Calcitonin Gene-related Peptide Monoclonal Antibodies Research Articles

Characterization of erenumab and rimegepant on calcitonin gene-related peptide induced responses in Xenopus Laevis oocytes expressing the calcitonin gene-related peptide receptor and the amylin-1 receptor

BackgroundThe clinical use of calcitonin gene-related peptide receptor (CGRP-R) antagonists and monoclonal antibodies against CGRP and CGRP-R has offered new treatment possibilities for migraine patients. CGRP activates both the CGRP-R and structurally related amylin 1 receptor (AMY1-R). The relative effect of erenumab and the small-molecule CGRP-R antagonist, rimegepant, towards the CGRP-R and AMY-R needs to be further characterized.MethodsThe effect of CGRP and two CGRP-R antagonists were examined in Xenopus laevis oocytes expressing human CGRP-R, human AMY1-R and their subunits.ResultsCGRP administered to receptor expressing oocytes induced a concentration-dependent increase in current with the order of potency CGRP-R> > AMY1-R > calcitonin receptor (CTR). There was no effect on single components of the CGRP-R; calcitonin receptor-like receptor and receptor activity-modifying protein 1. Amylin was only effective on AMY1-R and CTR. Inhibition potencies (pIC50 values) for erenumab on CGRP induced currents were 10.86 and 9.35 for CGRP-R and AMY1-R, respectively. Rimegepant inhibited CGRP induced currents with pIC50 values of 11.30 and 9.91 for CGRP-R and AMY1-R, respectively.ConclusionOur results demonstrate that erenumab and rimegepant are potent antagonists of CGRP-R and AMY1-R with 32- and 25-times preference for the CGRP-R over the AMY1-R, respectively. It is discussed if this difference in affinity between the two receptors is the likely reason why constipation is a common and serious adverse effect during CGRP-R antagonism but less so with CGRP binding antibodies.

CGRP Targeting Therapy for Chronic Migraine-Evidence from Clinical Trials and Real-world Studies.

Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor have become part of the standard treatment for migraine in clinical practice. The current review focuses on the clinical evidence of CGRP monoclonal antibodies in patients with chronic migraine (CM), including more challenging cases. CGRP monoclonal antibodies were more effective than placebo in reducing the number of monthly migraine days (MMDs), and the change relative to placebo in the treatment group was between - 1.2 and - 2.7days at 3months. CGRP monoclonal antibodies resulted in ≥ 50% response in 27.5 to 61.4% of patients, and doubled the odds for having ≥ 50% response. The findings were generally consistent in patients with coexisting medication overuse or with treatment failures to multiple preventive medications, including onabotulinumtoxinA. The results from real-world studies (RWS) were similar to those seen in clinical trials, and the changes from baseline in the number of MMDs and the response rates largely fell within the ranges of those reported in the treatment group in pivotal trials. The therapeutic effects typically started within a few days, and remained steady after regular treatment for up to 1year. These agents were generally well tolerated, and the discontinuation rates due to adverse events in clinical trials and in many RWS were < 4.5%. CGRP monoclonal antibodies are effective and safe in the treatment of patients with CM, including clinical challenging cases. However, the role of CGRP monoclonal antibodies in a number of conditions, such as cardiovascular or cerebrovascular diseases, pregnancy, and overuse of opioids or barbiturates, needs to be further clarified.

Atogepant: an emerging treatment for migraine

ABSTRACT Introduction Until recently, only nonspecific and not always well-tolerated medications were available for migraine prophylaxis. Currently, specific drugs such as calcitonin gene-related peptide (CGRP) monoclonal antibodies and second-generation gepants are marketed for migraine treatment. Atogepant, an orally active small molecule, is a potent, selective antagonist of the CGRP receptor and is the only gepant authorized exclusively for episodic migraine prophylaxis in adults. Areas covered Using literature obtained from PubMed, Scopus, Web of Science, Cochrane, and ClinicalTrials.gov (up to February 13rd, 2022), the authors summarize and evaluate the available data on atogepant for the prophylaxis of episodic migraine. Expert opinion From pivotal trials, the efficacy and tolerability of atogepant in episodic migraine prophylaxis seem comparable to those of CGRP monoclonal antibodies, even if comparative studies have not been conducted. To date, limited information is available on atogepant, including the optimal dose and duration of therapy; hence, it is difficult to establish whether it could be a first-line drug for migraine prophylaxis. Furthermore, it is important to evaluate if atogepant use is associated with the risk of cardiovascular and cerebrovascular events, which could result from potent and persistent blockade of vasodilation by CGRP.

