Effectiveness and safety of monthly versus quarterly fremanezumab for migraine prevention: An Italian, multicenter, real-life study.

BACKGROUND AND PURPOSE: Fremanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide for migraine prevention, is available in monthly (225 mg) and quarterly (675 mg) doses. Previous studies showed efficacy and safety for both regimens, but a real-life comparison is lacking. This study aimed to compare the effectiveness and safety of monthly and quarterly fremanezumab in a real-life setting. METHODS: This Italian, prospective, multicenter study enrolled 95 migraine patients. During a 3-month treatment period, patients received either monthly or quarterly fremanezumab (49 monthly, 46 quarterly). A 6-month treatment period involved 79 patients (43 monthly, 36 quarterly). Monthly headache (MHD) and migraine days (MMD), number of days (AMD) and pills (AMP) of acute medication intake, and Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS) test, and Numeric Rating Scale (NRS) scores were recorded at baseline and after 3 and 6 months of treatment. Adverse events (AEs), responder rates, and medication overuse were also investigated. RESULTS: Both monthly and quarterly treatments led to significant reductions in MMD, MHD, AMP, AMD, HIT-6, MIDAS, and NRS scores after 3 and 6 months. The monthly regimen exhibited a slightly greater reduction in MMD and MHD after the first quarter, with no significant difference observed after 6 months. The most common AE was transient injection-site reaction, without between-group differences. Responder rates and resolution of medication overuse did not significantly differ between the groups. CONCLUSIONS: Both monthly and quarterly regimens were effective and safe, with a tendency for an advantage of the monthly regimen only in the first quarter of treatment.

Psychopathological variables in chronic migraine patients with different therapeutic approach: psychological profile differences and impact on therapeutic efficacy in real life.

BACKGROUND: Migraine is a debilitating neurological condition linked to various psychological comorbidities. The aims of our study are: 1) to evaluate potential psychopathological differences between patients in treatment with anti-CGRP monoclonal antibodies (SPECIFIC group) and those with onabotulinumtoxin-A/oral pharmacotherapy (Group NON-SPECIFIC), 2) to compare treatment efficacy over time between groups, and examined whether psychopathological comorbidities can influence it. METHODS: This is a post-hoc ambispective study: a retrospective analysis of patient-level real-life data prospectively collected for clinical evaluation. We enrolled 102 patients with chronic migraine (CM), 64 in treatment with erenumab or galcanezumab, and 38 with botulinum toxin or oral pharmacotherapies. Psychopathological variables are assessed at baseline, whereas clinical factors over time. RESULTS: The NON-SPECIFIC group showed more pronounced emotion regulation difficulties (DERS, p = 0.001), alexithymia (TAS-20, p = 0.012), and impulsiveness (BIS-11, p = 0.002) with respect to the SPECIFIC group. Moreover, treatment efficacy overtime was more pronounced in the group with anti-CGRP treatment with a reduction of migraine frequency overtime, pain intensity, and improved quality of life up to six months post-treatment. Psychopathological comorbidity did not influence treatment efficacy. CONCLUSIONS: Our study highlighted more pronounced psychopathological comorbidities in patients in treatment with NON-SPECIFIC therapies in terms of impulsivity, alexithymia, and emotion regulation. Moreover, treatment efficacy overtime was more pronounced and stable over time in the SPECIFIC group, and psychopathological comorbidity did not influence it.

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.

Cerebral vasomotor reactivity in the acute phase and after 6 months in non-disabling stroke/TIA: A prospective cohort study.

BACKGROUND AND AIM: Cerebral Vasomotor Reactivity (VMR) is a property of cerebral hemodynamics that protects from cerebrovascular disease. We aimed to explore the VMR longitudinal changes in patients with acute non-disabling stroke/Transient Ischemic Attack (TIA) to understand its implication in stroke ethiopatogenesis. METHODS: VMR by Transcranial Doppler Breath Holding test was performed at 48-72 h from stroke onset (T1) and after 6 months (T2) on MCA of the non-affected hemisphere and PCA of the affected hemisphere. RESULTS: We consecutively enrolled 124 patients with a median age of 66.0 (IQR 54.75-74.25) years with a median NIHSS 2 (IQR 1-3). Both MCA (1.38 %/s SD 0.58) and PCA (1.35 %/s SD 0.75) BHI at T1 did not differ among different stroke subtypes (p=0.067 and p=0.350; N=124). MCA and PCA BHI decreased from T1 to T2 (respectively 1.39 %/s SD 0.56 vs 1.18%/s SD 0.44 and 1.30 %/s SD 0.69 vs 1.20 %/s SD 0.51; N=109) regardless of ethiopatogenesis (respectively p<0.0001 and p=0.111). CONCLUSION: The VMR is higher in acute phase than at 6 months in patients with non-disabling stroke/TIA, regardless of etiopathogenesis. The higher VMR in acute phase could be sustained by an increased Cerebral Blood Flow due to collateral circulation activation supporting the ischemic zone.

