biotrial ANSM
INFO LE FIGARO – The confidential investigation report of the Medicines Agency is much more severe than that given by the official commission.

It is a document which will not help Biotrial. The company realized on behalf of the Portuguese Bial laboratory, the now infamous fatal clinical trial in Rennes. On 10 January, Guillaume Molinet, voluntary 2508 was admitted to the emergency. He died seven days later. Five others were also hospitalized, and some of them still have neurologic sequelae. This accident is the most serious ever happened in Europe in the context of a clinical trial.

In this context, on 18 January the National Drug Safety Agency (ANSM) prepare a confidential internal investigation report signed by the Director of Evaluation, Cécile Delval. This document seen by Le Figaro is overwhelming to the trial sponsor, Biotrial but for ANSM who authorized. Among the most troublesome issues for the agency include that on his clinical assessment of the drug to be tested. This is to replay and approval of the Portuguese laboratory protocol before its establishment in Rennes, in which involved two reviewers (clinical and non-clinical). The internal investigation and noted that “the non-clinical evaluator submitted its report (…) alerting the evaluator on a central nervous system neuro-effect” particularly because of the lesions observed in dogs, mice, rats and monkeys. Alas, this alert did not prevent the clinical evaluation ANSM concluded that “patient safety is ensured in this study.”

Worse, “the clinical evaluation report does not include the signals of the non-clinical evaluator of neurological effects observed in animals,” soberly notes the Director of Evaluation. Finally, the clinical report highlights that this is a first-in-man, but said “it is not a question of a product at risk.” A widely disputed today analysis.
Side effects

Another very embarrassing spot – this time for Biotrial – the occurrence of adverse effects at lower doses than that which led the volunteer died in hospital. These side effects were identified, at least blurred vision, by the temporary specialized scientific committee (CSST, mandated by the ANSM) in early March, but they were gone unnoticed. Thus, two volunteers (cohort MAD) who took 10 mg of the molecule presented on two occasions, blurred vision and diplopia (double vision). To volunteer in 2308, unrest occurred twice, each time 5:15 after taking the product. For voluntary 2305 diplopia occurred respectively 5:35 ET 8:35 after taking. Four episodes that each time lasted between 1 and 2 h 30. But “this finding was not considered relevant event by the investigator and the monitoring committee and, in fact, has not been found in volunteers of the 20 mg cohort, “yet concludes the CSST.

Other adverse reactions suspected to alert also observed at 10 mg, headaches. First in the volunteer 2303. Again, the CSST report only mentions that “cases of dizziness or mild headache.” Without specifying, unlike the internal investigation report Cécile Delval, that headache lasted … almost 29 hours. And this time, the effect is still observed at 20 mg, in another patient (the number 2404) for 47 hours. In total, four different volunteers (groups who ingested 10 mg and 20) who have submitted unusual side effects without worry Biotrial. Contacted by Le Figaro, the Rennes business, through his counsel, ensures that “signs that happen in life and who are neither widespread nor repeated” are not worrisome.

This explains the statement “no serious adverse events had been reported” before hospitalization and death of the volunteer who received 50 mg. A neurologist interviewed by Le Figaro is surprised that “lightness” of Biotrial “If, in a study of the central nervous system, signals such as blurred vision or headaches are not regarded as effects side, we walk on the head. ”
Include cannabis smokers

Moreover, the people Protection Committee (PPC, responsible for ensuring that each biomedical research project on human beings by the rules) has accepted the request of Biotrial include smoking cannabis or marijuana at height of two cigarettes a day, four times a week during the six months preceding the test. “This could be a confounding factor, but not necessarily dangerous,” notes Professor Danielle Piomelli, professor of neurobiology but also pharmacology and biological chemistry at the University of California at Irvine. His judgment is, however, much more severe as the transition to high doses. “The real problem with BIA 102474 (the test molecule, Ed) is that the very high cumulative dose reached in the Phase 1 trial has produced what we call an effect off target. Why now she has tested as high a dose? It is not very clear, he explained to Le Figaro. They knew that a much lower dose of the compound completely blocked FAAH (the “target”) in 3 days in humans. ”

He added: “They can answer it is normal to increase the dose in a Phase 1 to ensure that a compound is safe. This is true, but only up to a point. The exposure levels (blood and tissue) they wanted to achieve no sense based on the pharmacology of the compound. “One point obviously misunderstood by the CSST right note in his report of 15 February: “the increase of the doses administered, although of a type sometimes practiced in phase 1, appears problematic as too brutal end of progression while the opposite would have been expected.” and if the escalating problem dose was not his brutality, but its uselessness? Quite simply.

 

 

 

 

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