Anti-calcitonin Gene-related Peptide Monoclonal Antibodies Research Articles

Migraine With Comorbid Depression: Pathogenesis, Clinical Implications, and Treatment.

Migraine is a neurological disorder that strongly relates to psychiatric conditions like depression. Lately, the increased prevalence of depression in migraineurs has come to attention. This article compiled various literature to explore the association between migraine and depression. Genetic overlap of various gene segments was studied, and heritability patterns were explored. Shared mechanisms such as serotonergic dysfunction, methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and hormonal effects were investigated, and commonalities like comorbidities, stress, and environmental factors were analyzed. Migraine with comorbid depression (MID) affects various aspects of life and its clinical impact on migraine disability, quality of life (QOL), progression, and medication overuse was investigated. We further inspected several types of research in order to provide options on various treatment modalities. Pharmacotherapy such as antidepressants and anti-Calcitonin Gene-Related Peptide (CGRP) monoclonal antibodies like fremanezumab were studied. Alternative treatment options such as onabotulinumtoxinA (OBTA) injections, cognitive behavioral therapy (CBT), and vagal nerve stimulations (VNS) were also appraised and the efficacies of each were compared.

Rapid resolution of migraine symptoms after initiating the preventive treatment eptinezumab during a migraine attack: results from the randomized RELIEF trial

BackgroundEptinezumab is an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody approved for the preventive treatment of migraine. In the phase 3 RELIEF study, eptinezumab resulted in shorter time to headache pain freedom and time to absence of most bothersome symptom (MBS; including nausea, photophobia, or phonophobia) compared with placebo when administered during a migraine attack. The objective of this exploratory analysis was to examine the earliest time points that eptinezumab separated from placebo (P < .05) on headache- and migraine-associated symptoms when administered during a migraine attack.MethodsRELIEF, a multicenter, parallel-group, double-blind trial, occurred from November 7, 2019, through July 8, 2020. Adults considered candidates for preventive treatment were randomized to eptinezumab 100 mg (N = 238) or placebo (N = 242) administered intravenously over 30 min within 1–6 h of migraine onset. Outcome measures included headache pain freedom/relief and absence of MBS, patient’s choice of photophobia, phonophobia, or nausea, at regular intervals from 0.5 to 48 h after infusion start. Censoring was applied at time of acute rescue medication use.ResultsAt hour 1, more eptinezumab-treated patients achieved headache pain freedom (9.7%), headache pain relief (38.7%), and absence of MBS (33.2%) versus placebo (4.1%, 26.9%, and 22.1%, respectively; P < .05 all), with separation from placebo (P < .05) through hour 48. Eptinezumab separated from placebo (P < .05) at hour 1 in absence-of-photophobia (29.4% vs 17.0%) and absence-of-phonophobia (41.2% vs 27.2%) and through hour 48. Initial separation from placebo (P < .05) in absence-of-nausea occurred at end-of-infusion (0.5 h; 36.7% vs 25.4%, respectively).ConclusionPreventive treatment with eptinezumab initiated during a migraine attack resulted in more patients achieving headache pain freedom/relief and absence of MBS, with separation from placebo (P < .05) as early as 0.5–1 h following the start of infusion. Rapid resolution of headache- and migraine-associated symptoms by a peripherally acting, intravenously administered antibody suggest a peripheral site of pharmacological action for CGRP blockade.Trial registrationClinicalTrials.gov Identifier: NCT04152083.

Evaluation of Headache Profiles in Pediatric Patients Pre and Post Participation in Anti-Calcitonin Gene-Related Peptide Monoclonal Antibody (Anti-CGRP mAb) Studies (P1-2.003)

Evaluation of Headache Profiles in Pediatric Patients Pre and Post Participation in Anti-Calcitonin Gene-Related Peptide Monoclonal Antibody (Anti-CGRP mAb) Studies (P1-2.003)

Treatment Satisfaction and Optimization With Real-World Use of Ubrogepant for the Acute Treatment of Migraine in Combination With an Anti-Calcitonin Gene–Related Peptide Monoclonal Antibody Preventive: Results From the COURAGE Study (P10-2.001)

Treatment Satisfaction and Optimization With Real-World Use of Ubrogepant for the Acute Treatment of Migraine in Combination With an Anti-Calcitonin Gene–Related Peptide Monoclonal Antibody Preventive: Results From the COURAGE Study (P10-2.001)

