The influence of pharmacodynamics and pharmacokinetics on the antimigraine efficacy and safety of novel anti-CGRPergic pharmacotherapies: a narrative review.

INTRODUCTION: Migraine is a complex disorder, and its etiology is not yet fully understood. In the last 40 years, calcitonin gene-related peptide (CGRP) has been central to the understanding of migraine pathophysiology, leading to the development of new molecules targeting the CGRPergic system. These new molecules, such as gepants and monoclonal antibodies, are effective, well-tolerated, and safe, and are approved for clinical use. AREAS COVERED: By searching multiple electronic scientific databases, this narrative review examined: (i) the role of CGRP in migraine; and (ii) the current knowledge on the effects of CGRPergic antimigraine pharmacotherapies, including a brief analysis of their pharmacodynamic and pharmacokinetic characteristics. EXPERT OPINION: Current anti-CGRPergic medications, although effective, have limitations, such as side effects and lack of antimigraine efficacy in some patients. The existence of patients with medication-resistant migraine may be due to the: (i) complex migraine pathophysiology, in which several systems appear to be deregulated before, during, and after a migraine attack; and (ii) pharmacodynamic and pharmacokinetic properties of antimigraine medications. As envisioned here, although seminal studies support the notion that CGRP plays a key role in migraine headache, the dysfunction of CGRPergic transmission does not seem to be relevant in all cases.

Changes in use of acute and preventive medications for migraine after erenumab initiation over 12 months: A United States retrospective cohort study.

OBJECTIVE: To assess changes in real-world use of acute and preventive medications for migraine over a 12-month follow-up period in the United States following initiation of the anti-calcitonin gene-related peptide (CGRP) pathway monoclonal antibody (mAb) erenumab. BACKGROUND: Early assessments of real-world use of acute and preventive medications for migraine after initiation of erenumab have been limited to 6 months of follow-up. METHODS: This retrospective cohort study used data from the IQVIA open-source longitudinal prescription (LRx) and medical (Dx) claims databases. Adult patients with an initial claim (index date) for erenumab between May 2018 and April 2020 were identified. RESULTS: Among 201,176 patients who met inclusion criteria, the mean (standard deviation [SD]) age was 47.5 (13.8) years and 85.6% (n = 172,153) were female. Most patients used one or more acute (88.4%; n = 177,795) and one or more traditional preventive (86.1%; n = 173,225) medications during the 12-month pre-index period. Adherence to erenumab (proportion of days covered [PDC] ≥0.80) was 40.2% (n = 80,927) with an overall mean (SD) PDC of 0.60 (0.34). Among all patients, 70.0% (n = 140,809) discontinued erenumab. After accounting for 24.7% (n = 49,720) of patients who restarted erenumab, discontinuation without reinitiation was observed in 45.3% (n = 91,089) of total patients. Switching to a different anti-CGRP pathway mAb was observed in 13.1% (n = 26,446) of total patients. Among 177,795 patients with pre-index use of one or more acute migraine medication class, 86.5% (n = 153,788) had post-index use of the same class, and 56.7% (87,134/153,788) of them discontinued one or more class of acute medication in the 12-month follow-up period. Similarly, among 173,225 patients with pre-index use of one or more traditional migraine preventive medication class, 67.7% (n = 117,274) had post-index use of the same class, and 46.7% (54,790/117,274) of them discontinued one or more class of traditional preventive medication in the 12-month follow-up period. CONCLUSIONS: In this long-term study, we observed the discontinuation of both acute and preventive medications for migraine post-erenumab initiation.

Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON).

BACKGROUND: Efficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab's tolerability and safety profile in individuals experiencing episodic and chronic migraines. METHODS: The study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption ('drug holiday') of up to 24 weeks. RESULTS: 701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed. CONCLUSIONS: APOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04084314 ( https://clinicaltrials.gov/study/NCT04084314 ), First submitted: 2019-09-06.

Impact of Erenumab on Migraine Disability: A Three-Month MIDAS (Migraine Disability Assessment Scale) Score Analysis at Dubai Health Facilities.

