Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial

Lipton, Richard B.; Croop, Robert; Stock, David A.; Madonia, Jennifer; Forshaw, Micaela; Lovegren, Meghan; Mosher, Linda; Coric, Vladimir; Goadsby, Peter J.

doi:10.1016/s1474-4422(22)00517-8

Cited by 63 publications

(85 citation statements)

References 26 publications

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“…The favorable safety results observed in these studies are consistent with findings from previous separate assessments of the ODT and oral tablet forms of rimegepant, which identified no safety concerns and found that the tolerability of rimegepant was comparable to placebo (5,7,9,10).…”

Section: Discussionsupporting

confidence: 88%

“…Rimegepant is an orally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist that has demonstrated efficacy in the acute and preventive treatment of migraine (5)(6)(7)(8)(9). A previous dose-ranging trial with rimegepant determined that the optimal dose in migraine, 75 mg, provided relief that was comparable to sumatriptan 100 mg (10).…”

Section: Introductionmentioning

confidence: 99%

“…A previous dose-ranging trial with rimegepant determined that the optimal dose in migraine, 75 mg, provided relief that was comparable to sumatriptan 100 mg (10). Two oral formulations of rimegepant have been evaluated in phase 3 trials: an ODT (6,9) that is the marketed formulation and an earlier development formulation of a conventional oral tablet (5,7,8). The pharmacokinetic (PK) profiles of rimegepant ODT and oral tablet have not previously been directly compared, nor has their bioequivalence been ascertained.…”

Section: Introductionmentioning

confidence: 99%

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Bioequivalence of rimegepant, a small molecule CGRP receptor antagonist, administered as an oral tablet, a sublingual orally disintegrating tablet, and a supralingual orally disintegrating tablet: two phase 1 randomized studies in healthy adults

Croop,

Bhardwaj,

Anderson

et al. 2024

Cephalalgia

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Background Rimegepant is an orally administered small molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine. Methods Two single-center, phase 1, open-label, randomized bioequivalence studies were conducted in healthy adult non-smokers, aged 18–55 years. One study compared the rate and extent of absorption of the marketed formulation of rimegepant 75 mg orally disintegrating tablet (ODT) administered sublingually with rimegepant 75 mg oral tablet, an earlier development formulation; the second compared the rate and extent of absorption of 75 mg rimegepant ODT administered supralingually with rimegepant oral tablet. Results The ln-transformed geometric mean ratios for the area under the curve (AUC) from time 0 to the last available concentration time point (time t) (AUC0-t), AUC from time 0 to infinity (AUC0-inf), and maximum observed concentration ( Cmax) of sublingual rimegepant ODT vs. rimegepant tablet were 97, 97, and 105%, respectively, and the 90% confidence intervals (CIs) were all within the predefined range (80–125%) for bioequivalence. The ln-transformed geometric mean ratios for the AUC0-t and AUC0-inf of supralingual rimegepant ODT vs. rimegepant tablet were 98%, the 90% CIs were within the predefined range (80–125%), and the geometric mean ratio for Cmax was 103% with the 95% upper confidence bound for the scaled average bioequivalence criterion of –0.0575 (within-participant coefficient of variation for the reference for Cmax > 30%) for bioequivalence. Conclusions Rimegepant 75 mg ODT, administered sublingually or supralingually, and rimegepant 75 mg oral tablet were bioequivalent.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bioequivalence of rimegepant, a small molecule CGRP receptor antagonist, administered as an oral tablet, a sublingual orally disintegrating tablet, and a supralingual orally disintegrating tablet: two phase 1 randomized studies in healthy adults

Croop,

Bhardwaj,

Anderson

et al. 2024

Cephalalgia

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“…This means that gepants, particularly zavegepant, could lead to effects on the central nervous system (CNS) despite being a good substrate for P-glycoprotein (23 ) . However, a recent phase III trial showed that individuals using zavegepant to treat a single migraine attack did not report any CNS-related adverse events (24 ) . Thus, CGRP antagonism might exert their therapeutic effect in the trigeminal ganglion and in trigeminal nerve fibers innervating dura mater and vascular and cutaneous tissues (25,26 ) .…”

Section: Calcitonin Gene-related Peptide (Cgrp)mentioning

confidence: 99%

Targeting CGRP pathways and aura: A peripheral site with a central effect

Al-Karagholi

2023

Cephalalgia

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Targeting CGRP-pathways has substantially expanded our options for treating individuals with migraine. Although the efficacy of these drugs on migraine aura is yet to be fully revealed, it seems from existing studies that CGRP antagonism reduces the number of migraine auras. The present perspective summarizes the evidence linking CGRP to the migraine aura and proposes a model by which targeting the CGRP-pathways and, thus, inhibition the interaction between C- and Aδ-trigeminal fibers might reverse a possible high cortical glutamate level leading to a reduced number of migraine auras.

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“…[50][51][52] While ubrogepant and rimegepant tabs are suited for oral intake, zavegepant was developed for intranasal administration. 50,51 In general, their therapeutic gain for acute treatment is lower than that of the triptans, but their tolerability seems to be better, in spite of causing mild nausea. Since symptoms and disease of the central nervous system involve several biochemical and neuronal pathways, perhaps soon an anti-CGRP responsive population will become identifiable.…”

Section: Monoclonal Antibodiesbeyond Migraine Prophylaxismentioning

confidence: 99%

The history and rationale of the development of new drugs for migraine treatment

Kowacs,

Sampaio Rocha-Filho,

Peres

et al. 2023

Arq Neuropsiquiatr

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Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers, flunarizine, valproic acid, topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.

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Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial

Cited by 63 publications

References 26 publications

Bioequivalence of rimegepant, a small molecule CGRP receptor antagonist, administered as an oral tablet, a sublingual orally disintegrating tablet, and a supralingual orally disintegrating tablet: two phase 1 randomized studies in healthy adults

Bioequivalence of rimegepant, a small molecule CGRP receptor antagonist, administered as an oral tablet, a sublingual orally disintegrating tablet, and a supralingual orally disintegrating tablet: two phase 1 randomized studies in healthy adults

Targeting CGRP pathways and aura: A peripheral site with a central effect

The history and rationale of the development of new drugs for migraine treatment

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