Real-World Effectiveness of Ubrogepant for the Acute Treatment of Migraine When Used in Combination With an Anti-Calcitonin Gene–Related Peptide Monoclonal Antibody Preventive: Results From the COURAGE Study (P10-2.003)

Real-World Effectiveness of Ubrogepant for the Acute Treatment of Migraine When Used in Combination With an Anti-Calcitonin Gene–Related Peptide Monoclonal Antibody Preventive: Results From the COURAGE Study (P10-2.003)

Real-world efficacy of galcanezumab for the treatment of migraine in Korean patients

We aimed to provide real-world data on the effectiveness of an anti-calcitonin gene-related peptide monoclonal antibody administered for treating migraine in Korean patients. We prospectively recruited patients with migraine who received galcanezumab treatment at a single university hospital from June 2020 to April 2021. The treatment response was assessed after three consecutive monthly injections. A 50% responder rate was evaluated based on ≥50% reduction in the number of moderate/severe headache days. Overall, 87 patients were included in the analysis. Most patients were women (83.9%). They had a mean age of 41.7 ± 12.3 years (range 17-72). Sixty-five patients (74.7%) had chronic migraine, 35 patients (40.2%) had a history of medication-overuse headache, and 32 patients (36.8%) were previously unresponsive to or found intolerable five classes of preventive medication. After three months of treatment, mean changes in numbers of monthly headache days, moderate/severe headache days, crystal clear days, and days of acute medication use were -7.2 ± 8.43, -4.3 ± 9.76, 7.3 ± 8.50, and -4.1 ± 7.93, respectively. The 50% responder rates were 58.3%, 44.2%, and 40.6% for patients with unsuccessful previous use of 0-1, 2-4, and 5 preventive medication classes, respectively. Headache Impact Test-6 and Migraine Disability Assessment Test scores also decreased (-4.4 ± 8.09 and -32.9 ± 77.04, respectively). In our cohort, the effectiveness and safety of galcanezumab were comparable with those reported in clinical trials, whereas a higher response rate was observed in the difficult-to-treat patient subset than that reported in trials. We provide real-world evidence of galcanezumab treatment benefits in Asian patients with migraine.

The importance of an early onset of migraine preventive disease control: A roundtable discussion

Background: Newly approved migraine preventive therapies have allowed for rapid control of migraine activity, offering potential to minimize the burden of migraine. This report summarizes a roundtable discussion convened to analyze evidence for early onset of prevention, ascertain its clinical relevance, and provide guidance for healthcare professionals in crafting goals and treatment expectations for patients with migraine initiating preventive therapy. Methods: A virtual roundtable meeting of migraine clinicians, researchers, and patient advocates convened in October 2020. Participants reviewed and discussed data summarizing patient and healthcare professional perceptions of migraine prevention and evidence from the peer-reviewed and gray literature to develop corresponding recommendations. Summary: Evidence from clinical studies of anti-calcitonin gene-related peptide monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and the chemodenervation agent onabotulinumtoxinA indicate that patients may experience reduction of migraine activity within 7 days of drug administration and early attainment of disease control is associated with improvements in clinically important outcomes. The roundtable of experts proposes that early onset be defined as demonstration of preventive benefits within 1 week of treatment initiation. We recommend focusing discussion with patients around “disease control” and potential benefits of early onset of prevention, so patients can set realistic preventive therapy goals and expectations.

The importance of an early onset of migraine prevention: an evidence-based, hypothesis-driven scoping literature review.

