3. • A drug that left one person dead and
four others with suspected brain
damage in a controlled trial had killed
several dogs in a previous test.
• Details of earlier testing of the molecule
cannot be published because of
industrial secrecy.
• Le Figaro said that pre-clinical trial of the
drug had left “a number” of dogs dead
and others with neurological damage.
4. • The molecule was produced by Portuguese drug maker Bial and tested in
healthy human volunteers in a phase I study by the French contract research
company Biotrial in Rennes.
• BIA 10-2474 inhibits an enzyme called fatty acid amide hydrolase (FAAH),
which breaks down endocannabinoids in the brain.
5. • FAAH inhibitors might help treat anxiety, chronic pain, or
neurodegenerative disorders such as Parkinson’s disease.
• Although other drug developers, including Pfizer, had already
dropped FAAH inhibitors because of disappointing efficacy studies,
most of the molecules were shown to be safe, as FDA confirmed.
6. • Primary objectives of the study:
• Safety and tolerability of BIA 10-2474 after single and multiple oral doses
• Effect of food on the pharmacokinetic (PK) and pharmacodynamics (PD) of BIA 10-
2474.
• Secondary objectives:
• PK profile of BIA 10-2474 (and its metabolites) after single and multiple oral doses
• Concentrations of N-arachidonoyl-ethanolamine (AEA) and related fatty acid
amides, and to assess several potential PD effects.
• It was a double-blind, randomized, placebo-controlled combined
single ascending dose (SAD) and multiple ascending dose (MAD)
study, including an additional food interaction part (which is an
open-label design), and a PD part.
• The study was conducted at the single center, and the persons were
to participate for the maximum of 13 weeks.
8. • Volunteers who were subjected to
multiple doses of test drug were
adversely affected.
• MRI of the affected patients showed
evidence of deep cerebral hemorrhage
and necrosis.
• Administration of the next dose of the
test drug to the remaining persons after
the occurrence of serious adverse event
is not ethical.
9. • However, Bial did not suspect that the
acute symptom was due to the test drug
and thus gave the next dose to remaining
five persons on the following day.
• The Trial was discontinued only after the
first volunteer who was hospitalized went
into coma; but by that time, the next dose
was already administered to the remaining
five persons of that cohort.
• These persons were also hospitalized later
due to the occurrence of adverse effects.
• The state prosecutor has opened an inquiry into how the trial was
carried out.
• A preliminary report absolved Biotrial, Bial and the French drug safety
agency Agence Nationale de Sécurité du Médicament (ANSM), which
approved the trial, of wrongdoing.
• Bial has published the protocol for the administration of the drug but
refuses to divulge more information on pre-clinical trials.
10. • Health agencies such as the US FDA, EMA, National Agency for the
Safety of Medicines, and Health Products (ANSM) has joined hands to
investigate the cause for this tragic trial.
• Possible causes can be divided into two categories: human error and
off-target action of the investigational drug.
11. • The researchers used a technique called activity-
based protein profiling, which allowed them to
screen the molecule’s activity against a very large
group of enzymes in living human cells.
• They found that at higher concentrations, the Bial
drug disrupted the activity of several lipases,
enzymes that break down fatty acids; the Pfizer
drug, by contrast, did not.
• One of the off-target enzymes is called PNPLA6;
previous studies have linked defects in the gene
encoding for PNPLA6 to rare neurological disorders.
12. • The results suggest that BIA 10-2474 may disrupt how neurons in the
cerebral cortex metabolize lipids.
• The researchers can’t be sure that the off-target effects actually
caused the brain damage seen in the volunteers, however.
13. • There is no evidence for a causal relationship yet.
One way to find out might be to analyze samples
of the deceased volunteer’s brain.
• The off-target effects can be species-dependent,
which could explain why studies in rats and mice
did not identify the drug’s danger.
• But Bial could have known about the risk if it had
thoroughly screened for off-target effects in
human cells, that’s what Pfizer did with its FAAH
inhibitor.
14. • No FAAH inhibitor is yet approved for
therapeutic use.
• Maybe in future, FAAH inhibitors which are
reversible, highly specific, with shorter
duration of action, and better safety profile
are developed.
• Bial welcomes “any study” that could help
shed light on the incident.
• In the wake of the case, the European
Medicines Agency is developing stricter rules
for “first-in-human” studies.
15. • Man left brain-dead after French drug trial dies in hospital,
www.theguardian.com
• New clues to why a French drug trial went horribly wrong Hinnerk
Feldwisch-Drentrup, www.sciencemag.org
• Journal of Pharmacology & Pharmacotherapeutics
• What failed BIA 10–2474 Phase I clinical trial? Global speculations and
recommendations for future Phase I trials Rimplejeet Kaur, Preeti
Sidhu, and Surjit Singh, Pubmed
• Ncbi.nlm.nih.gov
Editor's Notes
of them were admitted to hospital, out of which one of the volunteer was declared brain dead and other four, out of remaining five were said to have irreversible brain damage.
