Pre-filled Pen for Anti-calcitonin Gene-related Peptide Migraine Therapy

CGRP as a new target in prevention and treatment of migraine

Calcitonin gene-related peptide (CGRP) receptor antagonists effectively abort migraine headache and inhibit neurogenic vasodilatation in humans as well as rat models. Monoclonal antibodies typically have long half-lives, and we investigated whether or not function-blocking CGRP antibodies would inhibit neurogenic vasodilatation with a long duration of action and therefore be a possible approach to preventive therapy of migraine. During chronic treatment with anti-CGRP antibodies, we measured cardiovascular function, which might be a safety concern of CGRP inhibition. We used two rat blood flow models that measure electrically stimulated vasodilatation in the skin or in the middle meningeal artery (MMA). These vasomotor responses are largely dependent on the neurogenic release of CGRP from sensory afferents. To assess cardiovascular function during chronic systemic anti-CGRP antibody treatment, we measured heart rate and blood pressure in conscious rats. Treatment with anti-CGRP antibodies inhibited skin vasodilatation or the increase in MMA diameter to a similar magnitude as treatment with CGRP receptor antagonists. Although CGRP antibody treatment had a slower onset of action than the CGRP receptor antagonists, the inhibition was still evident 1 week after dosing. Chronic treatment with anti-CGRP antibodies had no detectable effects on heart rate or blood pressure. We showed for the first time that anti-CGRP antibodies exert a long lasting inhibition of neurogenic vasodilatation in two different rat models of arterial blood flow. We have provided strong preclinical evidence that anti-CGRP antibody may be a suitable drug candidate for the preventive treatment of migraine.

The neuropeptides substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) have been considered as important mediators in migraine and other primary headaches. CGRP and VIP have been found at increased concentrations in jugular venous plasma during attacks of migraine or cluster headache, and CGRP receptor antagonists have recently been shown to be effective in migraine therapy. Substance P and CGRP are produced from a subset of trigeminal afferents, whereas VIP derives from parasympathetic efferents. Release of these neuropeptides in the meninges can cause arterial vasodilatation, mast cell degranulation and plasma extravasation in animal experiments, but only CGRP seems to be relevant in migraine. Animal models have confirmed the important role of CGRP in meningeal nociception. The activity of spinal trigeminal neurons is a sensitive integrative measure of trigeminal activity and is partly under the control of CGRP, most likely via central mechanisms. CGRP released from central terminals of trigeminal afferents in the spinal trigeminal nucleus seems to facilitate nociceptive transmission via presynaptic mechanisms. The central effect of CGRP is substantiated by suppression of nociceptive c-fos activation and neuronal activity in the spinal trigeminal nucleus following CGRP receptor inhibition. These proposed functions are supported by the localization of CGRP receptor components in the rat cranial dura mater, trigeminal ganglion and spinal trigeminal nucleus. The currently available data indicate multiple sites of CGRP action in trigeminal nociception and the pathogenesis of migraine; however, central CGRP receptors are likely to be the essential targets in the treatment of migraine using CGRP receptor antagonists.

Effects of the prototype serotonin 5-HT 1B/1D receptor agonist sumatriptan and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP 8–37 on myocardial reactive hyperemic response in conscious dogs

Network meta-analysis of migraine therapies: balancing efficacy and safety.

Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

In the early 1990s, the neuropeptide calcitonin gene-related peptide (CGRP) was identified as a key messenger in the pathophysiology of migraine and emerged as a treatment target, fundamentally transforming our approach to migraine therapy. While previous prophylactic drugs were non-specific and often caused intolerable side effects, the discovery of CGRP marked the advent of a new era in migraine treatment. The two main classes of CGRP-specific migraine treatments are monoclonal antibodies that bind to CGRP or the CGRP receptor, and CGRP receptor antagonists, the so-called gepants. Extensive clinical trials have conclusively demonstrated the safety, tolerability, and efficacy of monoclonal CGRP(-receptor) antibodies in the prophylactic treatment of both episodic and chronic migraine. The same positive results apply to the use of various gepants. They have proven to be not only an effective alternative to triptans in acute migraine therapy but also promising options for continuous use as prophylactic treatments. In this review, we aim to present the current state of research on CGRP-specific migraine therapy and insights in real-world data from the first years after their launch in clinical practice.