Recently approved migraine preventive therapies facilitate rapid control of migraine activity, potentially improving patients’ lives and minimizing the societal burden of migraine. This review synthesizes available evidence on rates and timing of early onset of migraine prevention and identifies patient-level outcomes related to early onset prevention. This evidence-based scoping review identified all available clinical trial evidence regarding the early onset of prevention of migraine, under the hypothesis ‘Patients with migraine (episodic or chronic) report additional benefits when receiving an approved migraine preventive treatment that demonstrates an early onset of prevention’. Early onset of prevention was defined as migraine preventive benefits within 30 days post-administration. PubMed, EMBASE, and CINAHL were searched for publications between 1988 and 2020. Overall, 16 publications described 18 studies. All studies were conducted in approved treatments [four anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and one chemodenervation agent] in patients with episodic/chronic migraine; no publications were identified for traditional oral agents for early migraine prevention. Compared to placebo, erenumab (three studies) reduced weekly migraine days within 1 week; fremanezumab (six studies) increased reports of no headache of at least moderate severity on Day 1 and significantly reduced migraine frequency within 1 week; galcanezumab (three studies) significantly reduced the mean number of patients with migraine beginning Day 1 and each day of the first week; eptinezumab (four studies) significantly reduced migraine attack likelihood on Day 1 by > 50% versus baseline; and onabotulinumtoxinA (two studies) reduced headache and migraine days within 1 week. Four publications described function, disability, and quality of life improvements as early as Week 4; none reported cost–benefit. Anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and a chemodenervation agent (onabotulinumtoxinA) provide clinically relevant benefits during the first treatment week. Literature describing clinically relevant benefits regarding early onset of prevention in patients with migraine is limited.

Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies in the Treatment of Patients With Concussion

Investigate the efficacy of 3 anti-Calcitonin Gene-Related Peptide monoclonal antibodies (anti-CGRP mAbs), fremanezumab, galcanezumab, and erenumab, in concussion patients with post-traumatic headache (PTH) with a migraine phenotype. A study using monoclonal antibodies in mice with mild traumatic brain injury saw improvements in cutaneous allodynia.1 A study from Denmark using erenumab for PTH found patients had an 82% decrease in the number of headache days. This study also demonstrated that 44% of patients had a reduction in HIT-6 score = 5 after 9-12 weeks of treatment.2. Retrospective chart review of patients diagnosed with PTH (n = 168) evaluated HIT-6, number of reported headache days, and the number of modifiable concussion variables (headache, dizziness, attention/concentration deficit, mood and sleep disturbance) prior to initiation of anti-CGRP mAbs and after at least 3 months of treatment were recorded. Patients saw a decrease in HIT-6 score (p < 0.0001), with a mean difference of -4.26 from pre-treatment to at least 3 months after treatment. When evaluating 5 concussion symptom categories, patients experienced x¯ = 2.35 symptoms prior to anti-CGRP mAbs treatment, and x¯ = 1.67 after at least 3 months of treatment. Patients also experienced a decrease in the number of headache days per month (<0.0001) with a mean difference of -7.25 (range 0-30) headache days per month. Seven patients experienced adverse effects (1 patient had 2 different adverse effects), including injection site rash, fatigue, constipation, and dizziness. Only one patient discontinued medication due to adverse event. Anti-CGRP mAbs used to treat PTH showed improved headache severity and frequency, as well as a decreased number of overall concussion symptoms. There was a subset of patients with a more robust response. Switching anti-CGRP mAbs was beneficial in some patients.

Quality of Life Related to Functional Disability in Migraine Patients: A Systematic Review and Network Meta-analysis.

The aim of this study was to conduct a systematic review and network meta-analysis of all randomized trials investigating effect of anti-calcitonin gene-related peptide monoclonal antibodies on disability related to migraine in adult patients. Medline, Embase, and Cochrane Central Register of Controlled Trials searched from inception to July 2020 with an additional review of clinical trial registries. Disability evaluated using change in patient reported Migraine Disability Assessment scores from baseline were considered for the final analysis. The network meta-analysis was conducted in Bayesian framework using OpenBUGS and R, with the random effects model selected to allow for apparent heterogeneity between studies in the treatment comparison effects. Overall 41 studies (7095 migraineurs in 9 randomized trials) were included with treatment course of at least 12 weeks. Subcutaneous injections of fremanezumab 675+225+225 mg QM and 225+225+225 mg QM were more effective in reducing disability in chronic and episodic migraine patients, respectively, with higher median difference in Migraine Disability Assessment score from baseline compared with other treatments including erenumab (70 mg QM; 140 mg QM), galcanezumab (120 mg QM; 240 mg QM), and low doses of fremanezumab (225 mg single dose; 675 mg single dose). For short-term prevention of migraine, fremanezumab demonstrated slightly better improvement in disability compared with other anti-calcitonin gene-related peptide monoclonal antibodies in adult patients with migraine.

