Gepants — a long way to cure: a narrative review

Abstract

Calcitonin gene-related peptide (CGRP) is probably the most potent vasodilator in cerebral circulation. Forty years after its discovery, the new CGRP-targeted therapy monoclonal antibodies, and the small molecule gepants, are now available for clinical practice. While randomized controlled trials and real-world experience consistently demonstrated the high efficacy and tolerability of monoclonal antibodies, limited evidence is available to characterize gepants fully. Depending on pharmacokinetics, these CGRP receptor antagonists can be used for acute (ubrogepant, rimegepant, and the not yet approved zavegepant) or preventive (atogepant and rimegepant) migraine treatment. Randomized placebo-controlled trials demonstrated gepants efficacy in treating acute attacks to obtain 2 h pain freedom in about 20% of patients and pain relief in about 60%, while up to 60% of treated patients with episodic migraine may experience a 50% reduction in monthly migraine days. The most common treatment-related emergent adverse events were gastrointestinal (nausea, constipation) for the acute or preventive use. No vascular or hepatic concerns have emerged so far. More studies are ongoing to investigate gepant tolerability and safety also if associated with monoclonal antibodies targeting CGRP and other therapeutic classes. Gepants are also under investigation to treat other painful and non-painful conditions. Real-life studies are necessary to confirm the trials’ findings and investigate more practical clinical aspects.

Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation

“…However, these medications are inadequate for the control of severe migraine in many patients. Recent progress has led to the approval of several anti-CGRP therapeutics for acute or preventive treatment ( Goadsby et al, 2020 ; Ailani et al, 2021 ; Croop et al, 2021 ; Altamura et al, 2022 ). They include four anti-CGRP and anti-CGRP receptor antibodies (i.e., galcanezumab, fremanezumab, eptinezumab, and erenumab), and three small molecule anti-CGRP therapies.…”

“…The absolute difference in the pain-free rate was 6.4–7.5% ( Lipton et al, 2019 ; Switzer et al, 2022 ). In the meta-analysis, small molecule antagonists were shown to provide 2 h pain freedom in ∼20% of patients and pain relief in ∼60% ( Zhang et al, 2021 ; Altamura et al, 2022 ). Because these anti-CGRP therapies have an efficacy comparable to the currently used drugs, migraine headaches remain a life-long burden for many patients ( Krymchantowski et al, 2019 ).…”

“…In support of this hypothesis, four anti-CGRP and anti-CGRP receptor antibodies (i.e., galcanezumab, fremanezumab, eptinezumab, and erenumab) have been approved by the FDA to treat chronic migraine since 2018 ( Aiyar et al, 2001 ; Verheggen et al, 2002 ; Zeller et al, 2008 ; Mitsikostas and Rapoport, 2015 ; Shi et al, 2016 ; Deen et al, 2017 ; Tso and Goadsby, 2017 ; Choy, 2018 ; Tepper, 2018 ; Al-Hassany et al, 2022 ). In addition, three small molecule antagonists were recently approved for the prevention and/or treatment of acute migraine ( Goadsby et al, 2020 ; Ailani et al, 2021 ; Croop et al, 2021 ; Altamura et al, 2022 ). In addition to migraine, excessive CGRP release was associated with pain in patients with arthritis, complex regional pain syndrome, and diabetic neuropathy ( Schou et al, 2017 ).…”

The effects of certain TRP channels and voltage-gated KCNQ/Kv7 channel opener retigabine on calcitonin gene-related peptide release in the trigeminovascular system

“…There are the four FDA approved monoclonal antibodies (erenumab, fremanezumab, galcanezumab and eptinezumab) and the two FDA approved small-molecule antagonists (rimegepant and ubrogepant), which have undergone extensive safety studies (31). It has been reported that gepants provide at least a 50% reduction in monthly migraine days in approximately half of migraine patients (32). However, inhibition of CGRP release from trigeminovascular system by specific TRP antagonists and/or retigabine could pose a potential future target for further reduction of monthly migraine days, or for migraine sufferers for whom these drugs do not work.…”

Clinical Management of Migraine

“…Many experts now do not exclude the possible use of these mAbs as first-line therapy for many patients with early disease, before severe disability is evident [ 10 ]. Nevertheless, other novel effective therapies acting as an agonist of the 5-HT1F receptor (Ditans) or as a CGRP antagonist (Gepants) are ready to emerge on the market for a better management of migraine crisis and/or its prevention, with expected good safety and tolerability profiles [ 11 , 12 ].…”