Background: This observational study presents preliminary real-world evidence on the comparative efficacy and safety of combination therapy with onabotulinumtoxinA and the CGRP receptor antagonist atogepant versus atogepant monotherapy in patients with treatment-refractory chronic migraine. Methods: Twenty adult patients (aged 18-75) meeting ICHD-3 criteria for refractory chronic migraine - defined by 8 monthly migraine days, MIDAS ³11, and inadequate response or intolerance to ³ 3 preventive therapies - were enrolled. Ten patients received atogepant monotherapy, while ten initiated combination therapy with onabotulinumtoxinA and atogepant. Efficacy was assessed over three months using changes in monthly migraine days, headache severity (Numerical Rating Scale, NRS), and disability scores (HIT-6, MIDAS). Acute medication use and tolerability were also evaluated. Results: The combination therapy group demonstrated significantly greater reductions in monthly migraine days, headache intensity, and disability scores compared to the monotherapy group. Responders - defined as patients remaining migraine-free for ³6 consecutive weeks - were more frequent in the combination cohort. Both treatments were well tolerated, with no serious adverse events reported. Chronic migraine remains a debilitating condition, often resistant to standard preventive treatments. Dual blockade of the CGRP pathway - via onabotulinumtoxinA and a CGRP receptor antagonist - may offer synergistic benefits by targeting both peripheral and central CGRP mechanisms. Conclusion: These preliminary findings support the enhanced clinical efficacy and safety of combining onabotulinumtoxinA with CGRP receptor antagonists in managing refractory chronic migraine. This multimodal strategy may provide a personalized, mechanism-based approach to care and warrants further investigation in larger, controlled studies.

PurposeThe newly developed calcitonin gene-related peptide (CGRP) antagonists were recently launched on the US and European market, with Switzerland as the second country worldwide. To enable forthcoming comparisons with established migraine therapy, the aim of this study was to provide a comprehensive picture of migraine (prophylactic) treatment patterns. Recent data in daily clinical practice are lacking.Patients and methodsThis population-based cohort study included enrollees from a Swiss Healthcare Insurance Database with at least one triptan prescription in 2015. Treatment patterns were defined by assessing subsequent triptan and prophylactic medication use (after index prescription for triptan) within the following year, divided into four quarters.ResultsTriptans were used by 10,090 patients (1.3%) in 2015. Most of them used triptan only (82.6%), 12.9% changed the treatment between triptan and prophylactics, and 4.5% received both in combination within 1year. Among triptan users with ≥1 prophylactic prescription in the first quarter, 48.6% used beta-blockers (BB), 40.7% “other prophylactics than BB (eg, topiramate)”, and 10.7% “a combination of both”. Most patients who received both BB and other prophylactics in the first quarter used this drug combination continuously over all four quarters.ConclusionThis study provides comprehensive data on treatment patterns prior to the introduction of a new drug class in migraine therapy. The majority of triptan users had no prophylactic medication therapy; however, a small, but relevant group used BB and other prophylactics concurrently in all quarters. Findings quantify the population in potential need for optimized migraine therapy, ie, the potential target population of the novel CGRP-targeted drugs.

A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine. Randomized double-blind placebo-controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint. Gepants also improved migraine associated symptoms, such as nausea, photophobia and phonophobia. Two of the class have had their development stopped because of hepatotoxicity, which is emerging as being due to metabolites. Gepants have a good tolerability and can be safely used in patients with stable cardiovascular disease. Exciting results have been obtained targeting the calcitonin gene-related peptide pathway to abort acute migraine attacks, thus reinforcing the relevance of mechanism-based treatments specific for migraine.

Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from activated trigeminal sensory afferents in headache and facial pain disorders. There are a handful of CGRP-targeted therapies currently in phase 3 studies for migraine acute treatment or prevention. Currently, 4 monoclonal antibodies targeting either the CGRP ligand or receptor are being studied for migraine prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab), and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in clinical trials for cluster headache prevention as well. Several other small-molecular CGRP receptor antagonists are in earlier stages of development for acute migraine treatment or prevention. In this review, we will discuss the growing body of clinical trials studying CGRP-targeted therapies for migraine and cluster headache.