Different routes of administration in chronic migraine prevention lead to different placebo responses: a meta-analysis

Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. Thus, this meta-analysis aims to analyze how different routes of administration affect the placebo response in chronic migraine (CM). We conducted a meta-analysis with 7 randomized, double-blind, placebo-controlled clinical trials, with 5672 patients older than 18 years who suffer from CM without associated comorbidities. We compared those who received a placebo-administered agent for the preventive treatment of CM subcutaneous, endovenous, or oral against those who received multiple head injections. The primary outcome was reduction in the number of days with migraine in the month assessed at 12, 16, and 24 weeks of treatment compared with baseline. Our study shows that placebo responses were greater when botulinum toxin was applied to the head, followed by intravenous injection of the anti-calcitonin gene-related peptide monoclonal antibody eptinezumab. Oral topiramate and subcutaneous monoclonal showed no difference, being inferior to head injection. Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.

Use of Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies in Pediatric Migraine Prevention (4082)

Use of Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies in Pediatric Migraine Prevention (4082)

Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies in the Treatment of Patients with Concussion (2352)

Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies in the Treatment of Patients with Concussion (2352)

Long-term safety and tolerability of eptinezumab in patients with chronic migraine: a 2-year, open-label, phase 3 trial

BackgroundEptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody recently approved in the United States for preventive treatment of migraine in adults, was found to be well tolerated in double-blind, placebo-controlled studies in patients with episodic and chronic migraine. The objective of the PREVAIL study was to evaluate the long-term safety, immunogenicity, and impact on patient-reported outcomes of repeat doses of eptinezumab in patients with chronic migraine.MethodsPREVAIL was an open-label, phase 3 trial comprising a 48-week treatment phase followed by a second 48-week treatment phase. Adults with chronic migraine received eptinezumab 300 mg by 30-min intravenous administration every 12 weeks for up to 8 doses. Patients were followed for 20 weeks after the final infusion (end-of-study visit at week 104).ResultsOverall, 128 adults (mean age, 41.5 years) with chronic migraine were included. During the 2 years, the most frequently reported treatment-emergent adverse events were nasopharyngitis (14.1%), upper respiratory tract infection (7.8%), sinusitis (7.8%), influenza (6.3%), bronchitis (5.5%), and migraine (5.5%). The rate of study-drug discontinuation due to adverse events was 6.3%, which included 3 patients with infusion-related hypersensitivity. The incidence of anti-eptinezumab antibodies peaked at week 24 and declined despite continued dosing, to nondetectable levels at week 104. Improvements in patient-reported outcomes were observed at first assessment (week 4) and generally sustained through week 104.ConclusionIn adults with chronic migraine, eptinezumab 300 mg demonstrated a favorable safety profile, limited long-term immunogenicity, early and sustained reductions in migraine-related burden, and improvements in health-related quality of life over 2 years.Trial registrationClinicalTrials.gov (Identifier: NCT02985398).

Safety profile of anti-calcitonin gene-related peptide monoclonal antibodies in pregnancy, lactation and fertility: analysis of the WHO global pharmacovigilance database

Safety profile of anti-calcitonin gene-related peptide monoclonal antibodies in pregnancy, lactation and fertility: analysis of the WHO global pharmacovigilance database

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model.

Posttraumatic headache is one of the most common, debilitating, and difficult symptoms to manage after a traumatic head injury. The development of novel therapeutic approaches is nevertheless hampered by the paucity of preclinical models and poor understanding of the mechanisms underlying posttraumatic headache. To address these shortcomings, we previously characterized the development of posttraumatic headache-like pain behaviors in rats subjected to a single mild closed head injury using a 250 g weight drop. Here, we conducted a follow-up study to further extend the preclinical research toolbox for studying posttraumatic headache by exploring the development of headache-like pain behaviors in male rats subjected to a single, but more severe head trauma (450 g) as well as following repetitive, subconcussive head impacts (150 g). In addition, we tested whether these behaviors involve peripheral calcitonin gene-related peptide signaling by testing the effect of systemic treatment with an anti-calcitonin gene-related peptide monoclonal antibody (anti-calcitonin gene-related peptide mAb). Adult male Sprague Dawley rats (total n = 138) were subjected to diffuse closed head injury using a weight-drop device, or a sham procedure. Three injury paradigms were employed: A single hit, using 450 g or 150 g weight drop, and three successive 150 g weight drop events conducted 72 hours apart. Changes in open field activity and development of cephalic and extracephalic tactile pain hypersensitivity were assessed up to 42 days post head trauma. Systemic administration of the anti-calcitonin gene-related peptide mAb or its control IgG (30 mg/kg) began immediately after the 450 g injury or the third 150 g weight drop with additional doses given every 6 days subsequently. Rats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Injured animals also displayed delayed and prolonged extracephalic tactile pain hypersensitivity that remained present at 6 weeks post-injury. Repetitive subconcussive head impacts using the 150 g weight drop, but not a single event, led to decreased vertical rearing as well as cephalic and extracephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Early and prolonged anti-calcitonin gene-related peptide mAb treatment inhibited the development of the cephalic tactile pain hypersensitivity in both the severe and repetitive subconcussive head impact models. Severe head injury gives rise to a prolonged state of cephalic and extracephalic tactile pain hypersensitivity. These pain behaviors also develop following repetitive, subconcussive head impacts. Extended cephalic tactile pain hypersensitivity following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-calcitonin gene-related peptide mAb treatment, suggesting a mechanism linked to calcitonin gene-related peptide signaling, potentially of trigeminal origin.