BACKGROUND AND AIM: Migraine is a prevalent neurological disorder causing recurrent headaches that significantly impact daily life. Erenumab, a calcitonin gene-related peptide (CGRP) receptor antagonist, has emerged as a promising treatment for migraine. CGRP is thought to play a role in migraine pathophysiology, and erenumab works by blocking CGRP binding to its receptors. Erenumab has been found to be effective in reducing migraine frequency, with potential benefits for improving patient outcomes. This study investigated the impact of erenumab on migraine disability in patients treated at Dubai Health facilities. We specifically assessed changes in Migraine Disability Assessment Scale (MIDAS) scores before and after a three-month treatment period. METHODS: This retrospective analysis examined data from 26 patients diagnosed with migraine according to the established criteria. All patients received erenumab treatment for three months. MIDAS, a validated tool, was used to quantify migraine-related disability at baseline and after treatment completion. Due to potential skewness in the data distribution, the statistical analysis focused on the median change in MIDAS scores across groups based on gender and erenumab dosage. Non-parametric tests were employed to assess group differences. RESULTS: Erenumab treatment resulted in a median decrease of 13 points in MIDAS scores, suggesting a potential improvement in migraine disability at three months. Statistical analysis revealed no statistically significant group differences regarding MIDAS score changes between genders or erenumab dosage groups. However, trends toward improvement were observed in all subgroups. CONCLUSION: While not statistically significant due to the limited sample size and the absence of a control group, these findings suggest a potential benefit of erenumab in reducing migraine disability. Future research with more extensive, controlled trials is warranted to definitively assess erenumab's effectiveness and explore potential treatment regimen variations for optimal patient outcomes.

Exploring Erenumab's Efficacy and Safety for Migraine Prevention in Real-World Settings: A Systematic Review.

Migraine causes debilitating headaches and significantly impacts quality of life. Effective migraine-specific treatments have been lacking until the advent of monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) receptors, which have expanded therapy options for migraine treatment. This study explores the short- and long-term efficacy and safety of erenumab in migraine treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria guided this systematic review. Five databases - PubMed, PubMed Central, Google Scholar, ScienceDirect, and Sage Journal - were searched for published, freely accessible, full-text articles in English from the past five years. Eligible patients included those with episodic or chronic migraines who received erenumab intervention. From an initial search yielding 680 relevant studies, 12 prospective observational cohort studies were selected after assessing the risk of bias through the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. All included studies demonstrated a significant reduction in monthly migraine days (MMDs) by the end of the treatment period, with mild adverse effects observed. No significant short-term or long-term safety concerns were identified.

Real-world Efficacy of Erenumab on Migraine-associated Symptoms and Patient-reported Satisfaction Levels: A Retrospective Study in Japan.

Objective In randomized clinical trials and real-world studies, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), including erenumab, have demonstrated efficacy for migraine prevention. However, there have been no real-world studies focusing on erenumab in East Asia that investigated its efficacy on migraine-associated symptoms and patient-reported satisfaction levels. Methods This single-center, observational, retrospective, real-world study examined patients who received at least three doses of erenumab at Keio University Hospital, Tokyo, Japan, between December 2021 and March 2023 as their first CGRP mAb treatment in a real-world setting. The patients were administered 70 mg of erenumab monthly. We assessed changes in monthly migraine days (MMDs), responder rates, migraine-associated symptoms including photophobia, phonophobia, nausea/vomiting, and patient-reported satisfaction levels. In addition, injection site reactions and other adverse events were recorded to investigate safety. Results Nineteen patients were considered eligible for the analysis. At 3 months, erenumab decreased MMDs by 6.6 (95% confidence interval, 2.3-10.8; p<0.01). The 50% responder rate was 42%. A total of 83% (n=15), 56% (n=10), and 71% (n=10) of patients reported either improvement in or disappearance of photophobia, phonophobia, and nausea/vomiting, respectively, and 44% (n=8) and 28% (n=5) answered "very satisfied" and "somewhat satisfied", respectively, with erenumab treatment, leaving only 28% (n=5) as "unsatisfied". Injection site reactions (n=6, 32%) and constipation (n=4, 21%) were frequent adverse events. Conclusion In a real-world setting in Japan, erenumab proved to be effective in not only reducing migraine and headache frequency but also improving migraine-associated symptoms and satisfying the majority of patients.

