BIA 10-2474

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Structural formula
Bia 10-2474
General
Surname BIA 10-2474
other names

3- (1- (Cyclohexyl (methyl) carbamoyl) -1 H -imidazol-4-yl) pyridine-1-oxide ( IUPAC )

Molecular formula C 16 H 20 N 4 O 2
External identifiers / databases
CAS number 1233855-46-3
PubChem 46831476
Wikidata Q22082929
properties
Molar mass 300.36 g mol −1
safety instructions
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

BIA 10-2474 is an experimental inhibitor of fatty acid amide hydrolase , that of the Portuguese pharmaceutical company Bial Portela e C.ª, SA was developed. It interacts with the human endocannabinoid system . The drug was developed to pain relieve, for mood elevation to anxiety to deal with and the coordination of movements in neurodegenerative diseases to improve.

In a clinical study with the active ingredient on January 15, 2016 in Rennes ( France ), severe neurological side effects with one fatality occurred .

According to the French daily Le Figaro , BIA 10-2474 is 3- (1- (Cyclohexyl (methyl) carbamoyl) -1 H -imidazol-4-yl) pyridine-1-oxide.

Mode of action

Fatty acid amide hydrolase (FAAH) is a membrane- associated serine hydrolase that breaks down endogenous biologically active fatty acids , including the endocannabinoids anandamide and oleamide . FAAH is a crucial regulator of the signaling effect of anandamide in vivo and thus of the endogenous cannabinoid system that modulates pain perception. The effect of FAAH was proven using an animal model , knockout mice , which lack this enzyme. The animals have a 15-fold increased endogenous anandamide level in the brain and show, among other things, a reduced pain perception . The signal transduction of anandamide takes place by activating the cannabinoid receptor 1 (CNR1), the receptor that also mediates the effect of Δ 9 - tetrahydrocannabinol (THC) from Cannabis sativa , the active ingredient in marijuana . CNR1 is a G protein-coupled receptor that inhibits intracellular adenylate cyclase activity. The development of an FAAH inhibitor is therefore an attractive therapeutic goal, also as a substitute for marijuana-based therapies that have little social acceptance.

Phase I study

After corresponding tests on cell cultures and animal experiments , in 2015 BIAL commissioned the French research institute Biotrial in Rennes to conduct a phase 1 study with BIA 10-2474. Results from earlier stages of drug development have not been published. For safety reasons, phase 1 studies, the first human application, are started with low doses that are increased in the course of the study. According to the French Health Minister Marisol Touraine , the drug was tested in the first phase on 90 healthy volunteers (young healthy men) without serious complications. In addition, 18 other volunteer subjects received a placebo. In order to examine the compatibility of the substance, the substance was applied once.

Damage to health and death

In January 2016, a test group of six young healthy men was selected to be administered the test substance on consecutive days. After a preliminary examination, the administration began on January 7, 2016. According to the research institute, the first symptoms were observed on January 9 and the administration of the medication was therefore stopped the next day. The six men were admitted to the Rennes University Hospital. The substance attacked the central nervous system in five patients , one of whom suffered brain death that day and died a few days later. Among the five other participants, one was without symptoms. and could be released from the hospital. The three other test persons are feared permanent damage.

According to the clinic, the patients suffer from bleeding and necrosis in the brain. A forecast has not yet been made public. After the client of the study failed to provide information, the French daily Le Figaro published an English-language document of the study protocol on January 21, 2016. The study protocol explains that BIA 10-2474 should be used in cases where an increase in endogenous arachidonoylethanolamide (anandamide, AEA) can be beneficial. It is also mentioned that BIA 10-2474 was developed as a reversible, long-acting FAAH inhibitor with effects in the central and peripheral nervous system .

The occurrence of serious adverse events is extremely rare in phase 1 studies. The last known case with such severe effects was in 2006, when the monoclonal antibody TGN1412 caused multiple organ failure in six young men.

The French General Inspectorate for Social Affairs (IGAS), which is investigating the case, confirmed that the study as a whole had been properly approved, but criticized that various violations had occurred in its implementation. The contract research institute Biotrial did not obtain sufficient information about the health status of the first test subject before it had administered the next dose to the other test subjects. It also failed to inform the other test persons about the events of the previous day, so that they could not decide whether to continue participating in the study. Because of the seriousness of the incident, it should have been reported immediately to the drug authority ANSM and not, as was the case, four days after the delivery of the first test person and three days after the study was stopped. The final report should be available at the end of March.