To review and highlight current literature on emerging acute migraine treatments, focusing on CGRP receptor antagonists, gepants, and 5-HT1F receptor agonists (ditans). Current acute migraine therapy consists of nonspecific analgesia and triptans. Limitations to these medicines, including lack of efficacy in many patients, side effects and the contraindication of triptans in patients with cardiovascular disease, suggest that there is an unmet need for new treatments. Studies of serotonin pharmacology led to the development of triptans, 5-HT1B/1D receptor agonists, some of which have actions at the 5-HT1F receptor. Exploration of the role of calcitonin gene-related peptide (CGRP) has resulted in the development of CGRP receptor antagonists. The authors performed a literature search of Pubmed and Cochrane databases as well as reviewed abstracts presented at meetings: American Headache Society, American Academy of Neurology, European Headache Federation and the Migraine Trust International Symposium, as well as on-line sources. The authors briefly detail the relevant migraine pathophysiology pertaining to 5-HT1F receptor and the CGRP pathway relevant to acute therapies. Recent clinical trials of acute therapies in which 5-HT1F receptor agonists or CGRP receptor antagonists were studied are summarized. Two 5-HT1F receptor agonists have reached phase II clinical trials. One, lasmiditan, has completed 2 phase III clinical trials, demonstrating a significant effect for pain freedom and most bothersome symptom at 2 hours. Among the 6 gepants tested for the acute treatment of migraine to date, after issues for some of hepatic safety or efficacy, 2 CGRP receptor antagonists, rimegepant and ubrogepant, have completed phase III trials showing efficacy and safety. Current available therapies have either been nonspecific or had important limitations, including in patients with cardiovascular risk factors. Phase III clinical trials of lasmiditan, rimegepant and ubrogepant all met their primary endpoints, so the options for migraine-targeted acute therapy will likely soon increase.

The shift in our understanding of migraine as a vascular disorder to a brain disorder has opened new avenues for the development of novel therapeutics with neural targets. The advent of 5-HT1B/1D receptor agonists, the triptans, in the 1990s was a crucial step in the modern evolution of treatment. The use of triptans, like their predecessors, is limited by their vasoconstrictor effects, and new development has been slowed by poor academic research funding to identify new targets. The development of agents without vascular effects, such as calcitonin gene-related peptide receptor antagonists and selective serotonin 5-HT1F receptor agonists, will bring more effective treatments to a population currently without migraine-specific options. In addition, advances in understanding migraine pathophysiology have identified new potential pharmacologic targets such as acid-sensing ion channels, glutamate and orexin receptors, nitric oxide synthase (NOS), and transient receptor potential (TRP) channels. Although previous attempts to block subtypes of glutamate receptors, NOS, and TRP channels have had mixed outcomes, new molecules for the same targets are currently under investigation. Finally, an entirely new approach to migraine treatment with noninvasive neuromodulation via transcutaneous neurostimulation or transcranial magnetic stimulation is just beginning. Hopefully in the coming years we will see a new era of migraine therapy, with multiple classes of better-tolerated, more effective agents targeting diverse yet specific migraine mechanisms.

Rimegepant for migraine: acute efficacy beyond the USA

BackgroundCalcitonin gene-related peptide (CGRP) and nitric oxide (NO) are regarded as key mediators in migraine and other primary headaches. Migraineurs respond to infusion of nitroglycerin with delayed headaches, and inhibition of CGRP receptors has been shown to be effective in migraine therapy. In animal experiments nitrovasodilators like nitroglycerin induced increases in spinal trigeminal activity, which were reversed after inhibition of CGRP receptors. In the present study we asked if CGRP receptor inhibition can also prevent spinal trigeminal activity induced by nitroglycerin.MethodsIn isoflurane anaesthetised rats extracellular recordings were made from neurons in the spinal trigeminal nucleus with meningeal afferent input. The non-peptide CGRP receptor inhibitor MK-8825 (5 mg/kg) dissolved in acidic saline (pH 3.3) was slowly infused into rats one hour prior to prolonged glyceryl trinitrate (nitroglycerin) infusion (250 μg/kg/h for two hours).ResultsAfter infusion of MK-8825 the activity of spinal trigeminal neurons with meningeal afferent input did not increase under continuous nitroglycerin infusion but decreased two hours later below baseline. In contrast, vehicle infusion followed by nitroglycerin was accompanied by a transient increase in activity.ConclusionsCGRP receptors may be important in an early phase of nitroglycerin-induced central trigeminal activity. This finding may be relevant for nitroglycerin-induced headaches.