Erenumab versus topiramate: migraine-related disability, impact and health-related quality of life.

BACKGROUND AND PURPOSE: HER-MES was the first head-to-head study of erenumab against topiramate (standard of care). This post hoc analysis of the HER-MES study evaluated the effect of erenumab versus topiramate on patient-reported outcomes at week 24. METHODS: Adult patients with episodic or chronic migraine (n = 777) were randomized (1:1) to monthly subcutaneous erenumab (n = 389) or daily oral topiramate (n = 388). Migraine-related disability, as measured by the Headache Impact Test 6 (HIT-6) and Short Form 36 Health Survey version 2 (SF-36v2), was analysed in the entire study cohort and true completers. RESULTS: In the erenumab group (vs. topiramate), significant improvements were reported in Headache Impact Test 6 total scores (composite populations, -10.88 vs. -7.72; true completers, -11.92 vs. -10.61) and a higher proportion of patients achieved a ≥5-point reduction from baseline with erenumab (composite populations, 72.2% vs. 53.9%; true completers, 79.64% vs. 71.43%). The adjusted mean change from baseline in the SF-36v2 score was greater with erenumab for both physical component summary (composite population, 5.48 vs. 3.63; true completers, 5.95 vs. 5.23) and mental component summary (composite populations, 1.00 vs. -1.18; true completers, 1.74 vs. -0.33). A higher proportion of patients on erenumab versus topiramate had a ≥5-point improvement in SF-36v2 for the physical component summary (composite populations, 47.7% vs. 37.4%; true completers, 52.1% vs. 48.9%) and mental component summary (composite populations, 25.3% vs. 16.8%; true completers, 27.3% vs. 17.7%). CONCLUSIONS: This post hoc analysis demonstrated that patients treated with erenumab had significant improvements in headache impact and quality of life as measured by patient-reported outcomes versus patients treated with topiramate.

Changes in Use of Migraine Medications, Healthcare Resource Utilization, and Associated Direct Costs Over 12 Months Following Initiation of Erenumab: A US Retrospective Real-World Analysis.

INTRODUCTION: Erenumab-aooe is approved for the preventive treatment of migraine in adults. Recent publications have evaluated migraine medication use during the 6 months after starting erenumab, but longer-term follow-up data are limited. The objective of this study was to describe 12-month medication use and changes in healthcare resource utilization (HRU) and associated direct costs among patients initiating erenumab. METHODS: We identified adult patients with an erenumab claim in the Merative MarketScan Commercial and Medicare Databases from May 2018 through September 2019. Eligible patients had ≥ 12 months of continuous medical and pharmacy coverage before (pre-index period) and after (post-index period) the index date (first erenumab claim) in addition to pre-index evidence of migraine. Patients were stratified by post-index-period adherence to erenumab, defined as ≥ 80% of days covered (adherent) or < 80% of days covered (non-adherent). Outcomes were measured pre- and post-index, and differences between these periods were described. RESULTS: Among 7528 eligible patients, the mean (standard deviation) age was 45.1 (11.4) years and 85.4% were female; 38.5% of patients were adherent to erenumab. Most patients used acute or traditional migraine-preventive medications pre-index, with reductions in use observed post-index (acute medication was used by 95.6% of patients pre-index, compared to 92.3% post-index; traditional preventive medication was used by 89.6% of patients pre-index, compared to 81.9% post-index). Reductions were observed for HRU of emergency room visits (- 3.8%) and brain- and other head-imaging studies (- 7.5%). Overall costs associated with acute and traditional preventive medications were reduced (- $764), but costs for HRU increased slightly ($76). When stratifying by adherence and combining costs for acute and traditional preventive medications and HRU, adherent patients had cost decreases (- $1947), while non-adherent patients had cost increases ($101). CONCLUSION: Most patients initiating erenumab had prior use of acute and traditional migraine-preventive therapies. The reduction in acute and traditional migraine-preventive medication use and HRU over the 12-month follow-up supports the long-term clinical benefits of erenumab in the real-world setting.

Impact of duration of chronic migraine on long-term effectiveness of monoclonal antibodies targeting the calcitonin gene-related peptide pathway-A real-world study.

