Zavegepant: a promising intranasal medication for migraine treatment

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Migraine is the third most prevalent and seventh-highest specific cause of disability worldwide1. It is a neurobiological headache disorder that is caused by increased excitability of the central nervous system. This multifactorial ailment has various causes, including lack of sleep, hormonal imbalance, menstrual cycle, and emotional stress. Some individuals may even trigger migraine due to their choice of food, especially chocolate, milk, caffeine, cheese, and alcoholic beverages2. The variability seen in its clinical presentation includes the pattern of associated symptoms and pain intensity along with photophobia, osmophobia, phonophobia, vomiting, nausea, and movement sensitivity3. Considering the acute onset of this excruciating pain, patients demand rapid relief and the cure of all associated symptoms. Several medications have been introduced. However, nowadays, 5HT1B/1D receptor agonists (sumatriptan, zolmitriptan) and ergot alkaloids (dihydroergotamine mesylate) are being used as intranasal or parenteral medications for the immediate treatment of migraines. Many patients prefer intranasal medications over injectable ones because of their rapid action4. Triptans, one of the most effective treatment regimens for migraine, is unfortunately ineffective intranasally. Moreover, its contraindication for cardiovascular patients restricts its use in almost 10% of the migraine population. On the other hand, dihydroergotamine which is still less effective than triptans, the nasal spray is contraindicated in patients with uncontrolled hypertension, ischemic heart disease, and coronary artery vasospasm5. Co-administration with potent cytochrome P450 3A4 inhibitors may also result in potentially fatal peripheral and cerebral ischemia. Recent studies led to the discovery of novel modulators, like calcitonin gene-related peptide (CGRP), that are crucially implicated in the development and chronicity of migraine. This led to new medications known as gepants that can antagonize the CGRP receptor. Successive advances led to the introduction of first-generation and second-generation gepants. However, both were short-lived due to poor oral bioavailability6, associated liver injury, and less effectiveness, respectively. Zavegepant is the third generation but the first intranasally administered gepant. It is a high-affinity antagonist of the CGRP receptor, has adequate oral bioavailability, and, unlike triptans, does not induce active contraction of coronary arteries; therefore, it is safe for patients with cardiovascular comorbidities. Compared with the prior lead, the pharmacophore of zavegepant has a 2-quinolone and a 7-methylindazole, increasing oxidation stability and nasal irritancy potential while maintaining picomolar receptor binding potency7. In addition to that, it is also 10,000 times more selective for the CGRP receptor than for its counterpart, the amylin receptor8. It was FDA-approved in February 2020 for acute treatment, and results demonstrate that it is safe regarding hepatotoxicity9. Recently it cleared the phase 2 trials and now advancing to phase 3 ones. Zavegepant has a tmax of 15–20 minutes as it provides considerable efficacy over 48 hours, with ultra-rapid pain relief starting 15 minutes after a single therapeutic dose (P=0.0015), prolonged and persistent pain freedom for 2–24 hours and 2–48 hours, respectively, along with sustained pain relief for 2–24 hours10. This makes it highly potent and the safest in terms of side effects. Although the provided data gives ample proof that zavegepant is a revolutionary drug to combat migraine attacks but for definite, high-quality evidence about its efficacy and safety, results from the recent clinical trials and future research work are needed. Similarly, soft gel formulations of zavegepant also need more attention as it can be another option for the abortive treatment of migraine. Lastly, extensive trials are needed to see its effect on pregnant women and patients with severe liver and cardiovascular issues. For commercialization, it should be economically friendly so that it can compete with all the available formulas and a maximum number of patients can be benefitted from it. Rest assured. This third-generation gepant can be a promising medication in terms of timely relief from escalating pain, and further research may even help us find the ultimate cure for migraine. Ethical approval Not applicable. Sources of funding None. Author contribution The conceptualization was done by A.S. and B.S.R. The literature and drafting of the manuscript were conducted by A.S., T.N., A.W.K., S.D.E.Z.Z., A.Q. and H.S.R. The editing and supervision were performed by B.S.R. All authors have read and agreed to the final version of the manuscript. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor All authors take responsibility for the work, access to data and decision to publish.