Mechanistic Investigations Support Liver Safety of Ubrogepant

Abstract

Small-molecule calcitonin gene–related peptide (CGRP) receptor antagonists have demonstrated therapeutic potential for the treatment of migraine. However, previously investigated CGRP receptor antagonists, telcagepant and MK-3207, were discontinued during clinical development because of concerns about drug-induced liver injury. A subsequent effort to identify novel CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of ubrogepant. The selection of ubrogepant, following a series of mechanistic studies conducted with MK-3207 and telcagepant, was focused on key structural modifications suggesting that ubrogepant was less prone to forming reactive metabolites than previous compounds. The potential for each drug to cause liver toxicity was subsequently assessed using a quantitative systems toxicology approach (DILIsym®) that incorporates quantitative assessments of mitochondrial dysfunction, disruption of bile acid homeostasis, and oxidative stress, along with estimates of dose-dependent drug exposure to and within liver cells. DILIsym successfully modeled liver toxicity for telcagepant and MK-3207 at the dosing regimens used in clinical trials. In contrast, DILIsym predicted no hepatotoxicity during treatment with ubrogepant, even at daily doses up to 1000 mg (10-fold higher than the proposed clinical dose of 100 mg). These predictions are consistent with clinical trial experience showing that ubrogepant has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207.

Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults

“…MK‐3207, another gepant, was associated with delayed liver test abnormalities in phase I trials (ALT elevations following the discontinuation of MK‐3207 administration), which also led to discontinuation of its clinical development 23–25 . Integrated mechanistic data suggested that DILI associated with telcagepant and MK‐3207 was at least partly attributable to reactive metabolites 26 . In addition, it is believed that the formation of covalent adducts between MK‐3207 and endogenous liver proteins, which does not occur with atogepant, caused the delayed DILI.…”

“…[23][24][25] Integrated mechanistic data suggested that DILI associated with telcagepant and MK-3207 was at least partly attributable to reactive metabolites. 26 In addition, it is believed that the formation of covalent adducts between MK-3207 and endogenous liver proteins, which does not occur with atogepant, caused the delayed DILI. Atogepant is chemically distinct from telcagepant and MK-3207, and has characteristics hypothesized to be important for reducing the potential for DILI, such as greater potency and higher target engagement and, therefore, a lower dosing needed for clinical efficacy, and a reduced potential to form reactive metabolites.…”

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…Notably, the software was able to predict the safety profile for three potential migraine drug candidates. DILIsym successfully modeled the liver toxicity profiles of telcagepant and MK3207 and was also able to show the lower potential for hepatotoxicity with ubrogepant, an alternative migraine drug [63]. This ability to predict liver injury in drug development and also provide a better understanding of the mechanisms of DILI offers unique opportunities and promises in the hepatotoxicity field (Table 2).…”

“…While it was initially designed for one-time emergency contraception use, it has been approved for use for 3 months at a time for the treatment of uterine fibroids [71][72][73]. Several recent reports of Table 2 DILIsym predictions for telcagepant, MK-3207, and ubrogepant in a simulated patient population of healthy volunteers [63] ALT alanine aminotransferase, BID twice daily, N/A not applicable, q2h every 2 hours, QD once daily, ULN upper limit of normal hepatotoxicity associated with longer term use in fibroid treatment were found. For example, Meunier et al described a 58-year-old woman who developed fatigue, nausea, and abdominal discomfort followed by rising ALT/AST and international normalized ratio 2 months after beginning treatment with ulipristal acetate for symptomatic fibroids [74].…”

Gepants, calcitonin gene-related peptide antagonists, for abortive treatment of migraine: current status

“…36 Recent studies on mechanistic investigations in both in vitro and in vivo models support liver safety of ubrogepant and reported that it has lower potential to cause hepatotoxicity than has been observed with telcagepant and MK-3207. 35,37,38 It has also been reported that ubrogepant use is not associated medication overuse headache. 31,33…”