Atogepant for the Preventive Treatment of Migraine

Ailani, Jessica; Lipton, Richard B.; Goadsby, PJ; Guo, Hua; Miceli, Rosa; Severt, Lawrence; Finnegan, Michelle; Trugman, Joel M.

doi:10.1056/nejmoa2035908

Cited by 146 publications

(216 citation statements)

References 31 publications

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“…The gepants in clinical use are in general well tolerated as proved in the RCTs during clinical development. Apart from infections of the upper respiratory, urinary and/or gastrointestinal tract, nausea (1.8–4.7% of patients on gepants) was the most common gastrointestinal complaint reported in phase 3 trials of ubrogepant, rimegepant and atogepant ( Croop et al, 2019 ; Lipton et al, 2019a , b ; Ailani et al, 2020 , 2021 ; Omaer et al, 2021 ). Diarrhea was noted in 2.5–2.7% of patients on ubrogepant ( Ailani et al, 2020 ) while constipation was reported in 6.9–7.7% of subjects taking atogepant ( Ailani et al, 2021 ), but were not noticed in the trials of the other gepants.…”

Section: Gastrointestinal Side Effect Profile Of Anti-calcitonin Gene-related Peptide Migraine Therapeutics In Pre-approval Clinical Triamentioning

confidence: 99%

“…Apart from infections of the upper respiratory, urinary and/or gastrointestinal tract, nausea (1.8–4.7% of patients on gepants) was the most common gastrointestinal complaint reported in phase 3 trials of ubrogepant, rimegepant and atogepant ( Croop et al, 2019 ; Lipton et al, 2019a , b ; Ailani et al, 2020 , 2021 ; Omaer et al, 2021 ). Diarrhea was noted in 2.5–2.7% of patients on ubrogepant ( Ailani et al, 2020 ) while constipation was reported in 6.9–7.7% of subjects taking atogepant ( Ailani et al, 2021 ), but were not noticed in the trials of the other gepants. The proven efficacy of gepants in migraine prevention and treatment provided ample evidence for an implication of CGRP in the pathophysiology of migraine and fostered efforts to explore other routes to target the CGRP system.…”

Section: Gastrointestinal Side Effect Profile Of Anti-calcitonin Gene-related Peptide Migraine Therapeutics In Pre-approval Clinical Triamentioning

confidence: 99%

“…Whether the real world constipation rates for other gepants will also be higher than those in the pre-approval RCTs remains to be examined. Such a post-approval evaluation is in particular awaited for atogepant which in one phase 3 trial was reported to cause constipation in 6.9–7.7% of patients ( Ailani et al, 2021 ).…”

Section: Constipation As An Adverse Effect Of Calcitonin Gene-related Peptide and Calcitonin Gene-related Peptide Receptor Antibodies In mentioning

confidence: 99%

“…In its quest to explain whether constipation caused by anti-CGRP therapeutics can be explained by antagonism of the physiological role of CGRP in the intestine, this review was based on the disparity between the comparably low rates of constipation seen in the pre-approval RCTs of antibodies targeting CGRP or its receptor and the much higher rates reported in post-approval real-world surveys. Constipation was noted only in one RCT of atogepant ( Ailani et al, 2021 ) and fremanezumab ( Ferrari et al, 2019 ) but in three phase 3 trials of erenumab ( Goadsby et al, 2017 ; Tepper et al, 2017 ; Takeshima et al, 2021 ) although in five other RCTs of erenumab ( Sun et al, 2016 ; Dodick et al, 2018a ; Reuter et al, 2018 ; Goadsby et al, 2020 ; Hirata et al, 2021 ) constipation went unmentioned. It was unforeseen, therefore, that substantial rates of constipation in patients treated with erenumab, fremanezumab and galcanezumab (see Table 1 ) were reported in post-approval surveys.…”

Section: Mechanistic Basis Of Constipation Caused By Anti-calcitonin Gene-related Peptide Migraine Therapeuticsmentioning

confidence: 99%

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Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide’s Motor-Stimulating and Prosecretory Function in the Intestine

Holzer

Holzer‐Petsche

2022

Front. Physiol.

