Monitoring Pregnancies Exposed to Galcanezumab for Migraine in a United States Administrative Claims Database.

PURPOSE: Galcanezumab is a calcitonin gene-related peptide monoclonal antibody indicated for migraine prevention in adults. Due to the long half-life of galcanezumab and the prevalence of migraine in women of childbearing age, galcanezumab exposure may occur during pregnancy. However, real-world use and safety of galcanezumab during pregnancy has not been fully described. To help fill this gap, galcanezumab has two ongoing pregnancy safety studies, one of which is an insurance claims database study. METHODS: This database study is actively identifying and following pregnancies exposed to galcanezumab using commercial claims from the Healthcare Integrated Research Database (HIRD). Patient accrual is planned from September 2018 to June 2026, with a final study report planned for December 2027. This study requires 430 galcanezumab-exposed pregnancies with linked infants to reach power for comparative analysis of major congenital malformations. RESULTS: Recent monitoring of patient accrual, including data from 28 September 2018 to 31 January 2023, identified 207 galcanezumab-exposed pregnancies in women with migraine in the HIRD, of which 110 were live births and 73 of which were linked to an infant. This represents an annual accrual rate of approximately 17 pregnancies linked to infants, which is substantially lower than the 55 required annually to reach target size within current regulatory-committed study timelines. CONCLUSIONS: The accrual of a sufficient number of galcanezumab-exposed pregnancies represents a substantial, but not uncommon, barrier to conducting comparative analyses in pregnancy studies. Potential solutions that would allow for timely dissemination of important safety information to patients and providers may be available.

Cerebral Artery Vasoconstriction After Galcanezumab Loading Dose for Migraine Prevention: A Case Report.

Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies that target CGRP ligands or receptors, may cause a very rare side effect of reversible cerebral vasoconstriction syndrome (RCVS). This study is a case report of a patient who developed cerebral artery vasoconstriction documented on serial brain magnetic resonance angiography (MRA) scans without the typical manifestations of RCVS following galcanezumab loading dose. Case report: A 40-year-old female patient with high-frequency episodic migraine with visual aura on topiramate 100 mg/day developed transient numbness of the right upper and lower extremities and right face without headache and a normal neurological examination 10 min after a loading dose of galcanezumab, which resolved over the next 2 days. Magnetic resonance angiography brain imaging showed segmental arterial constriction of both middle cerebral arteries in the M1-2 segments and both posterior cerebral arteries in the P1-2 segments, which partial resolved in a subsequent study by the end of 6 months. There were no other supporting examination data, such as transcranial Doppler, which might provide additional information on the progression and improvement of the vasoconstriction. Her differential diagnosis included prolonged migraine sensory aura without headache, RCVS, or cerebral vasoconstriction secondary to the effect of an anti-CGRP monoclonal antibody. Further research needs to be conducted.

We report a case with numbness on the right upper and lower extremities and right face without headache 10 min after the loading dose of galcanezumab. These stroke-like symptoms resolved within 2 days. Cerebral blood vessels showed narrowing and then dilatation with residual narrowing of two or more vessels. The differential diagnosis is prolonged migraine aura without headache, reversible cerebral vasoconstriction syndrome, or cerebral vasoconstriction due to the effects of galcanezumab.

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.

A placebo controlled, randomized clinical trial of galcanezumab for vestibular migraine: The INVESTMENT study.