Effects of acute and preventive therapies for episodic and chronic cluster headache: A scoping review of the literature.

Cluster headache is the most common primary headache disorder of the trigeminal autonomic cephalalgias, and it is highly disabling. We undertake a scoping review to characterize therapies to prevent and acutely treat cluster headache, characterize trial methodology utilized in studies, and recommend future trial "good practices." We also assess homogeneity of studies and feasibility for future network meta-analyses (NMAs) to compare acute and preventive treatments for cluster headache. A priori protocol for this scoping review was registered and available on Open Science Forum. We sought studies that enrolled adult patients with cluster headache as identified by accepted diagnostic criteria. Both randomized controlled trials (RCTs) and observational studies (with a control group) were included. The interventions of interest were medications, procedures, devices, surgeries, and behavioral/psychological interventions, whereas comparators of interest were placebo, sham, or other active treatments. Outcomes were predefined; however, we did not exclude studies lacking these outcomes. A systemic search was conducted in Ovid Medline, Embase, and Cochrane. We performed a targeted search for conference abstracts from journals prominent in the field. We identified 56 studies: 45 RCTs, four studies only available in clinical trial registries, and seven observational studies. Of the 45 RCTs, 20 focused on acute therapies and 25 on preventive therapies. Overall, we determined that it is feasible to pursue a NMA for acute therapy focusing on 15 or 30-min headache reduction for acute trials, as we identified 11 trials in the combined population of patients with either episodic or chronic cluster headache (2 trials in populations with chronic cluster headache were also found). For preventive therapy of cluster headache, we identified trials with common outcomes that may be considered for NMA, however, as these trials had differences in treatment effect modifiers that could not be corrected, NMAs appear infeasible for this indication. We identified new studies looking at noninvasive vagal nerve stimulation, sphenopalatine ganglion stimulation, prednisone, and oxygen published since the most recent systematic review in the field, although these acute treatments were previously identified as effective. However, for calcitonin gene-related peptide (CGRP) monoclonal antibodies, galcanezumab demonstrated effectiveness in episodic cluster headache, but a lack of effectiveness in chronic cluster headache, and fremanezumab was not effective for episodic nor chronic cluster headache. This finding highlights that CGRP monoclonal antibodies may not show a class effect in cluster headache prevention and need to be considered individually. We describe the treatment landscape of cluster headache for both acute and preventive treatments. Last, we present the NMAs we will undertake in acute therapies of cluster headache.

Treatment Patterns for Calcitonin Gene-Related Peptide Monoclonal Antibodies Including Galcanezumab versus Conventional Preventive Treatments for Migraine: A Retrospective US Claims Study.