Dual Therapy With Anti-CGRP Monoclonal Antibodies and Botulinum Toxin for Migraine Prevention: Is There a Rationale?

To narratively review the pathophysiological rationale of dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A in treatment-resistant chronic migraine prevention. For the prevention of chronic migraine, several pharmacological therapies are available, including oral medications, botulinum toxin type A, and the newly approved monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. However, monotherapy does not yield benefits in some affected individuals, which raises the question of whether dual therapy with monoclonal antibodies and botulinum toxin type A hold promise in patients with treatment-resistant chronic migraine. We searched MEDLINE for articles published from database inception to December 31st, 2019. Publications were largely selected from the past 10years but commonly referenced and highly regarded older publications were not excluded. Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab - an antibody targeting the calcitonin gene-related peptide - mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers. There is currently only indirect preclinical evidence to support a rationale for dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A for chronic migraine prevention. Rigorous studies evaluating clinical efficacy, safety, and cost-effectiveness are needed.

Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury.

Females are thought to have increased risk of developing post-traumatic headache following a traumatic head injury or concussion. However, the processes underlying this susceptibility remain unclear. We previously demonstrated the development of post-traumatic headache-like pain behaviors in a male rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we conducted a follow-up study to explore the development of post-traumatic headache-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. Adult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device (n = 126), or to a sham procedure (n = 28). Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of intraperitoneal administration of a low dose of glyceryl trinitrate (100 µg/kg). Treatments included acute systemic administration of sumatriptan (1 mg/kg) and repeated systemic administration of a mouse anti-calcitonin gene-related peptide monoclonal antibody (30 mg/kg). Serum levels of calcitonin gene-related peptide were measured at baseline and at various time points post head injury in new cohorts of females (n = 38) and males (n = 36). Female rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, which was limited to the cephalic region and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan but was resistant to an early and prolonged treatment with the anti-calcitonin gene-related peptide monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of glyceryl trinitrate produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-calcitonin gene-related peptide treatment. Calcitonin gene-related peptide serum levels were elevated in females but not in males at 7 days post head injury. Development of post-traumatic headache-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to the data obtained from male rats in the previous study, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-calcitonin gene-related peptide treatment. The increased risk of females to develop post-traumatic headache may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral calcitonin gene-related peptide signaling.

Exploring the safety, tolerability, cost-effectiveness and efficacy of erenumab in chronic migraine

The complex pathophysiology of migraine is mirrored by the diverse pharmacological options available for sufferers, which have variable efficacy and tolerability. Recent studies have demonstrated that anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP MAbs) are efficacious in migraine prevention. An observational clinical audit was conducted, involving 16 adults with chronic migraine, all of whom had tried and failed four or more preventatives, including at least two cycles of onabotulinumtoxinA (Botox). The patients received 70 mg of erenumab at 4-weekly intervals. The objective was to assess the reduction in monthly headache days and severe headache days, reduction in acute treatments and improvement in quality of life compared with existing clinical data. This small audit demonstrated that erenumab could be an effective and well-tolerated migraine preventative for refractory patients who had not previously responded to four or more preventatives, including at least two cycles of Botox.

Anticalcitonin gene-related peptide monoclonal antibodies: An overview

Anticalcitonin gene-related peptide monoclonal antibodies: An overview