OBJECTIVE: To study if galcanezumab is effective for vestibular migraine (VM). BACKGROUND: There are currently no placebo-controlled trials showing that treatment is effective for VM. Therefore, we performed the first placebo controlled, randomized clinical trial of a calcitonin gene-related peptide-targeted monoclonal antibody for VM. METHODS: This was a single site, prospective, double-blind placebo controlled randomized clinical trial. Key inclusion criteria were as follows: participants aged 18-75 years with a diagnosis of VM or probable VM per Barany Society criteria. The primary outcome was change in VM-PATHI (Vestibular Migraine Patient Assessment Tool and Handicap Inventory) score, and secondary outcomes included change in DHI (Dizziness Handicap Inventory) score, and count of definite dizzy days (DDDs). Participants were randomized 1:1 to 3 months of treatment with galcanezumab or placebo via subcutaneous injection with a pre-filled syringe, 240 mg the first month, and 120 mg for the second and third months. RESULTS: Forty participants were randomized, and 38 participants were in the modified intent to treat analysis. VM-PATHI score was reduced 5.1 points (95% confidence interval [CI] -13.0 to 2.7) for placebo (N = 21), and 14.8 points (95% CI -23.0 to -6.5) for galcanezumab (N = 17), a difference of -9.6 (95% CI -20.7 to 1.5, p = 0.044). DHI dropped 8.3 points in the placebo arm (95% CI -15.0 to 1.6), and 22.0 points in the galcanezumab arm (95% CI -31.9 to -12.1), a difference of -13.7 (95% CI -20.4 to -8.5, p = 0.018). The count of DDDs per month dropped from 18 days (standard deviation [SD] 7.6) in the baseline month to 12.5 days (SD 11.2) in month 4 for those in the placebo arm, and from 17.9 days (SD 7.9) in the baseline month to 6.6 days (SD 7.3) in month 4 for those in the galcanezumab arm, a difference of -5.7 days (95% CI -10.7 to -0.7, p = 0.026). No serious adverse events were observed. CONCLUSIONS: In this pilot study, galcanezumab was effective in treating VM.

Efficacy of galcanezumab in proline-rich transmembrane protein 2 (PRRT2)-associated familial hemiplegic migraine: A case series.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. Variants in calcium voltage-gated channel subunit alpha1 A (CACNA1A), ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), and sodium voltage-gated channel alpha subunit 1 (SCN1A) genes have a well-established association with the development of FHM. Recent studies suggest that other genes may also have a significant role in the pathogenesis of FHM, including proline-rich transmembrane protein 2 (PRRT2). To our knowledge, there are currently no documented reports of the use of monoclonal antibodies targeting calcitonin gene-related peptide in FHM caused by a specific identified genetic mutation - and in particular not in FHM associated with PRRT2 mutations. The aim of our work is to describe the efficacy of galcanezumab as a prophylaxis treatment on patients from an Italian family consisting of six patient carriers of a PRRT2 pathogenic variant. METHODS: Inclusion criteria for treatment eligibility consisted of a confirmed diagnosis of genetically confirmed FHM as defined by the International Classification of Headache Disorders, third edition, number of headache days/month ≥4, and at least two previously failed migraine prophylaxis treatments. We evaluated clinical data of patients treated with galcanezumab regarding number of headache days/month, frequency of aura, disability caused by HM using the Migraine Disability Assessment (MIDAS), attack severity through a numerical rating scale (NRS), acute medications intake, and response to acute medications at baseline (t0) and after 3 (t1) and 6 (t2) months of treatment. RESULTS: Three out of six family members met inclusion criteria for treatment with galcanezumab. The average number of headache days/month, acute medications, and MIDAS significantly decreased in all treated patients, as well as the average NRS score. Aura frequency reduced by ≥50% compared to the baseline in all three patients. No adverse events related to galcanezumab were reported. CONCLUSION: Galcanezumab is a valid and well-tolerated treatment option in PRRT2-associated FHM.

Patients' Experiences During the Long Journey Before Initiating Migraine Prevention with a Calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibody (mAb).