BackgroundMost conventional, oral, preventive treatments for migraine are non-specific and ~50% of patients discontinue them within six months. In 2018, the Food and Drug Administration approved three preventive migraine treatments: monoclonal antibodies (mAb) targeting the calcitonin gene-related peptide (CGRP) pathway implicated in migraine; galcanezumab and fremanezumab which target CGRP ligand; and erenumab which targets CGRP receptor. Real-world treatment patterns for CGRP mAb are limited.PurposeTo compare real-world treatment patterns for CGRP mAb, specifically galcanezumab versus standard-of-care (SOC) migraine preventive treatments.Patients and methodsThis retrospective, observational study included 12-month baseline and 6- and 12-month follow-up analyses using IBM® MarketScan® databases. Patients identified were aged ≥18 years with ≥1 claim (first claim=index) for CGRP mAb (erenumab, fremanezumab, or galcanezumab) or SOC preventives (eg, antiepileptics, beta-blockers, antidepressants, or onabotulinumtoxinA) as index drugs between May/01/2018 and June/30/2019. Propensity score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), persistence (≤60-day gap), and first non-index drug switch. Descriptive, chi-square (categorical), and t-test (continuous) analyses were conducted.ResultsThe study included 3082 (CGRP mAb versus SOC) and 421 (galcanezumab versus SOC) matched patient pairs with 12-month follow-up. Mean age across cohorts ranged 43.2–44.4 years (females: 85.7–88.6%). Compared with SOC, the CGRP mAb cohort had higher mean persistence (212.5 vs 131.9 days), adherence (PDC: 55.1% vs 35.2%), and more patients were adherent with PDC ≥80% (32.7% vs 18.7%) (all p <0.001). During 12-month follow-up, fewer patients discontinued CGRP mAb versus SOC (58.8% vs 77.6%, p <0.001). Galcanezumab versus SOC comparisons yielded similar results. In the CGRP mAb cohort, most switchers (28.3%) used galcanezumab as subsequent treatment. Largely similar results were observed for 6-month follow-up cohorts.ConclusionPatients on CGRP mAb and specifically galcanezumab showed higher adherence and persistence than patients on SOC migraine preventive treatments.

Sex Differences in Chronic Migraine: Focusing on Clinical Features, Pathophysiology, and Treatments.

This review provides an update on sex differences in chronic migraine (CM), with a focus on clinical characteristics, pathophysiology, and treatments. Approximately 6.8-7.8% of all migraineurs have CM, with an estimated prevalence of 1.4-2.2% in the general population. The economic burden caused by CM, including medical costs and lost working ability, is threefold higher than that caused by episodic migraine (EM). Notably, the prevalence of migraine is affected by age and sex. Female migraineurs with CM experience higher levels of headache-related disability, including longer headache duration, higher frequency of attacks, and more severely impacted efficiency at work. Sex hormones, including estrogen, testosterone, and progesterone, contribute to the sexually dimorphic characteristics and prevalence of migraine in men and women. Recent neuroimaging studies have indicated that migraine may have a greater impact and cause greater dysfunction in the organization of resting-state functional networks in women. Accumulating evidence suggests that topiramate, Onabotulinumtoxin A and calcitonin gene-related peptide (CGRP) monoclonal antibodies are effective as the preventative treatments for CM. Recent evidence highlights a divergence in the characteristics of CM between male and female populations. The data comparing the treatment response for CM regarding sex are lacking.

Current status of calcitonin gene-related peptide-based therapies in migraine: a scoping review

A significant proportion of patients exhibit sub-optimal response to the standard treatment of acute migraine such as triptans and NSAIDs. Even the conventional preventive therapies (e.g. beta-blockers) indicated for patients with frequent migraine attacks have varying responses. Moreover, evidence from animal studies elucidated the role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine. Currently two classes are drug, the small molecule CGRP receptor antagonist or the ‘gepants’ (Ubrogepant, Rimegepant, Atogepant, Zavegepant) and CGRP monoclonal antibodies (Erenumab, Galcanezumab, Fremanezumab, Eptinezumab) have been found efficacious and safe in various clinical trials for the treatment and prevention of migraine. While the small molecule CGRP receptor antagonists are given orally, the monoclonal antibodies are injectable drugs. Ubrogepant and Rimegepant are the second-generation gepants approved for treatment of migraine. Zavegepant is a third generation gepant which has proven efficacy for acute treatment of migraine in a phase III trial. Atogepant has been approved for prevention of migraine. Rimegepant has also proven to be efficacious for preventing migraine attacks but has not yet been approved for this indication. Erenumab is the only monoclonal antibody which neutralizes the CGRP receptor. The latter three monoclonal antibodies target the CGRP peptide. The monoclonal antibodies have been approved for the prevention of migraine as a subcutaneously or intravenous infusion (Eptinezumab) given once a month or quarterly. Both the classes of drugs were well-tolerated in the clinical trials. Nausea was the most common adverse effect with gepants while injection-site pain was commonly reported with the antibodies.

