Oral repeated-dose toxicity studies of BIA 10–2474 in cynomolgus monkeys

Weber, Klaus; Häcker, R; Hardisty, Jerold F.; Harris, Stephen B.; Hayes, A. Wallace

doi:10.1016/j.yrtph.2019.104547

Cited by 9 publications

(11 citation statements)

References 14 publications

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“…Thus, subjects were euthanized after the fourth administration of either 125 or 250 mg/kg/day. In addition, one female was euthanized after the third administration at 60 mg/kg although the other subjects (2 males and one female) completed the study which reached doses of 110 mg/kg/day for 14 days (Weber et al 2020). During the up-titration phase of the 4-week study one female was found dead after receiving four administrations each of 10, 25, and 50 mg/kg/day and nine at 75 mg/kg/day.…”

Section: Maximum Tolerated Dose (Mtd) Studies and Uptitration Periodsmentioning

confidence: 99%

“…During the preclinical development of BIA 10-2474, a comprehensive series of regulatory toxicology studies were performed to support the application for clinical studies. These have been published in detail (Hardisty et al 2020;Harris et al 2020;Hayes 2020;Hayes, Hardisty, Harris, Okazaki, et al 2020;Hayes, Pressman, Hardisty, et al 2020;Hayes, Pressman, Moser, et al 2020;Weber et al 2020). The purpose of this review is to provide an overview of those studies and to explore similarities and differences between the species tested (mouse, rat, dog, and primate) in terms of test item exposure and clinical and pathological signs.…”

Section: Introductionmentioning

confidence: 99%

“…Dose-range finding studies will not be discussed in detail, except where they support observations in the other studies. The results of the individual studies will not be presented in detail as they are already available in published reports (Hardisty et al 2020;Harris et al 2020;Hayes 2020;Hayes, Hardisty, Harris, Okazaki, et al 2020;Hayes, Pressman, Hardisty, et al 2020;Hayes, Pressman, Moser, et al 2020;Weber et al 2020). Instead, the data from the different studies and across species will be collated to explore effects that are either common across species or specific to one.…”

Section: Introductionmentioning

confidence: 99%

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Non-clinical toxicology evaluation of BIA 10-2474

Hayes

Weber²,

Moser

et al. 2021

Critical Reviews in Toxicology

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In 2016, one subject died and four were hospitalized with neurological symptoms during a clinical trial with the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474. The present paper reviews the regulatory toxicology studies that were carried out to support the clinical trial application for BIA 10-2474. Animal studies complied with national and international standards including European regulatory guidelines (e.g. EEC Council Directive 75/318/EEC and subsequent amendments). The CNS effects seen in the rat and mouse appear to be common in rodents in such studies and do not in principle seem to be of the type to generate a signal. 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.

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Section: Maximum Tolerated Dose (Mtd) Studies and Uptitration Periodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Non-clinical toxicology evaluation of BIA 10-2474

Hayes

Weber²,

Moser

et al. 2021

Critical Reviews in Toxicology

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“…During microscopic evaluation, axonal dystrophy of the fasciculus cuneatus in the posterior medulla oblongata, edema in the pars nervosa of the pituitary gland, and vacuolation of the submucosal (Meissner's) plexus ganglia in all gastrointestinal segments were observed in several animals. 17 All these findings were atrributed to nerve sheath edema formation that was deemed to be a pharmacological effect of BIA 10-2474. Based on the complete or partial reversibility of the in-life and microscopic findings in monkeys 17 and rats, 18 they were not considered to be adverse by the company, even though 1 monkey had died.…”

Section: Bia 10-2474mentioning

confidence: 99%

“…17 All these findings were atrributed to nerve sheath edema formation that was deemed to be a pharmacological effect of BIA 10-2474. Based on the complete or partial reversibility of the in-life and microscopic findings in monkeys 17 and rats, 18 they were not considered to be adverse by the company, even though 1 monkey had died. Wording in the protocol stated that animal toxicity 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 had been conducted and that treatment with BIA 10-2474 produced no signs of toxicity in mice, rats, dogs, and monkeys up to the NOAEL.…”

Section: Bia 10-2474mentioning

confidence: 99%

Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies

Baldrick

Cosenza²,

Alapatt

et al. 2020

Int J Toxicol

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A challenge for all toxicologists is defining what study findings are actually adverse versus non-adverse in animal toxicity studies, and which ones are relevant for generating a no observed adverse effect level (NOAEL) to assess human risk. This article presents views on this challenge presented by toxicologists, toxicologic pathologists, and regulatory reviewers at the 2019 annual meeting of the American College of Toxicology during a workshop entitled “Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings.” The speakers noted that setting a NOAEL is not always straightforward, not only for small molecules but also for biopharmaceuticals, and that a “weight of evidence” approach often is more useful than a rigid threshold-setting algorithm. Regulators from the US Food and Drug Administration and European Union told how assessment of adverse nonclinical findings is undertaken to allow clinical studies to commence and drug marketing approvals to succeed, along with the process that allows successful dialogs with regulators. Nonclinical case studies of findings judged to be adverse versus non-adverse were presented in relation to the many factors that might halt or delay clinical development. The process of defining adverse findings and the NOAEL in final study reports was discussed, as well as who should be involved in the process.

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Inactivation Mechanism of the Fatty Acid Amide Hydrolase Inhibitor BIA 10‐2474

et al. 2022

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BIA 10-2474 is a time-dependent inhibitor of fatty acid amide hydrolase (FAAH) that was under clinical development for the treatment of neurological conditions when the program was terminated after one subject died and four were hospitalized with neurological symptoms during a first-in-human clinical study. The present work describes the mechanism of FAAH inhibition by BIA 10-2474 as a target-specific covalent inhibition, supported by quantum mechanics and molecular modelling studies. The inhibitor incorporates a weakly reactive electrophile which, upon specific binding to the enzyme's active site, is positioned to react readily with the catalytic residues. The reactivity is enhanced on-site by the increased molarity at the reaction site and by specific inductive interactions with FAAH. In the second stage, the inhibitor reacts with the enzyme's catalytic nucleophile to form a covalent enzymeinhibitor adduct. 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. It forms a hydrogen bond with the imidazole nitrogen of the inhibitor and helps lowering the activation free energy of the first step of the reaction, by pre-orienting and stabilizing the inhibitor in a near-reactive configuration. In the second step, Thr236 can also serve as a mechanistic alternative to protonate the leaving group.[a] N.

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Oral repeated-dose toxicity studies of BIA 10–2474 in cynomolgus monkeys

Cited by 9 publications

References 14 publications

Non-clinical toxicology evaluation of BIA 10-2474

Non-clinical toxicology evaluation of BIA 10-2474

Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies

Inactivation Mechanism of the Fatty Acid Amide Hydrolase Inhibitor BIA 10‐2474

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