INTRODUCTION: Migraine is under-diagnosed and under-treated. Many people with migraine do not seek medical care, and those who do may initially receive a different diagnosis and/or be dissatisfied with provided care on their journey before treatment with a CGRP-mAb (calcitonin-gene-related-peptide monoclonal antibody). METHODS: This is a cross-sectional, self-reported, online survey of subjects in Lilly's Emgality® Patient Support Program in 2022. Questionnaires collected insights into subjects' prior experiences with migraine and interactions with healthcare professionals before receiving CGRP-mAbs. RESULTS: Of the 250 participants with episodic and 250 with chronic migraine, 90% were female and white with a mean age of 26.2 years (± 11.9) at diagnosis and 40.6 (± 12.0) years at survey enrollment. Many participants (71%) suspected they had migraine before diagnosis, with 31% reluctant to seek help. Of these, approximately one-third were unaware of treatment, did not think that a physician could do anything more for migraine, would not take them seriously, or were reluctant due to a previous unhelpful experience. Participants mainly received information from friends/family (47%) or the internet (28%). Participants initially sought treatment due to an increase in migraine frequency (77%), attacks interfering with work or school (75%), or increased pain intensity (74%). Subjects saw a mean of 4.1 (± 4.3) healthcare providers before migraine diagnosis, and 20% of participants previously received a different diagnosis. Participants reported migraine causes included stress/anxiety/depression (42%), hormonal changes (30%), nutrition (20%), and weather (16%). Acute treatment of migraine included prescription (82%) and over-the-counter (50%) medications, changes in nutrition (62%), adjusting fluid intake (56%), and relaxation techniques (55%). Preventive medications included anticonvulsants (61%), antidepressants (44%), blood pressure-lowering medications (43%), and botulinum toxin A injections (17%). Most discontinuations were due to lack of efficacy or side effects. CONCLUSION: People with migraine describe reluctance in seeking health care, and misunderstandings seem common especially in the beginning of their migraine journey. Graphical abstract available for this article.

Efficacy of galcanezumab in migraine central sensitization

Galcanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide pathway (CGRP mAb), acts peripherally due to its large size. However, recent studies have suggested that CGRP mAbs may also have a central mode of action. This study aimed to evaluate the central effects of galcanezumab on migraine central sensitization.This prospective real-world study was conducted at three headache centers in Japan between May 2021 and May 2022. Patients treated with galcanezumab for migraines were included in the study. The primary outcome was the change in the validated Central Sensitization Inventory (CSI) score from baseline to six months of treatment. We also assessed changes in the Allodynia Symptom Checklist (ASC-12) score. Eighty-six patients with migraine (73 female and 13 male) were analyzed. At 6 months, CSI and ASC-12 scores were significantly reduced compared to baseline (CSI: 36.0 vs. 29.3, p < 0.001; and ASC-12: 5.55 vs. 4.26, p < 0.01). Furthermore, these effects were observed as early as three months of treatment. In this study, we demonstrated the real-world efficacy of galcanezumab in improving central sensitization in migraine, with significant effects seen in the early phase of treatment. Trial registration: This study was registered with UMIN-CTR on May 2, 2021 (UMIN000044096).

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.

The profile of refractory chronic cluster headache.

INTRODUCTION: Chronic cluster headache (CCH) is a relatively rare primary headache disorder whose management is often challenging. The prevalence of refractory CCH (rCCH) is unknown. Our aim is to describe the frequency of rCCH within a population of CCH, define the clinical profile of the refractory patients and the treatments they underwent. METHODS: We conducted a cross-sectional study through a review of the medical records of CCH patients in six hospitals in Madrid, Spain. Data on epidemiological, clinical presentation, treatment and disease activity at the moment were collected. The European Headache Federation diagnostic criteria were used for rCCH definition. High disease activity was defined as having at least 3 severe attacks per week that impact quality of life despite treatment. Non-rCCH and rCCH groups were compared. RESULTS: 88 CCH patients were analyzed, 68.2% (60/88) met rCCH criteria at some point in their evolution. A longer diagnostic delay (4.6 ± 7.1 vs. 3.2 ± 3.7 years, p = 0.017) was observed in rCCH. All rCCH patients tried therapies without established evidence from randomized clinical trials. OnabotulinumtoxinA and galcanezumab were initiated in 77.3% (68/88) and 5.7% (5/88), but discontinued in 52.9% (36/68) and 60.0% (3/5), respectively. Occipital nerve stimulation (ONS) was implanted in 29.6% (26/88), with 50.0% (13/26) still active. Other treatment options are described and discussed. Despite treatment, 60.2% (53/88) still have high disease activity. CONCLUSION: CCH is a disorder with poor prognosis, meeting refractoriness criteria in more than half. OnabotulinumtoxinA and ONS could be the effective in refractory patients.