Criticism and impact

The fact that BIAL, but also other pharmaceutical companies, in the early stages, especially after the incident, do not make any statements about the structure of the drug candidates, is criticized in scientific circles. The British Pharmacological Society has taken the new incident as an opportunity to publish a statement calling for more transparency and early access to all data in catastrophic cases like this. She cites the aviation industry's handling of incidents as a model. In particular, stricter rules are required, which provide that an entire group is not exposed to increased doses. The public criticizes that not only is BIAL uncooperative in providing information, but also that the French authorities are helping to withhold information. In response to the publication of the study protocol, the Royal Statistical Society published a statement calling for more details about the study, in particular the dosage, to be made public. At the same time, she criticizes the fact that the study protocol suggests that the recommendations published as a consequence of the TGN1412 incident in 2007 were not followed. In February 2016, in response to public criticism, details on the chronology of the study, in particular the dosage, were published. Accordingly, the study group of eight people was the fifth cohort to be administered BIA 10-2474 on consecutive days. Compared to the previous cohort, where there were no incidents, the dose was increased from 20 mg to 50 mg. Two subjects received a placebo.

After the incident became known, Johnson & Johnson announced that its subsidiary Janssen Pharmaceutica had interrupted two studies that were also investigating the effects of FAAH inhibitors. According to the company spokesman, no undesirable effects were observed in patients with anxiety disorders .

Web links

Individual evidence

  1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  2. ↑ Drame de Rennes: le protocole de l'essai clinique en accusation .
  3. ↑ Benjamin F. Cravatt, Dan K. Giang, Stephen P. Mayfield, Dale L. Boger, Richard A. Lerner, Norton B. Gilula: Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides . In: Nature . 384, No. 6604, 1996, pp. 83-87. doi : 10.1038 / 384083a0 .
  4. ↑ MH Bracey: Structural Adaptations in a Membrane Enzyme That Terminates Endocannabinoid Signaling . In: Science . 298, No. 5599, 2002, pp. 1793-1796. doi : 10.1126 / science.1076535 .
  5. ↑ Hui-Chen Lu, Ken Mackie: An Introduction to the Endogenous Cannabinoid System . In: Biological Psychiatry . 2015. doi : 10.1016 / j.biopsych.2015.07.028 .
  6. ^ CJ Fowler: The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review. Handbook of Experimental Pharmacology 231, 2015, pp. 95-128, PMID 26408159 .
  7. ↑ More details emerge on fateful French drug trial , editorial in Science Magazin (January 16, 2016).
  8. ↑ Researchers question design of fatal French clinical trial , Editorial in Nature (January 22, 2016, updated January 23, 2016).
  9. ↑ a b Spiegel.de: France: patient declared dead after drug test , January 18, 2016, accessed on February 2, 2016.
  10. ↑ What we know so far about clinical trial disaster in France , editorial in Science Magazin (January 15, 2016).
  11. ↑ drugmaker in fatal trial received EU funds .
  12. ↑ News Release - Phase I Clinical Trial Rennes . Archived from the original on January 22, 2016. Retrieved January 25, 2016.
  13. ↑ https://www.deutsche-apotheker-zeitung.de/news/artikel/2016/02/04/gesundheitsministerin-sieh-drei-bedeutende-verstosse-bei-biotrial
  14. ↑ Scientists in the dark after French clinical trial proves fatal , Editorial in Nature (January 18, 2016).
  15. ^ 'British Pharmacological Society (22 January 2016) Improve early access to data from catastrophic clinical trials: A statement on behalf of the British Pharmacological Society ( Memento from 25 January 2016 in the Internet Archive ).
  16. ↑ sueddeutsche.de: Now the cold-bloodedness of the industry is showing .
  17. ^ Declaration by the Royal Statistical Society
  18. ↑ Stephen Senn, Dipti Amin, Rosemary A. Bailey, Sheila M. Bird, Barbara Bogacka, Peter Colman, Andrew Garrett, Andrew Grieve, Peter Lachmann: Statistical issues in first-in-man studies . In: Journal of the Royal Statistical Society: Series A (Statistics in Society) . 170, No. 3, 2007, pp. 517-579. doi : 10.1111 / j.1467-985X.2007.00481.x .
  19. ^ [1] Study details (chronology).
  20. ↑ http://www.reuters.com/article/johnsonjohnson-drugtrial-idUSL2N1552YO .