Real-world effectiveness of Anti-CGRP monoclonal antibodies compared to OnabotulinumtoxinA (RAMO) in chronic migraine: a retrospective, observational, multicenter, cohort study.

BACKGROUND: Chronic migraine (CM) is a disabling condition with high prevalence in the general population. Until the recent approval of monoclonal antibodies targeting the calcitonin gene-related peptide (Anti-CGRP mAbs), OnabotulinumtoxinA (BoNT-A) was the only treatment specifically approved for CM prophylaxis. Direct comparisons between the two treatments are not available so far. METHODS: We performed an observational, retrospective, multicenter study in Italy to compare the real-world effectiveness of Anti-CGRP mAbs and BoNT-A. Patients with CM who had received either treatment according to Italian prescribing regulations were extracted from available clinical databases. Efficacy outcomes included the change from baseline in monthly headache days (MHD), MIgraine Disability ASsessment test (MIDAS), and monthly acute medications (MAM) evaluated at 6 and 12 months of follow-up. The primary outcome was MHD change from baseline at 12 months. Safety outcomes included serious adverse events (SAE) and treatment discontinuation. Unadjusted and adjusted models were used for the analyses. RESULTS: Two hundred sixteen potentially eligible patients were screened; 183 (86 Anti-CGRP mAbs; 97 BoNT-A) were included. One hundred seventy-one (80 Anti-CGRP mAbs; 91 BoNT-A) and 154 (69 Anti-CGRP mAbs; 85 BoNT-A) patients were included in the efficacy analysis at 6 and 12 months of follow-up, respectively. Anti-CGRP mAbs and BoNT-A both resulted in a mean MHD reduction at 6 (-11.5 and -7.2 days, respectively; unadjusted mean difference -4.3; 95%CI -6.6 to -2.0; p = 0.0003) and 12 months (-11.9 and -7.6, respectively; unadjusted mean difference -4.4; 95%CI -6.8 to -2.0; p = 0.0002) of follow-up. Similar results were observed after adjusting for baseline confounders. Anti-CGRP mAbs showed a significant MIDAS (-31.7 and -19.2 points, p = 0.0001 and p = 0.0296, respectively) and MAM reduction (-5.1 and -3.1 administrations, p = 0.0023 and p = 0.0574, respectively) compared to BoNT-A at 6 and 12 months. No SAEs were reported. One patient receiving fremanezumab discontinued treatment due to arthralgia. Treatment discontinuations, mainly for inefficacy, were comparable. CONCLUSION: Both Anti-CGRP mAbs and BoNT-A were effective in CM patients with Anti-CGRP mAbs presenting higher effect magnitude, with comparable safety. Still, BoNT-A remains a valuable option for CM patients with contraindications to Anti-CGRP mAbs or for frail categories who are candidates to local therapy with limited risk of systemic administration.

Maintenance of response and predictive factors of 1-year GalcanezumAb treatment in real-life migraine patients in Italy: The multicenter prospective cohort GARLIT study.

BACKGROUND AND PURPOSE: To evaluate the 1-year effectiveness and tolerability of galcanezumab in real life and the prognostic indicators of persistent response. METHODS: High-frequency episodic migraine (HFEM) and chronic migraine (CM) patients treated with galcanezumab who completed a 1-year observation were enrolled. The primary outcomes assessed during the 12 months (V1-V12) were the change in monthly migraine days (MMDs) from baseline and the response rates ≥50% in MMDs (MMD ≥50% RR). The secondary outcomes were changes in pain intensity (numerical rating scale [NRS]) and in monthly acute medication intake (MAMI). RESULTS: We enrolled 191 patients (77.5% CM). Twenty-three patients (12%) dropped out, two for nonserious adverse events. At least 40% of patients took add-on standard preventives from baseline to V12. At V12, MMDs were reduced by 6.0 days in HFEM and by 11.9 days in CM patients (both p < 0.00001); NRS and MAMI were also decreased in both groups (p < 0.00001). One-hundred eight (56.5%) patients presented MMD ≥50% RR for 9 cumulative months (interquartile range=8): we defined this value as the cutoff for a persistent response. Persistent responders were less likely to have a higher body mass index (BMI) (p = 0.007) but more frequently had a good response to triptans (p = 0.005) and MMD ≥50% RR at V1 (p < 0.0000001). Patients without a persistent response were on add-on therapy for longer periods of time (p < 0.001). CONCLUSIONS: Galcanezumab was effective and well-tolerated in the 1-year term, with most patients presenting MMD ≥50% RR for at least 9 months. Triptan response, lower BMI, and MMD ≥50% RR in the first month emerged as predictive factors for a persistent response.