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.

Effectiveness of galcanezumab on sleep quality, migraine outcome, and multidimensional patient-reported outcome measures: a real-world experience in Turkish patients with episodic and chronic migraine.

Introduction: This real-world study aimed to investigate the impact of galcanezumab on sleep quality, migraine outcome and multidimensional patient-reported outcomes measures (PROMs) in patients with episodic migraine (EM) and chronic migraine (CM). Methods: Fifty-four patients with episodic migraine (n = 24) or chronic migraine (n = 30) received a 3-month series of galcanezumab injections and were evaluated for sleep quality, measured using the Pittsburgh Sleep Quality Index (PSQI), as well as migraine outcomes such as monthly headache days (MHDs), monthly migraine days (MMDs), and headache severity. Patient-reported outcome measures (PROMs) such as the Migraine Disability Assessment Scale (MIDAS), Headache Impact Test-6 (HIT-6), SF-36 Health-related Quality of Life (HRQoL), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI) were additionally included in the assessment. Results: The percentage of patients with poor sleep quality (total PSQI scores ≥ 5) was 72.7% at baseline, decreasing to 57.5% and 56.2% at the 1st and 2nd months, respectively. By the 3rd month of galcanezumab injections, significant improvement was observed in the sleep disturbances domain in the overall study population (p = 0.016), and in subgroups of patients with low anxiety levels (p = 0.016) and none/minimal depression (p = 0.035) at baseline. Patients with sleep disorder at baseline exhibited marked improvements in total PSQI scores (p = 0.027) and in the subjective sleep quality (p = 0.034) and daytime dysfunction (p = 0.013) domains, by the 3rd month. Over the 1st, 2nd, and 3rd months, there were significant improvements in MHDs (p < 0.001), MMDs (p < 0.001), HIT-6 scores (p < 0.001 for each), BAI scores (p < 0.001 for each), BDI scores (p ranged from 0.048 to <0.001), and HRQoL scores (p ranged from 0.012 to <0.001). Conclusion: Galcanezumab demonstrates notable benefits in improving sleep quality, along with a comorbidity-based and domain-specific effect on sleep parameters, which involved sleep disturbances domain in patients without depression or anxiety at baseline but the total PSQI scores, subjective sleep quality and daytime dysfunction in those with sleep disorder at baseline. The treatment also facilitates rapid-onset enhancements in migraine outcomes as well as various PROMs.

Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan.

OBJECTIVE: To compare the real-world effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients. METHODS: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult-to-treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS). RESULTS: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (-13.0 vs. -8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (-13.0 vs. -9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication-overuse headache (MOH) (-13.3 vs. -9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (-42.2 vs. -11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs. CONCLUSIONS: In this multicenter, real-world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings.

Treatment Outcome After Switching From Galcanezumab to Fremanezumab in Patients With Migraine.

BACKGROUND AND PURPOSE: Monoclonal antibodies (mAbs) targeting calcitonin-gene-related peptide (CGRP) or its receptor (anti-CGRP-R) have been widely administered to patients with migraine who show inadequate responses to preventive medications. Among patients in whom a particular anti-CGRP-R mAb is ineffective, switching between different anti-CGRP-R mAbs can be the next option. Few studies have investigated treatment outcomes for antibody switching, especially between mAbs with the same target of the CGRP ligand. We aimed to determine the treatment outcome after switching between two anti-CGRP mAbs (galcanezumab to fremanezumab). METHODS: We identified migraine patients in a prospective headache clinic registry who received galcanezumab for ≥3 months and were switched to fremanezumab for a further ≥3 months at a single university hospital. We defined a treatment response as a ≥50% reduction in the number of days with a moderate or severe headache at the third month of treatment relative to baseline. The treatment response after switching to fremanezumab was compared with the initial treatment response to galcanezumab. RESULTS: Among 21 patients identified in the registry, 7 (33.3%) were initial responders to galcanezumab. After switching to fremanezumab, 7 (33.3%) showed a treatment response. The treatment response rate was 28.6% in the initial responders and 71.4% in the nonresponders to galcanezumab (p>0.999). CONCLUSIONS: Switching between anti-CGRP mAbs (galcanezumab to fremanezumab) yielded a treatment outcome comparable to that reported previously when switching from an anti-CGRP-R mAb (erenumab) to an anti-CGRP mAb (galcanezumab or fremanezumab). The treatment response to fremanezumab seems to be independent of the prior treatment response to galcanezumab. Our findings suggest that switching to another anti-CGRP mAb can be considered when a particular anti-CGRP mAb is ineffective or intolerable.