Direct cost and healthcare resource utilization of patients with migraine before treatment initiation with calcitonin gene-related peptide monoclonal antibodies by the number of prior preventive migraine medication classes

Objective This study compared all-cause direct cost and healthcare resource utilization (HCRU) among preventive migraine medication (PMM)-naïve patients and patients with up to 3 PMM category switches before initiating calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). Methods This was a retrospective analysis of the IBM Marketscan database. Patients who initiated injectable CGRP mAbs between May 2018 and December 2019 (index period) were included in 4 groups based on the number of prior non-CGRP PMM classes used during the 24-month pre-index period: P0 = none; P1 = one; P2 = two; P3 ≥ three. All-cause direct cost and HCRU for groups were compared without adjustment and after generalized propensity score (GPS) matching. Results Of the 23,288 patients included (mean age ± standard deviation [SD] 45.4 ± 12.0 years), 85.6% were females, and the mean Charlson Comorbidity Index was 0.69 ± 1.2. P3 group had the highest average annual unadjusted total healthcare costs per patient ($50,274±$76,629); the highest costs attributed to procedure/imaging-related expenses ($20,105±$36,401) and pharmacy ($11,633±$29,763). P0 group had the lowest cost ($25,288±$41,427). Pairwise comparison of GPS matched costs showed significantly greater average annual direct costs per patient in the P3 group vs. P0 (p = .003), P1 (p = .014), and P2 (p = .021) groups. GPS matched HCRU also increased with the number of prior PMM classes used. Anti-epileptics (48.9%) were the most commonly used PMM class, with triptans (75.2%) being the most common acute medication class. Conclusions Total direct healthcare cost and HCRU increased significantly with increasing use of PMM classes with the greatest cost difference existing between the P0 and the P3 groups.

The Safety and Efficacy of Calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibodies for the Preventive Treatment of Migraine: A Protocol for Multiple-Treatment Systematic Review and Meta-Analysis.

Background: Migraine is a common and disabling primary headache disorder, associated with many medical comorbidities, highly prevalent, with complex treatment and management. Currently, monoclonal antibodies targeting the trigeminal sensory neuropeptide, calcitonin gene-related peptide (CGRP), are available. The aim of this protocol is to provide a review comparing the effects and safety profile of different monoclonal antibodies in migraine patients. Methods: The literature search will be performed through the MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), Web of Science and Scopus databases, following the PICO strategy. Real World studies and randomized clinical trials assessing the effect of monoclonal antibodies against CGRP interventions (erenumab, eptinezumab, fremanezumab and galcanezumab) on monthly migraine days (MMD), monthly headache days (MHD), headache impact test (HIT-6) and triptan days of use (TriD) will be included. In Real World studies, the DerSimonian and Laird method will be used to calculate pooled estimates of the mean change difference and in randomized clinical trials, a network meta-analysis will be performed to estimate the comparative effects of different monoclonal antibodies against CGRP. Results: The findings of this study will be reported in a peer-reviewed journal. Conclusions: This study will provide evidence to health professionals on the efficacy and safety of different monoclonal antibodies against CGRP on the outcomes studied.

Headache in Pregnancy and Lactation.

This article discusses the many tools available for the treatment of pregnant and postpartum patients with headache. Adequate treatment of headache is an essential part of good prenatal and postnatal care. New therapies such as the calcitonin gene-related peptide monoclonal antibodies, lasmiditan, direct calcitonin gene-related peptide antagonists, and neuromodulation devices are available for the treatment of headache. This article contextualizes these new therapies in practice as they relate to the treatment of migraine in pregnancy and lactation. Headache is common in pregnancy, and neurologists should be prepared to care for pregnant patients with headache. Preconception counseling is an important part of providing safe care to patients of childbearing potential with headache. Identifying potentially dangerous secondary headache syndromes during pregnancy and the puerperium is also essential. The repertoire of available acute and preventive headache treatments is expanding. It is important to discuss the effectiveness and safety of these therapies in the context of individual patient circumstances during pregnancy and lactation in coordination with the patient's obstetric team.

Real-World Evidence for the Safety and Efficacy of CGRP Monoclonal Antibody Therapy Added to OnabotulinumtoxinA Treatment for Migraine Prevention in Adult Patients With Chronic Migraine.