OBJECTIVE: We assessed whether the effectiveness of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway changes according to the duration of chronic migraine (CM) over 12 months. BACKGROUND: In most patients, CM is a progressive disease starting with episodic migraine. Longer CM duration might be associated with more difficult treatment, probably because the mechanisms underlying chronicization are strengthened. Therefore, early treatment of CM could lead to better outcomes compared with later treatment. METHODS: This cohort study included individuals with CM treated with anti-CGRP mAbs in two tertiary headache centers from April 2019 to May 2023. The primary outcome included a change in monthly migraine days (MMDs) from baseline to the third trimester of treatment, 10-12 months. Secondary outcomes established whether response to anti-CGRP mAbs has a more rapid onset in individuals with shorter CM duration compared with longer duration; they included change in MMDs, monthly headache days (MHDs), and days and number of intakes of acute medication during each trimester compared to baseline. Additional outcomes included persisting MMDs, MHDs, and days and number of intakes of acute medication during each trimester of treatment. Patients were compared across tertiles of the overall CM duration. RESULTS: The study included 335 individuals with CM, with a median (interquartile range [IQR]) age of 48 (39-57) years; 270 (80.6%) were women. Patients in the highest tertile of CM duration (aged 18-60 years) were older than patients in the lower duration tertiles (0-7 years and 8-18 years, respectively), with a median (IQR) age of 56 (48-64) years compared with 42 (31-50) years, and 48 (39-56)years, respectively (p = 0.025); however, this difference was likely due to a correlation between age and disease duration. The change in MMDs from baseline to the last trimester of treatment (10-12 months) was comparable across tertiles of CM duration (median [IQR] -12 [-18 to -5] days, -12 [-17 to -6] days, and -12 [-18 to -4] days; p = 0.946). No difference emerged in secondary outcomes, suggesting a similar time to onset of anti-CGRP mAbs effect across all tertiles of CM duration. CONCLUSIONS: Our data showed that anti-CGRP mAbs are effective and have a rapid onset of action in CM regardless of disease duration.

Erenumab escalation in migraine - double dose without additional benefit - a retrospective experience.

BACKGROUND: Erenumab is a monoclonal antibody specifically targeting the CGRP-receptor. Several studies showed efficacy and safety in patients with migraine. Less is known regarding dosage increase, especially in a difficult to treat patients. The aim of the study is to evaluate the increased dosage under real world conditions with particular focus on 70 mg non-responders. METHODS: In a retrospective analysis, patients treated in tertiary headache centers (Halle or Jena, Germany) receiving 70 mg erenumab for at least 3 months with a dosage increase to 140 mg were analyzed. Data were evaluated regarding headache days, intake of acute medication, previous prophylaxis, and medication overuse. Baseline and all treatment intervals were determined as three-month periods. RESULTS: Datasets of 52 migraine patients (90.4% women) aged between 22 and 78 years (mean 50.4 years, SD 12.1 years) were analyzed. At baseline (mean headache-days 15.67 ± 6.37) 51.9% met criteria for chronic migraine and 56% were currently overusing acute medication. While therapy with 70 mg showed significant improvement in headache days and 50% response, further improvement was not achieved for therapy escalation to 140 mg. The same applies to the secondary endpoints and covers the entire study population as well as the subgroups of chronic and episodic migraine. The 50% response of the 70 mg non-responders for escalation was only 5.14%. CONCLUSIONS: In this difficult-to-treat patient cohort we reconfirmed the effectiveness of erenumab, but could not detect any additional benefit for a dosage escalation from 70 mg to 140 mg erenumab.

Additional effect of erenumab for patients with chronic migraine treated with onabotulinumtoxin A-real-world data from a preliminary cohort study.

