BIA 10 2474
/ Eisai
- LARVOL DELTA
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November 03, 2023
In vivo neuropathology: Detecting site-specific changes in neuroinflammation following treatment with low doses of known neurotoxins
(Neuroscience 2023)
- "To this end, we tested the neurotoxin trimethyltin (TMT), a gold standard for CNS toxicity; MK-801, an NMDA antagonist; kainic acid, a glutamate agonist; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); and BIA 10-2474, a FAAH antagonist. The ability for IVN to follow disease progression in the same rat over time, identifying specific brain areas at risk for neurotoxicity, is a huge advantage over traditional CNS toxicology methods. IVN offers an alternative to the traditional tests for assessing CNS neurotoxicity, can minimize the cost, expedite the process, and identify subtle changes in site-specific brain areas."
Preclinical • CNS Disorders • Vascular Neurology
September 03, 2023
3D ORGANOID MODELS FOR THE STUDY OF DRUG PERMEABILITY
(WCN 2023)
- " BIA-10-2474 is a long-acting inhibitor of fatty acid amide hydrolase (FAAH) that increases levels of the neurotransmitter anandamide in the central nervoussystem which failed in the Phase I trial... Blood brain barrier is diverse among species, so predicting the drug efficacy in preclinical studies are crucial for the failure of phase 1 clinical trials. Hence, 3D brain organoid model is very important and authenticated preliminary PK/PD clinical studies on dish. These models are used to study the neurotransmitters activity and disease-related biomarkers whose functions are still not well understood."
CNS Disorders
April 21, 2023
HARMONY: The Inspection Campaign of French Phase I/II Research Sites Following the BIA 10-2474 Accident
(clinicaltrials.gov)
- P1/2 | N=30 | Completed | Sponsor: Groupe Hospitalier Pitie-Salpetriere | Recruiting ➔ Completed | Trial completion date: Jul 2029 ➔ Apr 2023
Trial completion • Trial completion date
October 10, 2022
Brain-wide in situ visualization of cellular drug targets
(Neuroscience 2022)
- "We revealed potential off target binding sites of another FAAH inhibitor BIA10-2474, which is known to have clinical toxicity, and a distinct binding pattern of a monoamine oxidase inhibitor pargyline...More recently, we further optimized CATCH labeling kinetics, which allows for direct volumetric drug visualization, paving way for high-throughput, unbiased and brain-wide drug binding registration. In summary, CATCH represents the first endeavor to visualize in vivo drug binding with cellular resolution and opens exciting new opportunities for understanding drug actions in the brain."
CNS Disorders
July 20, 2022
Inactivation Mechanism of the Fatty Acid Amide Hydrolase Inhibitor BIA 10-2474.
(PubMed, Chembiochem)
- "The hydrolysis of this adduct is shown to be unlikely under physiological conditions, therefore leading to irreversible inactivation of FAAH. The results also reveal the important role played by FAAH Thr236 in the reaction with BIA 10-2474, which is specific to FAAH and is not present in other serine hydrolases."
Journal
January 11, 2022
BIA 10-2474: Some Lessons are Clear but Important Questions Remain Unanswered.
(PubMed, Clin Pharmacol Ther)
- No abstract available
Journal
May 20, 2021
Safety, Tolerability, and Pharmacokinetics of FAAH Inhibitor BIA 10-2474: A Double-Blind, Randomised, Placebo-Controlled Study in Healthy Volunteers.
(PubMed, Clin Pharmacol Ther)
- "BIA 10-2474 caused reversible, dose-related increases in plasma FAAs. In conclusion, we propose that these data, as well as the additional data generated since the clinical trial was stopped, do not provide a complete mechanistic explanation for the tragic fatality."
Clinical • Journal • PK/PD data
February 03, 2021
Non-clinical toxicology evaluation of BIA 10-2474.
(PubMed, Crit Rev Toxicol)
- "In the same way in non-human primates, insignificant alterations in the mesencephalon, and especially of the autonomic nervous system (Meissner's plexus in the bowel) in rodents and monkeys were observed in some animals treated with a high dose. Overall, these data, as well as the extensive additional data generated since the accident, support the conclusion that the tragic fatality that occurred during the clinical trial with BIA 10-2474 was unpredictable and that the mechanism responsible remains unknown, from a non-clinical toxicological perspective."
Clinical • Journal • CNS Disorders
January 26, 2020
Regulatory safety pharmacology evaluation of BIA 10-2474.