Case reports: Could sexual dysfunction in women with migraine be a side effect of CGRP inhibition?

BACKGROUND: The development and approval of antibodies targeting calcitonin gene-related peptide or its receptor mark a revolutionary era for preventive migraine treatment. Real-world evidence sheds light on rare, stigmatized or overlooked side effects of these drugs. One of these potential side effects is sexual dysfunction. CASE REPORTS: We present two cases of one 42-year-old and one 45-year-old female patient with chronic migraine who both reported sexual dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide. DISCUSSION: As calcitonin gene-related peptide is involved in vaginal lubrication as well as genital sensation and swelling, inhibiting the calcitonin gene-related peptide pathway may lead to sexual dysfunction as a potential side effect. CONCLUSION: Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of monoclonal antibodies targeting the calcitonin gene-related peptide pathway. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, we advocate for an open attitude and awareness among clinicians toward such side effects.

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.

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.

Clinical Evaluation After Discontinuation of Galcanezumab in Japanese Patients with Episodic and Chronic Migraine: Analysis of a Randomized, Placebo-Controlled Trial and Open-label Extension Study.

INTRODUCTION: This analysis of two Japanese clinical trials evaluated efficacy and safety after galcanezumab (GMB) discontinuation in patients with episodic migraine (EM) and chronic migraine (CM). METHODS: Data were from a 6-month, randomized, double-blind, placebo [PBO]-controlled primary trial (patients with EM) and a 12-month open-label extension trial (patients with EM/CM). Patients received 6 months' (primary) or 12/18 months' (extension) treatment with GMB 120 mg (GMB120) plus 240-mg loading dose or 240 mg (GMB240) with 4 months' post-treatment follow-up. Efficacy was assessed as number of monthly migraine headache days during post-treatment. Safety was assessed via post-treatment-emergent adverse events (PTEAEs). RESULTS: The analysis population included 186 patients from the primary trial (PBO N = 93; GMB120 N = 45; GMB240 N = 48), 220 patients with EM from the extension trial (PBO/GMB120 N = 57; PBO/GMB240 N = 55; GMB120/GMB120 N = 55; GMB240/GMB240 N = 53), and 55 patients with CM (GMB120 N = 28; GMB240 N = 27). In patients with EM receiving 6 months' GMB120, mean standard deviation (SD) monthly migraine headache days increased from 5.69 (4.64) at treatment end to 6.24 (4.37) at end of follow-up but did not return to pre-treatment levels (8.80 [2.96]). In the extension trial, mean monthly migraine headache days in patients with EM receiving GMB120 were 4.13 (3.85) after 12 months and 4.45 (3.78) at end of follow-up, and 3.59 (3.48) after 18 months and 3.91 (3.57) at end of follow-up. Monthly migraine headache days in patients with CM (12 months' GMB120) were 10.71 (4.61) at treatment end and 11.17 (5.64) at end of follow-up (pre-treatment 20.15 [4.65]). Similar results were seen for patients receiving GMB240. The most observed PTEAE after GMB discontinuation was nasopharyngitis. CONCLUSION: Galcanezumab exhibited post-treatment efficacy for up to 4 months in Japanese patients with EM and with CM. No unexpected safety signals were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02959177 and NCT02959190.

