A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine

Voss, Tiffini; Lipton, Richard B.; Dodick, David W.; Dupre, Nicole; Ge, Joy Yang; Bachman, Robert; Assaid, Christopher; Aurora, Sheena K.; Michelson, David

doi:10.1177/0333102416653233

Cited by 225 publications

(174 citation statements)

References 30 publications

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“…53,90,91,130,148,167,184 More recently, RCTs using humanized monoclonal antibodies to CGRP or to the CGRP receptor have shown efficacy in patients with migraine. 20,21,54,55,173 For instance, a 12-week study in patients with episodic migraine demonstrated that the humanized monoclonal antibody galcanezumab reduced the frequency of migraine headache days with low incidence of adverse events.…”

Section: Calcitonin Gene–related Peptide Migraine and The Trigemmentioning

confidence: 99%

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

Pain

459

364

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Calcitonin gene–related peptide (CGRP) is a 37-amino acid peptide found primarily in the C and Aδ sensory fibers arising from the dorsal root and trigeminal ganglia, as well as the central nervous system. Calcitonin gene–related peptide was found to play important roles in cardiovascular, digestive, and sensory functions. Although the vasodilatory properties of CGRP are well documented, its somatosensory function regarding modulation of neuronal sensitization and of enhanced pain has received considerable attention recently. Growing evidence indicates that CGRP plays a key role in the development of peripheral sensitization and the associated enhanced pain. Calcitonin gene–related peptide is implicated in the development of neurogenic inflammation and it is upregulated in conditions of inflammatory and neuropathic pain. It is most likely that CGRP facilitates nociceptive transmission and contributes to the development and maintenance of a sensitized, hyperresponsive state not only of the primary afferent sensory neurons but also of the second-order pain transmission neurons within the central nervous system, thus contributing to central sensitization as well. The maintenance of a sensitized neuronal condition is believed to be an important factor underlying migraine. Recent successful clinical studies have shown that blocking the function of CGRP can alleviate migraine. However, the mechanisms through which CGRP may contribute to migraine are still not fully understood. We reviewed the role of CGRP in primary afferents, the dorsal root ganglion, and in the trigeminal system as well as its role in peripheral and central sensitization and its potential contribution to pain processing and to migraine.

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Section: Calcitonin Gene–related Peptide Migraine and The Trigemmentioning

confidence: 99%

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

Pain

459

364

View full text Add to dashboard Cite

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“…45 Development of telcagepant was ultimately discontinued due to significant elevations of liver transaminase levels. 47 AEs were similar to placebo, with the most common being dry mouth, nausea, fatigue, dizziness, and somnolence. 46 Ubrogepant (MK-1602) has been studied for acute migraine treatment.…”

Section: Cgrp Receptor Antagonists (Gepants)mentioning

confidence: 84%

“…41,43 It was tolerated in patients with coronary artery disease 44 and stable angina. 47 Ubrogepant 100 mg was significantly superior to placebo for 2-hour pain freedom (25.5% vs 8.9%). 37 The development of another gepant, MK-3207, was also discontinued due to delayed liver test abnormalities.…”

Section: Cgrp Receptor Antagonists (Gepants)mentioning

confidence: 89%

“…37 The development of another gepant, MK-3207, was also discontinued due to delayed liver test abnormalities. 47 Two phase 3 studies (ACHIEVE I, ACHIEVE I) showed significantly higher than placebo pain freedom rate and absence of most bothersome symptom at 2 hours, and frequency of AEs <5%. A phase 2b randomized, doubleblind, placebo-controlled trial compared ubrogepant (1, 10, 25, 50, 100 mg) to placebo.…”

Section: Cgrp Receptor Antagonists (Gepants)mentioning

confidence: 99%

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Novel Medications for the Treatment of Migraine

2019

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Objective To describe the new classes of medication for headache management and their roles in clinical practice. Background Calcitonin gene‐related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of medications – the gepants and the CGRP monoclonal antibodies (mAbs) – for both acute and preventive treatment. A third class, the ditans, is being developed to target the 5‐HT1F receptor to provide acute treatment without vasoconstrictive effects. Methods This article reviews the pathophysiology of migraine that has led to these new pharmacologic developments. Available information from randomized controlled trials, abstracts, press releases, and relevant preclinical studies is summarized for each class of medications. Results At the time of this writing, one ditan has been submitted to the U.S. Food and Drug Administration (FDA) for approval. One gepant is anticipated to be submitted within the first quarter of 2019, and others are in clinical trials. Three CGRP mAbs have been FDA approved and are now available in clinical practice, and a fourth was submitted in the first quarter of 2019. Conclusions The development of new migraine‐specific classes of medications provides more treatment options for both acute and preventive treatment of migraine.

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“…Unfortunately, development was complicated by pharmacokinetic issues and for telcagepant and MK-3207 by hepatotoxicity. Ubrogepant is still under development for acute treatment [34] and atogepant for prevention (NCT02848326). Despite initial setbacks, these clinical trials have provided the proof of principle that targeting the CGRP pathway can effectively treat migraine.…”

Section: Clinical Trialsmentioning

confidence: 99%

Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?

Tso

Goadsby

2017

Curr Treat Options Neurol

137

121

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Opinion statementMigraine is a very disabling disorder with severe impact on patients’ lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder.

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A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine

Abstract: This trial supports ubrogepant's efficacy and provides further evidence that CGRP-RAs are viable options for the acute treatment of migraine.

Cited by 225 publications

References 30 publications

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Novel Medications for the Treatment of Migraine

Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?

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