Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults

Peter J. Goadsby; Stewart J. Tepper; Paul B. Watkins; Girma Ayele; Rosa Miceli; Matthew Butler; Lawrence Severt; Michelle Finnegan; Armin Szegedi; Joel M. Trugman; Abhijeet Jakate

doi:10.1177/0333102419869918

Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults

Peter J. Goadsby, Stewart J. Tepper, Paul B. Watkins, Girma Ayele, Rosa Miceli, Matthew Butler, Lawrence Severt, Michelle Finnegan, Armin Szegedi, Joel M. Trugman, Abhijeet Jakate^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

Abstract

Background: Ubrogepant is a novel, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants. Methods: In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18–50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability. Results: Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation. Conclusion: Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity. Trial Registration: NA.

Original language	English
Pages (from-to)	1753-1761
Number of pages	9
Journal	Cephalalgia
Volume	39
Issue number	14
DOIs	https://doi.org/10.1177/0333102419869918
Publication status	Published - 1 Dec 2019

Keywords

aminotransferases
CGRP
gepant
healthy participants
migraine

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10.1177/0333102419869918

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Goadsby, P. J., Tepper, S. J., Watkins, P. B., Ayele, G., Miceli, R., Butler, M., Severt, L., Finnegan, M., Szegedi, A., Trugman, J. M., & Jakate, A. (2019). Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults. Cephalalgia, 39(14), 1753-1761. https://doi.org/10.1177/0333102419869918

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title = "Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults",

abstract = "Background: Ubrogepant is a novel, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants. Methods: In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18–50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability. Results: Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation. Conclusion: Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity. Trial Registration: NA.",

keywords = "aminotransferases, CGRP, gepant, healthy participants, migraine",

author = "Goadsby, {Peter J.} and Tepper, {Stewart J.} and Watkins, {Paul B.} and Girma Ayele and Rosa Miceli and Matthew Butler and Lawrence Severt and Michelle Finnegan and Armin Szegedi and Trugman, {Joel M.} and Abhijeet Jakate",

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doi = "10.1177/0333102419869918",

language = "English",

volume = "39",

pages = "1753--1761",

journal = "Cephalalgia",

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T1 - Safety and tolerability of ubrogepant following intermittent, high-frequency dosing

T2 - Randomized, placebo-controlled trial in healthy adults

AU - Goadsby, Peter J.

AU - Tepper, Stewart J.

AU - Watkins, Paul B.

AU - Ayele, Girma

AU - Miceli, Rosa

AU - Butler, Matthew

AU - Severt, Lawrence

AU - Finnegan, Michelle

AU - Szegedi, Armin

AU - Trugman, Joel M.

AU - Jakate, Abhijeet

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Background: Ubrogepant is a novel, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants. Methods: In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18–50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability. Results: Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation. Conclusion: Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity. Trial Registration: NA.

AB - Background: Ubrogepant is a novel, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants. Methods: In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18–50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability. Results: Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation. Conclusion: Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity. Trial Registration: NA.

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KW - CGRP

KW - gepant

KW - healthy participants

KW - migraine

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DO - 10.1177/0333102419869918

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AN - SCOPUS:85073952122

SN - 0333-1024

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JO - Cephalalgia

JF - Cephalalgia

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ER -

Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults

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Keywords

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