Calcitonin Gene-Related Peptide Systemic Effects: Embracing the Complexity of Its Biological Roles-A Narrative Review.

The calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed throughout the human body. While primarily recognized as a nociceptive mediator, CGRP antagonists are currently utilized for migraine treatment. However, its role extends far beyond this, acting as a regulator of numerous biological processes. Indeed, CGRP plays a crucial role in vasodilation, inflammation, intestinal motility, and apoptosis. In this review, we explore the non-nociceptive effects of CGRP in various body systems, revealing actions that can be contradictory at times. In the cardiovascular system, it functions as a potent vasodilator, yet its antagonists do not induce arterial hypertension, suggesting concurrent modulation by other molecules. As an immunomodulator, CGRP exhibits intriguing complexity, displaying both anti-inflammatory and pro-inflammatory effects. Furthermore, CGRP appears to be involved in obesity development while paradoxically reducing appetite. A thorough investigation of CGRP's biological effects is crucial for anticipating potential side effects associated with its antagonists' use and for developing novel therapies in other medical fields. In summary, CGRP represents a neuropeptide with a complex systemic impact, extending well beyond nociception, thus offering new perspectives in medical research and therapeutics.

Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study.

BACKGROUND AND PURPOSE: A rapid response to preventive therapy is of pivotal importance in severely disabled patients with chronic migraine (CM) and diverse preventive treatment failures. This prospective, observational, multicenter real-life study aimed at investigating the effectiveness of galcanezumab in the first 3 months of treatment of CM patients at 14 Italian headache centers. METHODS: All consecutive adult patients with CM diagnosis with the clinical indication for galcanezumab were considered. We collected patients' baseline characteristics, monthly headache days, monthly painkiller intake, migraine clinical characteristics, and disability scale scores during a 1-month run-in period (baseline) and the first 3 months of therapy. Possible predictive factors of treatment were considered. RESULTS: A total of 156 patients (82.4% female, aged 47.3 ± 12.3 years) were enrolled. The 65 (41.7%) patients with a consecutive ≥50% response rate (RR) in the 3 months of therapy presented a lower body mass index (p = 0.004) and more frequently presented unilateral migraine pain (p = 0.002) and good response to triptans (p = 0.003). Persistent conversion from CM to episodic migraine was observed in 55.8% (87/156) of patients. They more frequently presented a good response to triptans (p = 0.003) and unilateral pain (p = 0.046). At baseline, 131 of 156 (83.9%) patients presented medication overuse (MO). Of these, 61.8% (81/131) no longer displayed MO consistently during the 3 months. These patients were more frequently responders to triptans (p = 0.002) and less frequently suffered from gastrointestinal comorbidity (p = 0.007). CONCLUSIONS: Unilateral pain, good response to triptans, and normal weight may be associated with a persistent positive response in the first 3 months of therapy with galcanezumab in CM patients.

Improving distress perception and mutuality in migraine caregivers after 6 months of galcanezumab treatment.