Background: This preliminary retrospective cohort study investigates the potential additive prophylactic effect of erenumab, a fully human monoclonal antibody that blocks the calcitonin gene-related peptide receptor, in combination with ongoing onabotulinumtoxin A (onaBoNT-A) treatment in patients suffering from chronic migraine. Methods: The study included 218 patients and investigated the effects of adding erenumab to the existing treatment regimen. The primary outcome was the MIDAS (Migraine Disability Assessment) score assessed 3 months after the introduction of erenumab. Results: The results indicated a significant improvement of the MIDAS score, suggesting a reduction in migraine-related disability following the addition of erenumab to onaBoNT-A. In the inter group comparison, dual therapy showed a significantly greater reduction of the MIDAS when compared to a switch from onaBoNT-A to erenumab monotherapy, but not compared to initiation of onaBoNT-A monotherapy. It is hypothesized that the observed additive effects are due to the independent modes of action of erenumab and onabotulinumtoxin A. Conclusion: This study suggests that the combination of erenumab with onaBoNT-A may offer an improved approach for the treatment of chronic migraine in selected patients. However, the results highlight the need for prospective, controlled studies to validate these findings and determine the optimal combination of treatments tailored to the individual patient.

Persistent effectiveness of CGRP antibody therapy in migraine and comorbid medication overuse or medication overuse headache - a retrospective real-world analysis.

BACKGROUND: Management of patients with migraine who have concomitant medication overuse (MO) or medication overuse headache (MOH) is a major problem in clinical practice. Detoxification of acute analgesics before or during initiation of prophylactic therapy has long been recommended although this concept has recently been questioned. Additionally, relapse after detoxification is a common problem. This real-world study analyses the initial and sustained effectiveness of prophylactic migraine therapy with CGRP (receptor) antibodies without prior detoxification in patients with comorbid MO or MOH for up to one year. METHODS: A retrospective real-world analysis was performed on 291 patients (episodic migraine (EM) with MO (EM-MO; n = 35), EM without MO (EM-noMO; n = 77), chronic migraine (CM) with MOH (CM-MOH; n = 109), CM without MOH (CM-noMOH; n = 70). All patients began treatment with either erenumab (n = 173), fremanezumab (n = 70) or galcanezumab (n = 48) without prior detoxification. Data were available for up to 12 months of treatment. Responder rates for monthly headache days (MHD), monthly migraine days (MMD) and monthly acute medication intake (AMD) were analysed. RESULTS: All groups showed a significant reduction in MHD, MMD and AMD at the last observed time point compared to baseline. In patients with CM and MOH, 60.6% (66/109) no longer fulfilled the definition of MO or MOH and a further 13.8% (15/109) had only EM-MO. In the EM cohort, 89% (31/35) of MO patients lost their MO during therapy. MHD and AMD 30% responder rates were comparable for CM-MOH and CM-noMOH (MHD: CM-MOH: 56.0% vs. CM-noMOH: 41.4%, p = 0.058, AMD: CM-MOH: 66.1% vs. CM-noMOH: 52.9%, p = 0.077). MMD responder rate did not differ significantly (after Bonferroni adjustment) (CM-MOH: 62.4% vs. CM-noMOH: 47.1%, p = 0.045, α = 0.017). After successful initiation of therapy, 15.4% of the initial CM-MOH patients relapsed and met the criterion for CM-MOH at the end of follow-up. There were no antibody specific differences in response to therapy. CONCLUSIONS: Our data confirms the effectiveness of CGRP antibody treatment in migraine patients with additional MOH or MO in a real-world setting. Low relapse rates after initial successful therapy support an early start of CGRP antibody treatment in patients with MOH or MO. TRIAL REGISTRATION: No registration, retrospective analysis.

Real-world experiences of migraine patients on Erenumab: a Kuwait single center cohort.

BACKGROUND: Migraine is a prevalent headache disorder with a significant impact on the quality of life. This study aims to investigate the effectiveness and safety of erenumab, mAb targeting the CGRP receptor, in treating chronic (CM) and episodic (EM) migraine in clinical practice Kuwait, providing region-specific insights to treatment options. METHOD: This was a prospective observational cohort study of patients diagnosed with EM or CM treated with erenumab. The primary outcome of the study was to assess the proportion of patients achieving ≥ 50% reduction in monthly mean migraine days, and several changes including the mean number of monthly migraine days, the frequency of analgesic use, attack severity, AEs, and QoL. RESULTS: The study included 151 patients with a mean age of 44.0±11.4 years, and 81.9% female. The primary outcome was achieved in 74.2% of patients, with a significant (p < 0.001) reduction in headache frequency, pain severity, analgesic use, and improvement in QoL. Age and duration of migraine were significant predictors of achieving a ≥ 50% reduction in headache frequency after therapy (OR = 0.955; p = 0.009) and (OR = 0.965; p = 0.025), respectively. Treatment compliance was observed in 76.2% of patients, and 24.5% discontinued treatment. Constipation was the most commonly reported AEs (6.0%), and conservative management was the most common approach to managing AEs. CONCLUSION: Erenumab was effective in reducing the frequency and severity of migraine attacks and improving QoL, and safe with manageable AEs in a real-world setting in Kuwait. Further research is needed to better understand erenumab's effectiveness and safety in different populations and settings, as well as to compare it with other migraine prophylactic treatments.