Background: OnabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) target different migraine pathways, therefore, combination treatment may provide additional effectiveness for the preventive treatment of chronic migraine (CM) than either treatment alone. The objective of this study was to collect real-world data to improve the understanding of the safety, tolerability, and effectiveness of adding a CGRP mAb to onabotulinumtoxinA treatment for the preventive treatment of CM.Methods: This was a retrospective, longitudinal study conducted using data extracted from a single clinical site's electronic medical records (EMR) of adult patients (≥18 years) with CM treated with ≥2 consecutive cycles of onabotulinumtoxinA before ≥1 month of continuous onabotulinumtoxinA and CGRP mAb (erenumab, fremanezumab, or galcanezumab) combination treatment. Safety was evaluated by the rate of adverse events (AE) and serious adverse events (SAE). The proportion of patients who discontinued either onabotulinumtoxinA, a CGRP mAb, or combination treatment, and the reason for discontinuation, if available, was collected. The effectiveness of combination preventive treatment was assessed by the reduction in monthly headache days (MHD). Outcome data were extracted from EMR at the first CGRP mAb prescription (index) and up to four assessments at ~3, 6, 9, and 12 months post-index. The final analyses were based on measures consistently reported in the EMR.Results: EMR were collected for 192 patients, of which 148 met eligibility criteria and were included for analysis. Erenumab was prescribed to 56.7% of patients, fremanezumab to 42.6%, and galcanezumab to 0.7%. Mean (standard deviation [SD]) MHD were 20.4 (6.6) prior to onabotulinumtoxinA treatment and 14.0 (6.9) prior to the addition of a CGRP mAb (baseline). After real-world addition of a CGRP mAb, there were significant reductions in MHD at the first assessment (~3 months) (mean −2.6 days/month, 95% CI −3.7, −1.4) and at all subsequent visits. After ~12 months of continuous combination treatment, MHD were reduced by 4.6 days/month (95% CI −6.7, −2.5) and 34.9% of patients achieved ≥50% MHD reduction from index. AEs were reported by 18 patients (12.2%), with the most common being constipation (n = 8, 5.4% [onabotulinumtoxinA plus erenumab only]) and injection site reactions (n = 5, 3.4%). No SAEs were reported. Overall, 90 patients (60.8%) discontinued one or both treatments. The most common reason for discontinuing either treatment was lack of insurance coverage (40%); few (~14%) patients discontinued a CGRP mAb and none discontinued onabotulinumtoxinA due to safety/tolerability.Conclusion: In this real-world study, onabotulinumtoxinA was effective at reducing MHD and the addition of a CGRP mAb was safe, well-tolerated and associated with incremental and clinically meaningful reductions in MHD for those who stayed on the combination treatment. No new safety signals were identified. Of those who discontinued, the majority reported lack of insurance coverage as a reason. Prospective real-world and controlled trials are needed to further evaluate the safety and potential benefits of this combination treatment paradigm for people with CM.

Six-month therapy of CGRP monoclonal antibodies in real-world clinical practice: an interim analysis of efficacy and safety data

Introduction. Migraine is one of the most common disabling neurological disorders. Recently developed monoclonal antibodies to calcitonin gene-related peptide (CGRP) or its receptor are the first targeted medication for preventive therapy of both episodic and chronic migraine. They have been thoroughly investigated in clinical trials; however, there is little data from real-world clinical practice available to date. The aim of this study is to assess the efficacy and safety of 6 months of treatment with erenumab in real-world clinical practice and investigate the effect of the drug on the patients’ sensitivity to medicines for migraine headaches relief and patient satisfaction after treatment.Materials and methods. Our observational cohort prospective study included patients in our Headache Clinic prescribed monoclonal antibodies blocking the CGRP-receptor – erenumab. During the investigation, we evaluated the previous preventive therapy and its efficacy, the number of days with migraine per month, adverse events occurring during the erenumab treatment, depression and anxiety (HADS), migraine disability (MIDAS), the presence of allodynia (ACS-12) and improved response to acute therapy after treatment. A total of 42 patients participated in the study: 6 men, 36 women, the average age was 43.9 ± 12.2. Of them, 38 patients (90%) had chronic migraine. Thirty-two patients (76%) had previously been prescribed preventive therapy, which proved ineffective, and 10 patients (24%) had not once received any type of migraine prevention.Results. Among our patients, we identified 11 patients with resistant migraine and one patient with refractory migraine. During the study, two patients dropped out due to adverse events (constipation). Thirty patients continued the administration of erenumab 70 mg for at least six months. The average number of migraine days per month before treatment was 22.8, and after six months of treatment, it dropped to 7.3. Twenty-nine patients (72.5%) also noted that the response to acute headache treatment improved after the therapy.Conclusion. The results of our study are consistent with the international experience of using erenumab and confirm its effectiveness for migraine preventive therapy, including difficult-to-treat migraine cases. However, further studies with more participants and evaluation of predictors of successful monoclonal antibody therapy are still needed.

Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

Cluster headache is a primary headache disorder and is the most prevalent of the trigeminal autonomic cephalalgias. Cluster headache significantly impacts those affected, necessitating early diagnosis and management. Despite unique clinical features, such as patients experiencing attacks in a circannual pattern and often with a circadian rhythm within bouts, cluster headache patients often are misdiagnosed, mismanaged and have a delay in diagnosis. Preclinical, neuroimaging and clinical studies have advanced our understanding of cluster headache pathophysiology. The trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamus are all involved in the pathophysiology of cluster headache. As our understanding of the pathophysiology of cluster headaches has evolved, new therapeutic options, such as calcitonin gene-related peptide monoclonal antibodies, non-invasive vagal nerve stimulation and sphenopalatine ganglion stimulation, have proved to have efficacy in the treatment of cluster headache. Herein, we aim to review developments to aid readers in their understanding of this debilitating disorder.

Modern strategies of targeted migraine therapy

Migraine is a chronic common neurological disorder. It is an extremely disabling and significantly reduces the quality of life of patients. Developments of the field of fundamental research and functional neuroimaging studies have improved the understanding of the pathophysiology of migraine. New specific drugs and methods of treatment have appeared. They significantly reduced the severity of headache attacks and the course of the disease. Therefore the aim of this work is to analyze and summarize the information of modern professional literature of the pathophysiology and treatment of migraine. Data on the neurophysiological features of the brain in migraine, the emergence of drugs with other therapeutic targets, such as glutamate, amylin, adrenomedullin, orexins, and pituitary adenylate cyclase-activating polypeptide are presented. Recommendations are given for emergency treatment of a migraine attack, depending on the severity of the attack, the degree of maladaptation of the patient, concomitant symptoms, concomitant diseases and the patient's response to treatment. Prophylactic treatment can be divided into first-, second- and third-line drugs, but the choice of drugs and the order of their use depend on local practical recommendations and availability in individual regions and cost. Efficacy, safety of new drugs for specific migraine therapy are discussed such as molecules targeting calcitonin gene-related peptide (hepants and monoclonal antibodies) and serotonin 5-HT1F receptor agonists (ditans). Diagnosis and clinical management of migraine worldwide remain suboptimal. A large number of studies lead to a deeper understanding of the neurobiology of this disorder, the search for new treatment methods that are more adapted to the needs of patients and fundamentally change the approach to the disease. Keywords: calcitonin gene-related peptide, therapy, hepants, monoclonal antibodies, ditans.

CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs

BackgroundSeveral drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor.MethodsThe present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained.ResultsAlthough being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention.ConclusionsBalancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.

Switching medication within 12 months of initiating calcitonin gene-related peptide monoclonal antibodies versus other preventive treatments for migraine

Monoclonal antibodies targeting calcitonin gene-related peptide pathway (CGRP mAb) for migraine prevention are FDA-approved. This study assessed 12-month real-world switching patterns for patients initiating CGRP mAb versus other preventive migraine (non‑CGRP) treatments.

Calcitonin Gene-Related Peptide Monoclonal Antibodies Versus Botulinum Neurotoxin a in the Preventive Treatment of Chronic Migraine: An Adjusted Indirect Treatment Comparison Meta-Analysis.