OBJECTIVE: This prospective cohort, real-life study aimed to evaluate whether galcanezumab, a monoclonal antibody anti-calcitonin gene-related peptide (CGRP) ligand, can reduce caregivers' distress and improve their mutuality with patients. BACKGROUND: Migraine is a highly disabling chronic disease that negatively impacts patients' and often their relatives' lives, occurring during an active phase of life with direct consequences on leisure- and work-related activities. The figure of caregiver is crucial in several neurological conditions but poorly accounted for in migraine care so far. Studies on monoclonal antibodies against the CGRP pathway, recently introduced as migraine-preventive treatments, demonstrated that they significantly reduce migraine frequency and disability in the first weeks of treatment. METHODS: Consecutive patient-caregiver dyads were evaluated at baseline and after 6 months of treatment with galcanezumab (V6) at our headache center from September 2020 to September 2021. Enrolled patients were requested to report their monthly migraine days, monthly intake of acute medications, attack pain intensity (on the Numeric Rating Scale), concomitant preventives, and disability questionnaires (Headache Impact Test, Migraine Disability Assessment). Each dyad filled in the Mutuality Scale to check their reciprocity; moreover, the Relatives' Stress Scale was used to detect caregivers' distress. RESULTS: We enrolled 27 patient-caregiver dyads. At 6 months, migraine burden significantly improved with reductions in monthly migraine days (falling from 14.8 [SD = 4.8] days by 10.3 [SD = 4.8] days; 95% CI: 8.4, 12.2; p < 0.001) and Migraine Disability Assessment scores (lowering from 83.6 [SD = 46.7] by 71.5 points [SD = 49.3]; 95% CI: 51.2, 91.9; p < 0.001). From baseline to month 6, the caregiver Relatives' Stress Scale score significantly decreased (falling from 20.7 [SD = 13.7] by 6.5 [SD = 14.1] points; 95% CI: 0.8, 12.2; p = 0.027), while the Mutuality Scale's caregiver total score increased (from 3.04 [SD = 0.61] by 0.29 [SD = 0.49] points; 95% CI: -0.508, -0.064; p = 0.014). CONCLUSIONS: Our findings preliminarily demonstrated that patients' migraine improvement after 6 months of galcanezumab treatment could be favorably perceived by caregivers, significantly reducing their distress with better reciprocity within the dyad.

Gepants - a long way to cure: a narrative review.

Calcitonin gene-related peptide (CGRP) is probably the most potent vasodilator in cerebral circulation. Forty years after its discovery, the new CGRP-targeted therapy monoclonal antibodies, and the small molecule gepants, are now available for clinical practice. While randomized controlled trials and real-world experience consistently demonstrated the high efficacy and tolerability of monoclonal antibodies, limited evidence is available to characterize gepants fully. Depending on pharmacokinetics, these CGRP receptor antagonists can be used for acute (ubrogepant, rimegepant, and the not yet approved zavegepant) or preventive (atogepant and rimegepant) migraine treatment. Randomized placebo-controlled trials demonstrated gepants efficacy in treating acute attacks to obtain 2 h pain freedom in about 20% of patients and pain relief in about 60%, while up to 60% of treated patients with episodic migraine may experience a 50% reduction in monthly migraine days. The most common treatment-related emergent adverse events were gastrointestinal (nausea, constipation) for the acute or preventive use. No vascular or hepatic concerns have emerged so far. More studies are ongoing to investigate gepant tolerability and safety also if associated with monoclonal antibodies targeting CGRP and other therapeutic classes. Gepants are also under investigation to treat other painful and non-painful conditions. Real-life studies are necessary to confirm the trials' findings and investigate more practical clinical aspects.

Task-switching abilities in episodic and chronic migraine.

Migraineurs show impaired cognitive functions interictally, mainly involving information processing speed, basic attention, and executive functions. We aimed to assess executive impairment in migraine patients with different attack frequencies through a task-switching protocol designed to assess different sub-processes of executive functioning. We enrolled 42 migraine patients and divided them into three groups based on the attack frequency: 13 subjects had episodic migraine with a low frequency (LFEM, 4-7 migraine days per month), 14 subjects had high-frequency episodic migraine (HFEM, 8-14 days) and, finally, 15 subjects presented chronic migraine (≥ 15 headache days/month, CM); we compared them to 20 healthy control (HC), matched to both gender and education. Patients with high headache frequencies (CM and HFEM) showed worse performance than LFEM and HC controls, as indicated by poor accuracy, increased switch cost, and reaction times. Our study demonstrated a difference in task-switching abilities in patients with high frequency or chronic migraine compared with low-frequency episodic migraine and healthy controls. These difficulties in executive control processes could be related to altered functioning of the frontal cortex and its cortical and subcortical connections.

Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study).

BACKGROUND: Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. METHODS: This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals. RESULTS: Sixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85-0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason. CONCLUSIONS: Fremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.

Predictors of response to anti-CGRP monoclonal antibodies: a 24-week, multicenter, prospective study on 864 migraine patients.

BACKGROUND AND OBJECTIVES: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM). METHODS: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. RESULTS: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57-11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05-2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15-3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04-2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07-0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42-8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14-2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22-3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. CONCLUSIONS: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.