Implications of therapy interruption on monthly migraine days and modified migraine disability assessment in patients treated with erenumab for chronic and episodic migraine: SQUARE study interim results.

BACKGROUND: There are limited real-world data in Switzerland examining the impact of erenumab, a fully human IgG2 monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor, on migraine-related quality of life. OBJECTIVE: This 18-month interim analysis of 172 patients with episodic or chronic migraine from the SQUARE study provides first prospective insights on the impact of mandatory erenumab treatment interruption, following Swiss-reimbursement requirements, in a real-world clinical setting in Switzerland. FINDINGS: Recruited patients receiving 70 or 140 mg erenumab underwent treatment interruption on average 11.2 months after therapy onset with a mean duration of 4 months. There were sustained improvements in mean monthly migraine days (MMD) and migraine disability (mMIDAS) during initial treatment with erenumab. Treatment interruption was associated with a temporary worsening of condition. Symptoms ameliorated upon therapy reuptake reaching improvements similar to pre-break within 3 months. CONCLUSIONS: Treatment interruption was associated with a temporary worsening of condition, which improved again after therapy restart.

Hypersensitivity to CGRP as a predictive biomarker of migraine prevention with erenumab.

BACKGROUND: The present study aimed to investigate the predictive value of calcitonin gene-related peptide (CGRP)-induced migraine attacks for effectiveness to erenumab treatment in people with migraine. METHODS: In total, 139 participants with migraine underwent a single experimental day involving a 20-min infusion with CGRP. Following this, the participants entered a 24-week treatment period with erenumab. The primary endpoints were the predictive value of CGRP-induced migraine attacks on the effectiveness of erenumab, defined as ≥50% reduction in monthly migraine days, or ≥ 50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity. RESULTS: Among participants with CGRP-induced migraine attacks, 60 of 99 (61%) achieved ≥50% reduction in monthly migraine days during weeks 13-24 with erenumab. Conversely, 13 of 25 (52%) where CGRP infusion did not induce a migraine achieved the same endpoint (p = 0.498). There were no significant differences between the ≥50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity between CGRP-sensitive and non-sensitive participants (p = 0.625). CONCLUSIONS: Our findings suggest that the CGRP-provocation model cannot be used to predict erenumab's effectiveness. It remains uncertain whether this finding extends to other monoclonal antibodies targeting the CGRP ligand or to gepants.Trial Registration: The study was registered at ClinicalTrials.gov (NCT04592952).

Blood pressure monitoring in elderly migraineurs starting an anti-CGRP monoclonal antibody: a real-world prospective study.

BACKGROUND: While monoclonal antibodies (mAbs) targeting the CGRP pathway have revolutionized migraine management due to their improved tolerance and adherence, concerns remain about their potential impact on blood pressure (BP), especially in older patients, due to CGRP-mediated vasodilation blockade. Given the growing use of these therapies in older populations, assessing their cardiovascular (CV) safety is of paramount importance. METHODS: This multicentric observational prospective study focused on migraine sufferers aged ≥ 60 who began erenumab, galcanezumab, or fremanezumab for prevention. Baseline, three-month, and twelve-month BP measurements were collected. Changes in antihypertensive medication and "Newly or Worsened Hypertensive" patients (NWHP) were assessed. RESULTS: Among 155 patients receiving anti-CGRP mAbs (40 Erenumab, 47 Galcanezumab, 68 Fremanezumab), 42.5% had hypertension history and 39% were on antihypertensive treatment. No significant systolic or diastolic BP changes occurred at any time point compared to baseline (all p > 0.05), with no differences between the three groups. After one year, 20/155 (12.9%) patients were considered NWHP; 11/20 had prior hypertension, and 5/11 adjusted antihypertensive therapy. Among 9/20 newly hypertensive patients, 5/9 had a single measurement above the normal threshold with no requirement for new pharmacological therapy. A higher baseline BP value was associated with increased BP (p = 0.002). CONCLUSIONS: The study concludes that treatment with anti-CGRP mAbs over one year does not significantly affect BP in patients aged ≥ 60, nor does it increase the incidence of hypertension compared to general population trends. Nonetheless, continuous monitoring and further long-term studies are necessary to fullya scertain the cardiovascular safety of these medications in the elderly.