Reporting Quality and Risk of Bias Analysis of Published RCTs Assessing Anti-CGRP Monoclonal Antibodies in Migraine Prophylaxis: A Systematic Review.

Objective: Phase II/III randomized clinical trials (RCTs) are vulnerable to many types of bias beyond randomization. Insights into the reporting quality of RCTs involving migraine patients treated with monoclonal antibodies targeting the calcitonin gene-related peptide system (anti-CGRP MAbs) are currently lacking. Our aim was to analyze the reporting quality of phase II/III RCTs involving migraine patients treated with anti-CGRP MAbs. Methods: A systematic search was performed on the PubMed and EMBASE databases, according to PRISMA guidelines, for relevant RCTs in either episodic or chronic migraine prevention. Additionally, an adapted version of the 2010 CONSORT statement checklist was utilized. The ROBvis online tool was used to document the risk of bias. Results: From the initially identified 179 articles, we finally found 31 RCTs that were eligible for evaluation. The average CONSORT compliance was 88.7% (69.7-100%), while 93.5% (N = 29) of the articles had a compliance greater than 75%. Twenty-eight CONSORT items were reported in more than 75% of the articles. The average compliance of the analyzed RCTs was 93.9% for Galcanezumab, 91.3% for Fremanezumab, followed by 85.4% for Erenumab and Eptinezumab studies. Implementation of the ROB2 tool showed some concerning "missing information" arising from the inadequate reporting. Specifically, 50% of the studies (N = 16) were categorized as having inadequate information regarding the randomization process. Conclusions: Adequate reporting quality was disclosed in the evaluated RCTs with anti-CGRP MAbs in migraine prevention. However, some methodological issues need to be highlighted to be addressed in future studies assessing the efficacy of new molecules targeting CGRP or other candidate pathways implicated in migraine pathophysiology.

Observational Retrospective Study in Patients Treated with Galcanezumab as Preventive Treatment for Migraine: The ORYGAM Study.

INTRODUCTION: The efficacy of galcanezumab has been demonstrated in randomized controlled trials, but evidence about its use under clinical practice conditions is still limited. This study aimed to describe the characteristics of the patients treated with galcanezumab in routine clinical practice in Spain as well as treatment patterns, persistence, and effectiveness. METHODS: A retrospective chart review study was carried out in six hospitals. Information of adults with migraine, who started treatment with galcanezumab between November 2019 and September 2021, was analyzed until end or loss of follow-up. Continuous variables were described as mean (standard deviation, SD) and median (interquartile range, IQR), and categorical variables as frequency and percentages. Persistence to treatment was estimated using Kaplan-Meier analysis. RESULTS: A total of 314 patients were analyzed over median follow-up period of 17.5 months (13.8-20.7), with a mean age of 46.3 (12.6), 85% women, 80.6% chronic migraine, and reporting a mean of monthly migraine days of 16.7 (7.8). Overall, 72.9% had comorbid conditions, with anxiety and depression disorders being the most frequent. More than 60% had received ≥ 6 previous preventive drugs, the most common being antiepileptics, antidepressants, and botulinum toxin (95.2%, 89.8% and 84.1%, respectively). Overall, 60.3% of the patients with other preventive treatments maintained them after galcanezumab initiation. The median time on galcanezumab was 14.6 months (9.4-22.8); 95.7%, 82.0%, 76.2% and 59.8% of patients were persistent to treatment at 3, 6, 9 and 12 months, respectively. Of the patients who discontinued (151: 48.1%), 57.6% were due to lack of effectiveness and 31.1% were due to improvement in migraine. The average reduction of monthly migraine days at 3, 6, 9 and 12 months was 7.9 (7.2), 9.1 (7.5), 8.8 (6.6) and 9.0 (6.9) days, respectively. CONCLUSIONS: In real clinical practice, galcanezumab is an effective treatment and has a high persistence in patients with migraine, mostly chronic and with multiple use of previous preventive treatments.