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Headache
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Stephen Silberstein, Shuhan Zhu
Calcitonin gene-related peptide (CGRP) receptor antagonists: Known as the “gepants”, these include ubrogepant and rimegepant, which received FDA approval in 2019 and 2020 respectively. Animal studies have shown adverse effects from both drugs and is not recommended for patients who are pregnant. There is little registry data due to the newness of these drugs.
Headache
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Gepants, CGRP receptor antagonists, are now available for the acute treatment of migraine. They have no direct vasoconstrictor liability and block a key pathway in migraine in some patients. They are very well tolerated. Ubrogepant 50 or 100 mg po is now available in the US,31,32 and apart from a contraindication with strong CYP3A4 inhibitors, is easy to deploy in patients who have not responded to, or in whom triptans are contraindicated. Similarly, rimegepant 75 mg po33,34 is also available in the US and can be used in triptan non-responders. Both gepants are effective and well tolerated.
Headache Disorders
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Several touted “migraine-specific” agents have been recently developed, including CGRP receptor antagonists (for abortive use) and monoclonal antibodies targeting CGRP receptors or the protein itself (preventive use). These medications represent a great advancement in current treatment of migraine to a more specific, tailored therapy based on known pathophysiologic mechanisms. Several oral CGRP receptor antagonists in development have shown promising efficacy in treating migraine with superiority to placebo and comparability to triptans, but many of the trials have been discontinued due to concerns of hepatotoxicity after taking the drug for multiple consecutive days. A phase II RCT published in 2016 found that ubrogepant, a CGRP receptor antagonist, yielded modest results as an abortive agent in the indicator single migraine freedom at two hours after medication administration when compared to placebo; there were no signs of hepatotoxicity within 1 week of drug administration.30 These agents are on track for possible FDA approval.
Targeting CGRP for migraine treatment: mechanisms, antibodies, small molecules, perspectives
Published in Expert Review of Neurotherapeutics, 2020
Eleonora De Matteis, Martina Guglielmetti, Raffaele Ornello, Valerio Spuntarelli, Paolo Martelletti, Simona Sacco
The efficacy, safety and tolerability of ubrogepant have been studied by a phase 2 RCT and two phase 3 RCTs. The phase 2 double-blind RCT compared different drug dosages and showed the efficacy of the 100 mg dose in terms of two-hour pain freedom compared with placebo (25.5% vs 8.9%; P < 0.001). The same dosage led to a higher headache response rate compared with placebo for the two-hour headache response (defined as reduction in headache severity from grade 2 or 3 at baseline to grade 1 or 0 on a pain scale from 0 to 3), but this difference was not statistically significant [88]. The two phase 3 trials, ACHIEVE I and ACHIEVE II, ran similar analyses comparing ubrogepant with placebo [89,90]. Specifically, ACHIEVE I investigated the efficacy of the 50 and 100 mg dosages, while ACHIEVE II investigated that of 25 and 50 mg dosages. Both studies confirmed the superiority of ubrogepant over placebo, with better results for the higher dosages (100 mg in ACHIEVE I and 50 mg in ACHIEVE II) in terms of the principal endpoints of freedom from pain and from the most bothersome migraine symptoms at two hours. In ACHIEVE I, 19.2% of patients were free from pain within two hours from the 50 mg ubrogepant administration; this proportion increased to 21.2% in patients who received the 100 mg dosage [89]. Similarly, in ACHIEVE II, 20.7% patients receiving the 25 mg dosage were free from pain at two hours compared to 21.8% patients who were treated with the 50 mg ubrogepant (Figure 3a) [90].
Gepants for the treatment of migraine
Published in Expert Opinion on Investigational Drugs, 2019
Andrea Negro, Paolo Martelletti
The characterization of the population pharmacokinetic of ubrogepant in the treatment of acute migraine in individuals with migraine was later investigated in the study MK-1602–007 (PN007; NCT01657370), which was a phase 2b, multicenter randomized, double-blind, placebo-controlled, parallel-group trial (Table 3) [86]. The trial also investigated the influence of demographic and other variables on ubrogepant pharmacokinetics, as well as the relationship between ubrogepant concentrations and efficacy of the drug. Patients were randomized to receive three administrations of placebo or three administration of a specific dose of ubrogepant (1, 10, 25, 50, and 100 mg): dose 1 at the onset of a moderate or severe migraine (day 1), dose 2 in the evening of day 3 and dose 3 on day 4.
Ubrogepant for the treatment of migraine
Published in Expert Opinion on Pharmacotherapy, 2020
Martina Curto, Matilde Capi, Fabiola Cipolla, Giusy Ylenia Cisale, Paolo Martelletti, Luana Lionetto
Migraine acute attacks are traditionally treated with NSAIDs, acetaminophen, triptans, or ergots alkaloids. In particular, triptans are considered the first-line medications for acute migraine management, as selective 5-HT1B/1D agonists [15]. Recently, a new drug class targeting selectively the 5-HT1F, called ditans, have been developed as neurally acting anti-migraine agents. Unlike triptans, ditans inhibit trigeminovascular pathways with no significant vasoconstrictive effects. However, among ditans, only lasmiditan is being currently evaluated in Phase 3 clinical trials [10]. Moreover, several small compounds antagonizing CGRP receptors have been developed in the last decade, considering the role of CGRP in migraine pathophysiology [15]. These molecules, also known as gepants, are effective to alleviate headache attacks without vasoconstrictive side effects [16]. Therefore, targeting CGRP activity might represent an effective therapeutic alternative for migraine patients not responding to triptans or with cardiovascular diseases. Among gepants, olcegepant, the first molecule with proved efficacy for migraine in humans, has been discontinued due to the lack of an oral formulation and telcagepant has been discontinued due to hepatotoxicity when used for migraine prophylaxis [17]. Moreover, rimegepant, ubrogepant, and BHV-3500 are presently being evaluated in phase II/III clinical trials for acute migraine treatment and atogepant as a preventive medication [5]. This paper will review data on pharmacokinetics, metabolism, safety, and efficacy of ubrogepant, as reported in the completed and ongoing clinical trials.