Analysis to retreatment with monoclonal antibodies in chronic/episodic migraine: Real world data. / [Artículo traducido] Análisis del retratamiento con anticuerpos monoclonales en la migraña crónica/episódica: datos en vida real.

OBJECTIVE: To analyze the response to retreatment in patients with chronic/episodic migraine who discontinued therapy with erenumab/fremanezumab after one year of treatment. METHODS: Observational, retrospective, single-center, multidisciplinary study in patients with chronic/episodic migraine who received therapy with erenumab/fremanezumab for at least one year and discontinued it after achieving an adequate response (optimization). The evaluation of the response after retreatment included the following variables: migraine days per month, MIDAS and HIT-6 scales at the beginning of retreatment and 3 months later. The response was evaluated in different subgroups (episodic/chronic, erenumab/fremanezumab and time until retreatment). RESULTS: 48 patients were included. 70.8% (n=34) required retreatment with mAb, with a median of 3.9 (2.9-6.4) months until reintroduction. Clinical response after retreatment was achieved in 67.6% (n=23) of patients. No statistically significant differences were found in the analyzed subgroups. CONCLUSION: Interruption of treatment with erenumab/fremanezumab for chronic/episodic migraine produces a clinical worsening of the disease requiring retreatment in most cases, approximately after 4 months. Two out of three patients respond positively after restarting monoclonal therapy. This response does not appear to be related to the type of migraine, the specific monoclonal antibody prescribed, or the time to retreatment.

MicroRNA profiling in women with migraine: effects of CGRP-targeting treatment.

BACKGROUND: Migraine lacks biomarkers that can trace the biological pathways of the disease and predict the effectiveness of treatments. Monoclonal antibodies targeting calcitonin gene-related peptide pathway - including erenumab - offer the opportunity of investigating potential migraine biomarkers due to their specific mechanism of action in preventing both episodic (EM) and chronic (CM) migraine. Our study aims at evaluating the expression levels of circulating microRNAs (miRNAs) according to migraine type, before and after treatment with erenumab and based on treatment response, in order to identify miRNAs with potential role as epigenetic biomarkers. METHODS: The study included women aged 25-50 years with EM or CM treated with erenumab according to clinical indications. MiRNAs expression levels were assessed before (baseline) and after a 16-week treatment with erenumab, 140 mg every four weeks (post-treatment). An extensive miRNAs profiling was performed by qRT-PCR in small, pooled groups of ≤ 8 women each, classified according to migraine frequency (EM and CM) and the degree of response to erenumab. The expression levels of selected miRNAs were also validated using single miRNA assays in each woman with EM and CM. RESULTS: During the study, 36 women with migraine (19 with EM and 17 with CM) out of 40 who were initially screened, performed the assessment of miRNA expression at baseline and post-treatment, Erenumab treatment significantly improved migraine burden in both EM and CM. MiRNA profiling revealed differential expression levels of a wide set of miRNAs (hsa-let-7d-3p, hsa-miR-106b-3p, hsa-miR-122-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-16-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-25-3p, hsa-miR-29b-2-5p, hsa-miR-326, miR-363-3p, hsa-miR-424-5p, hsa-miR-485-3p, hsa-miR-532-5p, hsa-miR-543, hsa-miR-629-5p, hsa-miR-660-5p, hsa-miR-92a-3p) depending on treatment response. Among them, single miRNA assays confirmed the progressive decrease of hsa-miR-143-3p expression levels in relation to increasing response to erenumab in women with EM (7 with low, 6 with medium, and 6 with high response; p = 0.02). Additionally, single assays showed higher hsa-miR-34a-5p and hsa-miR-382-5p expression levels at baseline in women with CM compared with those with EM (p = 0.0002 and p = 0.0007, respectively), as well as their expression level decrease in women with CM from baseline to follow-up (p = 0.04 and p = 0.02, respectively). CONCLUSIONS: Our study suggests that targeting the CGRP pathway in migraine changes the expression levels of certain miRNAs. These miRNA levels are linked to the levels of response to CGRP receptor blockage. Future research challenges include assigning specific functions to the modulated miRNAs to unravel pathways modulated by the disease and the treatment. TRIAL REGISTRATION: The study was registered in clinicaltrials.gov with code NCT04659226 and in the Novartis database with code CAMG334AIT05T.