Comparing the relative and absolute effect of erenumab: is a 50% response enough? Results from the ESTEEMen study.

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

Erenumab does not alter cerebral hemodynamics and endothelial function in migraine without aura.

OBJECTIVE: To assess whether erenumab influences cerebral vasomotor reactivity and flow-mediated dilation in migraine patients. METHODS: Consecutive migraineurs prescribed erenumab at our Headache Centre and age and sex-matching controls were invited to participate in this observational longitudinal study. Patients were evaluated for cerebral vasomotor reactivity to hypercapnia (breath-holding index) in middle and posterior cerebral arteries and for brachial corrected flow mediated dilation at baseline (T0), after 2 weeks from the first erenumab injection (T2) and after 2 weeks from the fourth Erenumab injection (T18). Patients displaying a reduction of at least 50% in monthly migraine days after completing the fourth month of therapy were classified as responders. RESULTS: Sixty patients and 25 controls agreed to participate. Middle and posterior cerebral artery mean flow velocities, breath-holding index and flow-mediated dilation did not differ at T0 and from T0 to T2 in patients and controls. In patients, we neither observed a variation of the explored variables from T0 to T18 nor an interaction between evaluation times (T0-T2 or T0-T18) and chronic condition at T0, responder state or erenumab fourth dose. CONCLUSIONS: Our findings demonstrate that erenumab preserves cerebral vasomotor reactivity and flow-mediated dilation in migraineurs without aura.

Clinical features, disease progression, and use of healthcare resources in a large sample of 866 patients from 24 headache centers: A real-life perspective from the Italian chROnic migraiNe (IRON) project.

OBJECTIVE: To develop a dedicated Italian chronic migraine (CM) database (IRON project) to overcome disease misconceptions, improve clinical administration, reduce patients' burden, and rationalize economic resource allotment. BACKGROUND: Proper CM management requires a comprehensive appraisal of its full clinical, social, and economic complexity. METHODS: In this cross-sectional study, CM patients were screened in 24 certified headache centers with face-to-face interviews. Information on sociodemographic factors, medical history, characteristics of CM, and of prior episodic migraine (EM), and healthcare resource use was gathered using a semistructured web-based questionnaire. RESULTS: A total of 866 CM patients were enrolled. CM started ~20 years after EM onset (age at EM onset 17.4 ± 9.1 vs. age at CM onset 35.3 ± 12.5 [mean ± SD]). CM prophylaxis, used by 430/866 (49.6%) of the patients, was often ineffective, not tolerated, and prematurely discontinued. Medications and diagnostic workup, frequently inappropriate, were mostly subsidized by the Italian national health service. CM patients with ≥25 headache days/month revealed substantial clinical differences and heavier disability and economic burden compared with those with <25 headache days/month. CONCLUSIONS: CM is a heterogeneous headache disorder deserving more in-depth clinical characterization, sharper diagnostic criteria, and tailored treatments. CM registries are expected to improve clinical management, resulting in increased disease awareness, better healthcare resource allocation, and reduced economic burden.

Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study.

OBJECTIVE: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. BACKGROUND: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. METHODS: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15 headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18-65 years. Each patient was treated with erenumab 70 mg, administered monthly. The dose was switched to 140 mg in nonresponders and in responders who had become nonresponders for at least 4 weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45-48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. RESULTS: A total of 242 patients with migraine received at least one dose of erenumab 70 mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48 weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3 migraine-preventive medication classes. From baseline to Weeks 45-48, erenumab treatment reduced MMD by 4.3 ± 5.3 (mean ± SD) in patients with HFEM, and MHD by 12.8 ± 8.9 (mean ± SD) in subjects with CM. VAS and HIT-6 scores were decreased by 1.8 ± 1.9 (mean ± SD) and 12.3 ± 11 (mean ± SD) in HFEM, and by 3.0 ± 2.2 (mean ± SD) and 13.1 ± 11.2 (mean ± SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0-13.0) to 5 (IQR 2.0-8.0) in HFEM and from 20.0 (IQR 15.0-30.0) to 6.0 (IQR 3.8-10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52-19.41; p = 0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03-8.7; p = 0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05-1.20; p = 0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15-0.87; p = 0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64-0.92; p = 0.004). CONCLUSIONS: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140 mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

Erenumab in the prevention of high-frequency episodic and chronic migraine: Erenumab in Real Life in Italy (EARLY), the first Italian multicenter, prospective real-life study.