Purpose: Calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) are new agents approved by the US Food and Drug Administration for preventive treatment of chronic migraine. Comparison between CGRPmAbs and previously approved Botulinum neurotoxin A (BoNT-A) will inform optimal preventive treatment of chronic migraine, but head-to-head trials are lacking. We therefore aimed to perform adjusted indirect comparison between CGRPmAbs and BoNT-A through a meta-analysis. Methods: OVID MEDLINE, EMBASE and the Cochrane central register of controlled trials, clinical registries, and government websites were searched from inception to September 2019. Randomized controlled trials comparing CGRPmAbs or BoNT-A with placebo in the preventive treatment of chronic migraine were included. The primary outcomes were headache days and migraine days measured at week 12. Data were synthesized by using a frequentist approach; and the treatments were ranked by P-score. Results: We included 10 trials (n = 4,678) after screening 1049 candidates. Six trials were with low risk of bias. Fremanezumab had an effect similar to BoNT-A in the reduction of headache days at week 12 (standard mean difference [SMD] 0.08, 95%CI -0.55 to -0.7). Galcanezumab reduced more migraine days than BoNT-A at week 12 (SMD, -0.94, 95%CI −1.24 to −0.63); fremanezumab showed similar findings (SMD, −0.55, 95%CI −0.85 to −0.24). Galcanezumab and fremanezumab had better effect in mitigating headache impact at week 12. CGRPmAbs and BoNT-A had similar adverse event rate. Conclusion: CGRPmAbs and BoNT-A had similar effect in the preventive treatment of chronic migraine. BoNT-A might be preferentially selected owing to its cost-effectiveness profiles. Further studies with direct comparison of the two treatments are warranted.

Safety efficacy and tolerability of the calcitonin gene-related peptide monoclonal antibodies for migraine prevention treatment of migraine, Kuwait experience. (1816)

Safety efficacy and tolerability of the calcitonin gene-related peptide monoclonal antibodies for migraine prevention treatment of migraine, Kuwait experience. (1816)

PACAP Induces Light Aversion in Mice by an Inheritable Mechanism Independent of CGRP.

The neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about one-third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex linked, although there was a trend for greater responses among male mice. RNA-sequencing analysis of trigeminal ganglia yielded hierarchical clustering of responder and nonresponder mice and revealed a number of candidate genes, including greater expression of the Trpc5 and Kcnk12 ion channels and glycoprotein hormones and receptors in a subset of male responder mice. Importantly, an anti-PACAP monoclonal antibody could block PACAP-induced light aversion but not CGRP-induced light aversion. Conversely, an anti-CGRP antibody could not block PACAP-induced light aversion. Thus, we propose that CGRP and PACAP act by independent convergent pathways that cause a migraine-like symptom in mice.SIGNIFICANCE STATEMENT The relationship between the neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) in migraine is relevant given that both peptides can induce migraine in people, yet to date only drugs that target CGRP are available. Using an outbred strain of mice, we were able to show that most, but not all, mice respond to PACAP in a preclinical photophobia assay. Our finding that CGRP and PACAP monoclonal antibodies do not cross-inhibit the other peptide indicates that CGRP and PACAP actions are independent and suggests that PACAP-targeted drugs may be effective in patients who do not respond to CGRP-based therapeutics.

Ubrogepant in the Acute Management of Migraine: A Narrative Review.

Ubrogepant is a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist that received Food and Drug Administration (FDA) approval for the acute treatment of migraine with and without aura in adults. The ACHIEVE I and ACHIEVE II Phase III clinical trials showed that ubrogepant was superior to placebo for pain freedom and freedom of the most bothersome migraine-associated symptom at 2 hours after medication intake. The 52-week open label extension of the Phase III trials demonstrated safety of ubrogepant. A real-world study conducted at a tertiary headache center also confirmed the efficacy and safety of ubrogepant. Adverse event rates were higher in the real-world population. Studies are needed to evaluate its long-term efficacy and safety, especially in the setting of co-administration with other CGRP modulating therapies such as the CGRP monoclonal antibodies.