(PubMed, J Pharmacol Toxicol Methods)
- "In conscious dogs monitored by telemetry, BIA 10-2474 (20, 50 and 100 mg/kg p.o.) did not significantly modify arterial blood pressure as compared with controls (inter-group comparison), although a tendency toward an increase in arterial blood pressure was observed at 100 mg/kg, with systolic blood pressure being the most affected parameter. In conclusion, BIA 10-2474 had no adverse effects on any of the major vital organ systems, and, unfortunately, the data shed no further light on the mechanism(s) responsible for the clinical trial accident with BIA 10-2474."
Clinical • Journal • Gastrointestinal Disorder
December 25, 2019
Oral repeated-dose toxicity studies of BIA 10-2474 in CD-1 mice.
(PubMed, Regul Toxicol Pharmacol)
- "Toxicokinetic analysis in the 4- and 13-week studies showed that exposure was broadly dose-proportional with no evidence of accumulation. On the basis of the changes seen during the 13-week study, the NOAEL was established at 75 mg/kg/day."
Journal • Preclinical • Renal Disease
November 24, 2019
Developmental and reproductive toxicity studies of BIA 10-2474.
(PubMed, Regul Toxicol Pharmacol)
- "When administered during post-natal development to rats the maternal NOAEL was 6 mg/kg/day. The parental reproductive NOAEL, the NOAEL for viability and growth of the F1 offspring, the F1 parental NOAEL and the F1 reproductive NOAEL were all considered to be 20 mg/kg/day."
Journal
December 25, 2019
Oral repeated-dose toxicity studies of BIA 10-2474 in beagle dogs.
(PubMed, Regul Toxicol Pharmacol)
- "Because of the continued signs, the doses in both groups were further reduced to 20 mg/kg/day from day 77. Under the conditions of this study and given the severe signs recorded in groups treated at 100-50-20 and 50-35-20 mg/kg/day and only very occasional presence of signs in the group treated for the 13-week period at 20 mg/kg/day (abnormal respiratory sounds once in two animals), the dose of 20 mg/kg/day was considered the No Observed Adverse Effect Level (NOAEL)."
Journal • Infectious Disease • Movement Disorders • Ophthalmology • Pain • Pneumonia • Respiratory Diseases
November 24, 2019
Oral repeated-dose toxicity studies of BIA 10-2474 in Wistar rat.
(PubMed, Regul Toxicol Pharmacol)
- "Exposure to metabolites differed between sexes with higher concentrations of BIA 10-2445 in females compared to males, but the inverse for BIA 10-2583. Although a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day was concluded following the 4-week study, the histopathological findings at that dose in the 13- and 26-week studies resulted in the NOAEL being determined to be 10 mg/kg/day."
Journal • Preclinical • Gastrointestinal Disorder • Pain • Renal Disease
December 25, 2019
The absence of genotoxicity of a novel fatty acid amide hydrolase inhibitor, BIA 10-2474.
(PubMed, Regul Toxicol Pharmacol)
- "All tests were conducted with and without a rat liver S9 metabolic activation system. None of the test results were judged to be positive with regards to the mutagenicity/genotoxicity of BIA 10-2474 making it unlikely that any such effect was involved in the toxicity observed in the clinic."
Journal • Pain
December 10, 2019
Oral repeated-dose toxicity studies of BIA 10-2474 in cynomolgus monkeys.
(PubMed, Regul Toxicol Pharmacol)
- "Similar clinical signs and histological alterations as noted in monkeys of the 28-day study were observed in monkeys at 37.5 or 75 mg/kg/day. All findings recovered, and the dose of 75 mg/kg/day was considered the NOAEL."
Journal • Gastrointestinal Disorder • Movement Disorders • Pain
November 24, 2019
Commentary on BIA 10-2474.
(PubMed, Regul Toxicol Pharmacol)
- No abstract available
Journal
June 07, 2020
First-in-human dose: current status review for better future perspectives.
(PubMed, Eur J Clin Pharmacol)
- "Early phase clinical trials are basically foundation stones on which lies the entire onus of the later stages of development. Deciding FIH dose is a crucial step that necessitates the incorporation of detailed data from the preclinical stages and application of the most conservative approach for the safety/benefit of the volunteers in these studies."
Journal • P1 data
February 21, 2020
Shared Learnings on the New EMA First-in-Human and Early Clinical Trial Guideline: Proceedings From a DIAlogue Session at DIA Europe 2018.