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The development of small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and of monoclonal antibodies targeting the CGRP system has been a major advance in the management of migraine. In the randomized controlled trials before regulatory approval, the safety of these anti-CGRP migraine therapeutics was considered favorable and to stay within the expected profile. Post-approval real-world surveys reveal, however, constipation to be a major adverse event which may affect more than 50% of patients treated with erenumab (an antibody targeting the CGRP receptor), fremanezumab or galcanezumab (antibodies targeting CGRP). In this review article we address the question whether constipation caused by inhibition of CGRP signaling can be mechanistically deduced from the known pharmacological actions and pathophysiological implications of CGRP in the digestive tract. CGRP in the gut is expressed by two distinct neuronal populations: extrinsic primary afferent nerve fibers and distinct neurons of the intrinsic enteric nervous system. In particular, CGRP is a major messenger of enteric sensory neurons which in response to mucosal stimulation activate both ascending excitatory and descending inhibitory neuronal pathways that enable propulsive (peristaltic) motor activity to take place. In addition, CGRP is able to stimulate ion and water secretion into the intestinal lumen. The motor-stimulating and prosecretory actions of CGRP combine in accelerating intestinal transit, an activity profile that has been confirmed by the ability of CGRP to induce diarrhea in mice, dogs and humans. We therefore conclude that the constipation elicited by antibodies targeting CGRP or its receptor results from interference with the physiological function of CGRP in the small and large intestine in which it contributes to the maintenance of peristaltic motor activity, ion and water secretion and intestinal transit.

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Section: Gastrointestinal Side Effect Profile Of Anti-calcitonin Gene-related Peptide Migraine Therapeutics In Pre-approval Clinical Triamentioning

confidence: 99%

Section: Gastrointestinal Side Effect Profile Of Anti-calcitonin Gene-related Peptide Migraine Therapeutics In Pre-approval Clinical Triamentioning

confidence: 99%

Section: Constipation As An Adverse Effect Of Calcitonin Gene-related Peptide and Calcitonin Gene-related Peptide Receptor Antibodies In mentioning

confidence: 99%

Section: Mechanistic Basis Of Constipation Caused By Anti-calcitonin Gene-related Peptide Migraine Therapeuticsmentioning

confidence: 99%

See 2 more Smart Citations

Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide’s Motor-Stimulating and Prosecretory Function in the Intestine

Holzer

Holzer‐Petsche

2022

Front. Physiol.

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“…At the time of writing, several abstracts are available as first results of the new phase III trials. The phase III trial ADVANCE (NCT03777059) [ 57 ], analysed 873 participants with episodic migraine, randomized in this occasion to four groups, consisting of atogepant at 10 mg, 30 mg or 60 mg doses or a placebo. The efficacy endpoint was similar to the phase IIb/III trial and was fulfilled in all the branches.…”

Section: Resultsmentioning

confidence: 99%

New Generation Gepants: Migraine Acute and Preventive Medications

Pérez‐Fernández

Villar-Martínez

Goadsby

2022

JCM

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Migraine is a debilitating disease whose clinical and social impact is out of debate. Tolerability issues, interactions, contraindications, and inefficacy of the available medications make new options necessary. The calcitonin-gene-related peptide (CGRP) pathway has shown its importance in migraine pathophysiology and specific medications targeting this have become available. The first-generation CGRP receptor antagonists or gepants, have undergone clinical trials but their development was stopped because of hepatotoxicity. The new generation of gepants, however, are efficacious, safe, and well tolerated as per recent clinical trials. This led to the FDA-approval of rimegepant, ubrogepant, and atogepant. The clinical trials of the available gepants and some of the newer CGRP-antagonists are reviewed in this article.

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Rates of Response to Atogepant for Migraine Prophylaxis Among Adults

et al. 2022

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Key Points Question What is the distribution of responder rates to the oral, small-molecule, calcitonin gene–related peptide receptor antagonist atogepant for preventing migraine? Findings In a secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial of 902 adults with migraine, all doses of atogepant significantly increased the proportion of participants who achieved a 25% or greater, 50% or greater, 75% or greater, and 100% reduction in mean monthly migraine-days during 12 weeks of treatment. The atogepant and placebo groups reported similar rates of treatment-emergent adverse effects. Meaning Atogepant appears to be effective and well tolerated for the preventive treatment of migraine as measured by 4 levels of the clinically meaningful end point of responder rates.

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Atogepant for the Preventive Treatment of Migraine

Cited by 146 publications

References 31 publications

Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide’s Motor-Stimulating and Prosecretory Function in the Intestine

Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide’s Motor-Stimulating and Prosecretory Function in the Intestine

New Generation Gepants: Migraine Acute and Preventive Medications

Rates of Response to Atogepant for Migraine Prophylaxis Among Adults

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