NDA 211-765 (ubrogepant, AGN-241688)

Authors: Freed LM
Software: DILIsym®
Division: DILIsym Services
Therapeutic Areas: CNS, Neurology

Summary of selected (key) nonclinical findings

In the investigative hepatotoxicity assays using HepG2 (human hepatocellular carcinoma) cells and HepaRG spheroids (a metabolically active system) and a proprietary in silico analysis system, the effects of ubrogepant were compared to those of two other CGRP receptor
antagonists, for which development was discontinued because of hepatotoxicity. The results indicated that ubrogepant inhibited bile acid transporters, inhibited HepG2 oxygen consumption rate in a concentration-dependent manner (suggesting the potential to induce mitochondrial
toxicity), and exhibited “a modest induction of oxidative stress in HEPG2 cells,” considered an effect of ubrogepant itself rather than metabolite(s). Based on “Eight different clinical protocols of ubrogepant…investigated in SimPops,” the sponsor concluded that …despite in vitro results, no ALT elevations were predicted for any of the protocols tested…indicating that ubrogepant would be safe at doses up to 10-fold higher than the clinical dose in the hepatic safety clinical study (dosing 100 mg 2 days on, 2 days off for 56 days, 28 total doses).” The maximum recommended clinical dose for the proposed indication (acute migraine) is 200 mg/day, suggesting a 5-fold safety margin with a similar dosing regimen.

By Freed LM