OBJECTIVE: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. BACKGROUND: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. METHODS: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18-65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70 mg, administered subcutaneously every 4 weeks. Treatment duration was planned to last from 6 to 12 months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9-12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). RESULTS: In total, 372 migraine patients were treated with at least one dose of erenumab 70 mg. At weeks 9-12, erenumab decreased MMDs by 4.5 ± 4.1 days (mean ± SD) in patients with HFEM and by 9.3 ± 9.1 (mean ± SD) days in those with CM compared to baseline. At weeks 9-12 VAS score was reduced by 1.9 ± 1.9 (mean ± SD), HIT score by 10.7 ± 8.8 (mean ± SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0-14.0) to 5.0 (IQR 3.0-7.0) in HFEM. In CM patients, VAS was reduced by 1.7 ± 2.0 (mean ± SD), HIT by 9.7 ± 10.4 (mean ± SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0-30.0) to 8.0 (IQR 5.0-15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24-7.40; p = 0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02-1.11; p = 0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14-3.52; p = 0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20-0.93; p = 0.003). CONCLUSIONS: Erenumab 70 mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

Discontinuing monoclonal antibodies targeting CGRP pathway after one-year treatment: an observational longitudinal cohort study.

BACKGROUND: Monoclonal antibodies anti-calcitonin gene-related peptide (mAbs anti-CGRP) pathway are effective and safe on migraine prevention. However, some drug agencies limited these treatments to one year due to their high costs. This study aimed at evaluating the effect of discontinuing mAbs anti-CGRP on monthly migraine days (MMDs) and disability in high-frequency episodic (HFEM) and chronic migraine (CM) patients. METHODS: This observational longitudinal cohort study was conducted at 10 Italian headache centres. Consecutive adult patients were followed-up for three months (F-UP1-3) after discontinuation of a one-year erenumab/galcanezumab treatment. The primary endpoint was the change in F-UP MMDs. Secondary endpoints included variation in pain intensity (Numerical Rating Scale, NRS), monthly acute medication intake (MAMI), and HIT-6 scores. We also assessed from F-UP1 to 3 the ≥50% response rate, relapse rate to CM, and recurrence of Medication Overuse (MO). RESULTS: We enrolled 154 patients (72.1% female, 48.2 ± 11.1 years, 107 CM, 47 HFEM); 91 were treated with erenumab, 63 with galcanezumab. From F-UP1 to F-UP3, MMDs, MAMI, NRS, and HIT-6 progressively increased but were still lower at F-UP3 than baseline (Friedman's analysis of rank, p < .001). In the F-UP1-3 visits, ≥50% response rate frequency did not differ significantly between CM and HFEM patients. However, the median reduction in response rate at F-UP3 was higher in HFEM (- 47.7% [25th, - 79.5; 75th,-17.0]) than in CM patients (- 25.5% [25th, - 47.1; 75th, - 3.3]; Mann-Whitney U test; p = .032). Of the 84 baseline CM patients who had reverted to episodic migraine, 28 (33.3%) relapsed to CM at F-UP1, 35 (41.7%) at F-UP2, 39 (46.4%) at F-UP3. Of the 64 baseline patients suffering of medication overuse headache ceasing MO, 15 (18.3%) relapsed to MO at F-UP1, 26 (31.6%) at F-UP2, and 30 (42.3%, 11 missing data) at F-UP3. Lower MMDs, MAMI, NRS, and HIT-6 and higher response rate in the last month of therapy characterized patients with ≥50% response rate at F-UP1 and F-UP3 (Mann-Whitney U test; consistently p < .01). CONCLUSION: Migraine frequency and disability gradually increased after mAbs anti-CGRP interruption. Most patients did not relapse to MO or CM despite the increase in MMDs. Our data suggest to reconsider mAbs anti-CGRP discontinuation.

Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study).

BACKGROUND: The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting. METHODS: This multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation. RESULTS: One hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p < .001). NRS, MPI, HIT-6 and MIDAS scores significantly decreased (p < .001). Ten patients (6.1%) dropped out for inefficacy and classified as non-responders. Patients with ≥50%RRs, i.e. responders, were 76.5% in the HFEM and 63.5% in the CM group at V6. Among CM patients, the V6 responders presented a lower body mass index (p = .018) and had failed a lower number of preventive treatments (p = .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times. CONCLUSIONS: Galcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04803513 .