Effect of erenumab on the reversion from chronic migraine to episodic migraine in an Asian population: A post hoc analysis of the DRAGON study.

BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene-related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date. OBJECTIVE: Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration). METHODS: Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double-blind treatment period. In addition, migraine-related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non-reverters using the Headache Impact Test-6 (HIT-6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS). RESULTS: Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1-2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT-6 total score for reverters versus non-reverters compared to placebo (erenumab: -9.5 [0.6] vs. -5.1 [0.5]; placebo: -8.9 [0.7] vs. -4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: -22.1 [1.2] vs. -6.3 [1.8]; placebo: -19.9 [1.3] vs. -7.9 [1.6]). Substantial improvements were reported in MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non-reverters in erenumab treatment groups (MPFID-PI: -5.9 [0.3] vs. -1.9 [0.6]; MPFID-EA: -7.9 [0.4] vs. -3.4 [0.6]) and in placebo (MPFID-PI: -5.4 [0.4] vs. -1.0 [0.5]; MPFID-EA: -7.1 [0.5] vs. -3.2 [0.5]). CONCLUSIONS: This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient-reported outcomes in the erenumab group.

Reducing the Impact of Headache and Allodynia Score in Chronic Migraine: An Exploratory Analysis from the Real-World Effectiveness of Anti-CGRP Monoclonal Antibodies Compared to Onabotulinum Toxin A (RAMO) Study.

BACKGROUND: Chronic migraine (CM) is a disabling and hard-to-treat condition, associated with high disability and high cost. Among the preventive treatments, botulinum toxin A (BoNT-a) and monoclonal antibodies against the calcitonin gene-related protein (anti-CGRP mAbs) are the only disease-specific ones. The assessment of the disease burden is complex, and among others, tools such as the allodynia symptoms checklist (ASC-12) and headache impact test (HIT-6) are very useful. This exploratory study analysed the impact of these two therapies on migraine burden. METHODS: The RAMO study was a multicentre, observational, retrospective investigation conducted in two headache centres: the Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan) and the Fondazione Policlinico Campus Bio-Medico (Rome). This study involved patients with chronic migraine treated with mAbs or BoNT-A. We conducted a subgroup exploratory analysis on HIT-6 and ASC-12 scores in the two groups. The Wilcoxon rank-sum test, Fisher's exact test, and ANOVA were performed. RESULTS: Of 126 patients, 36 on mAbs and 90 on BoNT-A had at least one available follow-up. mAbs resulted in a mean reduction of -11.1 and -11.4 points, respectively, in the HIT-6 at 6 and 12 months, while BoNT-A was reduced -3.2 and -3.6 points, respectively; the mAbs arm resulted in mean reductions in ASC-12 at 6 and 12 months of follow-up of -5.2 and -6.0 points, respectively, while BoNT-A showed lesser mean changes of -0.5 and -0.9 points, respectively. The adjusted analysis confirmed our results. CONCLUSIONS: In this exploratory analysis, anti-CGRP mAbs showed superior effectiveness for HIT-6 and ASC12 compared to BoNT-A. Reductions in terms of month headache days (MHD), migraine disability assessment test (MIDAS), and migraine acute medications (MAM) were clinically relevant for both treatments.