Safety, Tolerability, and Pharmacokinetics of FAAH Inhibitor BIA 10‐2474: A Double‐Blind, Randomized, Placebo‐Controlled Study in Healthy Volunteers

Abstract

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor, after first administration to healthy male and female participants. Participants (n = 116) were recruited into this phase I, double-blind, randomized, placebo-controlled, single ascending dose and multiple ascending dose (10-day) study. The primary outcome was the safety and tolerability of BIA 10-2474. Secondary outcomes were pharmacokinetics of BIA 10-2474 and pharmacodynamics, considering plasma concentrations of anandamide and three other fatty acid amides (FAAs) and leukocyte FAAH activity. Single oral doses of 0.25-100 mg and repeated oral doses of 2.5-50 mg were evaluated. BIA 10-2474 was well tolerated up to 100 mg as a single dose and up to 20 mg once daily for 10 days. In the cohort receiving repeated administrations of 50 mg, there were central nervous system adverse events in five of six participants, one with fatal outcome, which led to early termination of the study. BIA 10-2474 showed a linear relationship between dose and area under plasma concentration-time curve (AUC) across the entire dose range and reached steady state within 5-6 days of administration, with an accumulation ratio, based on AUC 0-24h , of <2 on Day 10. BIA 10-2474 was rapidly absorbed with a mean terminal elimination half-life of 8-10 hours (Day 10). 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.

De‐risking Clinical Trials: The BIAL Phase I Trial in Foresight

“…In this issue of CPT, 1 investigators from the company BIAL describe the ill‐fated experiment of 2016. The paper is co‐authored by company staff and two toxicology consultants.…”

“…and its supplement that contains the various publications with (references to) preclinical data on BIA 10‐2474. 1 More information on the IB‐de‐risk process, as well as examples of compounds with acceptable IB‐profiles, can be found elsewhere. 4 We also included data from the human phase I clinical trials that were performed.…”

Probability of Success in Drug Development

“…This was perhaps best illustrated by the dissection of the tragic BIA 10-2474 trial in a recent issue of CPT. [5][6][7] The fact that this compound attrited in phase I was of course completely dwarfed by the fatal outcomes of the trial in healthy volunteers. Such cases are (thankfully) very rare, and therefore determining risk of harm (RoH) cannot rely on the Bayesian principles underpinning the PoS framework.…”

“…If all successes are not equal, we should also not forget that not all failures are the same and that probability of failure (PoF) cannot simply be defined as PoF = 1‐PoS . This was perhaps best illustrated by the dissection of the tragic BIA 10‐2474 trial in a recent issue of CPT 5–7 . The fact that this compound attrited in phase I was of course completely dwarfed by the fatal outcomes of the trial in healthy volunteers.…”

A commentary on drug safety and genomics: Promising new agents may require expansion of guidelines for subject screening in clinical trials

“…The well-conducted classical nonclinical safety studies together with a demonstrated absence of concerning findings in the early clinical evaluation of BIA 10-2474 4 seem to call for a re-examination and expansion of the International Council for the Harmonization of Technical Requirements for Pharmaceuticals (ICH) testing paradigm, and specifically, the S2(R1) Genotoxicity Testing guidelines finalized in 2011 5 and subsequently adopted by the FDA in 2012. 6 New guidelines should modify the protocols to include more comprehensive and powerful predictive toxicology, perhaps encompassing some specific genomic fingerprinting of the test organism/subject, with an eye to systematic interrogation of the data that illuminates possible interactions between the agent being evaluated and the genetically determined drug metabolomics of the host.…”