(PubMed, Ther Innov Regul Sci)
- "Following the 2016 incident in France with BIA 10-2474, and in light of the substantial evolvement of how early clinical development has been undertaken during the last 10 years, for example, conducting integrated (FIH) studies that include multiple parts (eg, single ascending doses, multiple ascending doses, food effect), EMA decided to update the existing 2007 FIH guideline...Using two case studies as examples, the session participants discussed the nonclinical and clinical considerations for applying the newly revised recommendations, and interacted with a panel including regulators and industry representatives. The proceedings from this session reflect practical considerations for the implementation of the revised guideline."
Clinical • Journal • P1 data
January 30, 2020
Results of the 2017 inspection campaign of French phase I/II research sites in Île-de-France following the BIA 10-2474 accident: Medical vs. regulatory relevance.
(PubMed, Therapie)
- "Maintenance of on-site inspections periodically carried out by regulatory authorities granting authorisations to perform phase I/II trials are justified. However, the medical relevance of these inspections can be improved with more emphasis on factors affecting the safety of research participants than on administrative or purely regulatory issues."
Journal • P1/2 data
February 01, 2019
Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.
(PubMed, ACS Chem Biol)
- "Using alkynylated probes for click chemistry-ABPP in human cells, we show that des-methylated metabolites of BIA 10-2474 covalently modify the conserved catalytic cysteine in aldehyde dehydrogenases, including ALDH2, which has been implicated in protecting the brain from oxidative stress-related damage. These findings indicate that BIA 10-2474 and its metabolites have the potential to inhibit multiple mechanistically distinct enzyme classes involved in nervous system function."
Clinical • Journal
January 06, 2020
Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474.
(PubMed, Br J Pharmacol)
- "BIA 10-2474 potently inhibits FAAH in vivo, similarly to PF-04457845, but also interacts with a number of lipid processing enzymes, some previously identified in human cells as off-targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off-targets in the clinical trial accident remains unclear."
Journal • Preclinical
October 01, 2019
18 World Congress of Basic and Clinical Pharmacology: thought-provoking lectures on drug safety issues.
(PubMed, Expert Opin Drug Saf)
- "Areas covered: Of the 380 invited lectures, this report reviews the opening presentation on immune checkpoint inhibitors and three talks dealing with drug safety issues (irreproducibility of nonclinical data, clinical Phase 1 catastrophes by TGN1214 and BIA-102474-101 in healthy volunteers, and Phase I sentinel dosing to reduce risk to clinical study participants). Expert opinion: The nonclinical safety assessment of drug candidates preceding clinical investigations requires the adoption of more human predictable biological assays and a careful and critical analysis of all available knowledge on a candidate to ensure the safety of clinical trial participants."
Clinical • Journal
August 17, 2018
Discovery of a Potent, Long Acting and CNS Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.
(PubMed, ChemMedChem)
- "Lead optimization efforts carried out with benzotriazolyl- and imidazolyl-N-carboxamide series led to the discovery of clinical candidate 8l (BIA 10-2474) as a potent and long acting inhibitor of FAAH. However, during a Phase I clinical trial with compound 8l, unexpected and unpredictable serious neurological adverse events occurred affecting five healthy volunteers, including the death of one subject."
Journal
May 09, 2019
HARMONY: The Inspection Campaign of French Phase I/II Research Sites Following the BIA 10-2474 Accident
(clinicaltrials.gov)
- P1/2; N=30; Recruiting; Sponsor: Groupe Hospitalier Pitie-Salpetriere
New P1/2 trial
May 16, 2019
Shared Learnings on the New EMA First-in-Human and Early Clinical Trial Guideline: Proceedings From a DIAlogue Session at DIA Europe 2018.
(PubMed, Ther Innov Regul Sci)
- "...Following the 2016 incident in France with BIA 10-2474, and in light of the substantial evolvement of how early clinical development has been undertaken during the last 10 years, for example, conducting integrated (FIH) studies that include multiple parts (eg, single ascending doses, multiple ascending doses, food effect), EMA decided to update the existing 2007 FIH guideline...Using two case studies as examples, the session participants discussed the nonclinical and clinical considerations for applying the newly revised recommendations, and interacted with a panel including regulators and industry representatives. The proceedings from this session reflect practical considerations for the implementation of the revised guideline."
Clinical • Journal • P1 data
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