Galcanezumab for the treatment of chronic migraine and medication overuse headache: Real‐world clinical evidence in a severely impaired patient population

Abstract Background Galcanezumab is a monoclonal antibody acting against the calcitonin gene‐related peptide approved for the preventive treatment of migraine. The aim of this article is to explore its effectiveness and safety of galcanezumab in chronic migraine (CM) with medication overuse‐headache (MOH). Methods Seventy‐eight patients were consecutively enrolled at the Modena headache center and followed up for 15 months. Visits were scheduled every 3 months, and the following variables were collected: the number of migraine days per month (MDM); the painkillers taken per month (PM); the number of days per month in which the patient took, at least, one painkiller; the six‐item headache impact test; and the migraine disability assessment questionnaire (MIDAS) score. Demographic features of the analyzed sample were collected at the baseline and adverse events (AEs) were collected at every visit. Results After 12 months, galcanezumab significantly reduced the MDM, the PM, the number of days on medication, the HIT‐6 as well as the MIDAS scores (all p < .0001). The greatest amelioration was obtained in the first trimester of treatment. A higher MDM, a higher NRS score at the baseline, and a higher number of failed preventive treatments negatively predict the CM relief at the year of treatment. No serious AEs were registered and only one drop‐out was due to AE. Conclusions Galcanezumab is effective and safe for the treatment of patients affected by CM and MOH. Patients with a higher impairment at the baseline may found less benefits with galcanezumab.


INTRODUCTION
and represents a significant burden for society (Lanteri-Minet et al., 2011).
Indeed, the recurrent pain strongly limits patients in performing their social and working activities, thus potentially leading to working impairment and social exclusion, even followed by the development of anxiety and depression (Nielsen et al., 2019). Additionally, until the approval of the new drugs acting upon the calcitonin gene-related peptide (CGRP) pathway, CM complicated with MOH was the most refractory form of headache, and a painkiller withdrawal was necessary before a new preventive treatment could be started (Nielsen et al., 2019). Anti-CGRP monoclonal antibodies (mAbs) are well tolerated and effective drugs for CM, even without a drug withdrawal (Pensato et al., 2022). In particular, galcanezumab is an anti-CGRP mAb that has shown promising efficacy and safety in treating CM in randomized placebo-controlled trials (Detke et al., 2018). Additionally, galcanezumab showed a good efficacy even in patients with previous preventive treatment failures (Ruff et al., 2019), showing a stable efficacy over time (Födrerreuther et al., 2018;Pozo-Rosich et al., 2022). Notably, galcanezumab showed a good efficacy even in patients affected by CM and MOH (Dodick et al., 2021). Despite this, no studies have explicitly focused on galcanezumab action upon in real-word settings, CM and MOH, even if some evidence suggests a positive action of galcanezumab even in this condition (Vernieri, Altamura, et al., 2021).
Hence, this article aims to explore the effectiveness and safety of galcanezumab in a cohort of patients affected by CM and MOH after 1 year of therapy. Moreover, the clinical course of patients after the suspension of galcanezumab has also been explored. Finally, potential predictors of the response to galcanezumab have been searched.

Study design and ethical approval
This single-center, prospective study was conducted at the University hospital of Modena. All participants signed an informed consent to participate in the research and for data publication. This study was approved by the Area Vasta Emilia Nord Ethics Committee of Mod-ena (protocol number: 625/2020/OSS/AOUMO) and was conducted in accordance with the latest version of the Declaration of Helsinki.  (Födrerreuther et al., 2018) and the European Medicines Agency (EMA) summary of product characteristics (https://www.ema.europa.eu/en/documents/productinformation/aimovig-epar-product-information_en.pdf). All patients received a dose of galcanezumab of a vial of 120 mg subcutaneously every month, except for the first injection when a double loading dose was administered. After reaching the year of treatment, galcanezumab was discontinued (Sacco et al., 2019) and the patients were reevaluated after 3 months. The drug was restarted in case of migraine worsening (Sacco et al., 2019). Visits were scheduled every 3 months. The following variables were collected: the average number of migraine days per month (MDM), the average number of painkillers taken per month (painkillers per month, PM), the mean number of days per month in which the patient took, at least, one painkiller (number of days on medication, NDM), the average migraine intensity using the numeric rating scale for pain (NRS) score, the six-item headache impact test (HIT-6) score (Yang et al., 2011) and the migraine disability assessment questionnaire (MIDAS) score (Bigal et al., 2003), and the hospital anxiety and depression scale (HADSd for depression and HADSa for anxiety) score (Bjelland et al., 2022). The following variables were collected only at the baseline visit: age, sex, familiarity with headache, presence of migraine aura, duration of migraine, duration of CM, the number of preventive treatments failed in the past, the concomitant assumption of another preventive medicine, and the performing of an in-hospital drug withdrawal before starting galcanezumab. Adverse events (AEs) were collected at every visit and analyzed. Local adverse events related to the injection procedure were considered only if lasted for more than 24 h.

Statistical analysis
Continuous variables were checked for normal distribution using the Shapiro-Wilk test and compared with the one-way analysis of variance followed by Sidak's test for multiple comparisons if normally distributed. Otherwise, a Kruskal-Wallis rank-sum test was used. Categorical variables were expressed as subject counts and percentages and compared using the chi-squared test for homogeneity of odds.
The variables collected at the baseline were compared between those patients who were still suffering from CM after 12 months of treatment and those who were not suffering from CM after 12 months of treatment. In particular, a logistic univariate analysis was performed first, followed by multiple logistic regression analyses with backward elimi-

Demographic features
Globally, 78 patients were enrolled. The analyzed sample was mainly composed of middle-aged women with a long duration of CM and MOH. Moreover, the present sample displayed a high number of previous preventive treatments failures and an almost-daily migraine and analgesic consumption. Demographic features are summarized in Table 1.

Predictors of CM relief after 12 months of treatment
In the univariate analysis, patients who were still CM sufferers after 1 year of treatment displayed the following: a higher number of MDM at the baseline (28.64 ± 2.78 vs. 24.47 ± 5.45, p = .002), a higher number of PTPM at the baseline (56.93 ± 31.04 vs. 33.04 ± 26.82, p = .004), a higher NDM at the baseline (28.46 ± 3.16 vs. 24.09 ± 6.08, p = .003), a higher NRS score at the baseline (9.14 ± 0.45 vs. 8.72 ± 0.71, F I G U R E 1 Migraine days per month (MDM), painkillers per month (PM), number of days on medication (NDM), numeric rating scale for pain (NRS) score, six-item headache impact test (HIT6) score, and migraine disability assessment questionnaire (MIDAS) score at every month F I G U R E 2 HADSa and HADSd at every month TA B L E 2 Comparison between chronic migraine (CM) sufferers after 1 year and the ones who became episodic migraineurs

Adverse events and drop-outs
Twenty-eight patients suffered from, at least one AE, and the percent-  Table 3. Globally, three dropouts were registered. In particular, two patients were lost at follow-up before the 3rd and 6th month, while

DISCUSSION
The present study confirmed the effectiveness of galcanezumab even in a severely impaired population of CM and MOH sufferers, which are notoriously the most refractory to the preventive treatments for migraine (Vandenbussche et al., 2020). Furthermore, the analyzed sample displayed an almost-daily migraine frequency at the baseline; patients had to take an average number of even more than one painkiller per day to treat their attacks and had failed a high number of preventive treatments in the past. The significant impairment at the baseline was summarized by the MIDAS score, which indicated a severe impact of migraine on patients' quality of life. Despite this, after the first 3 months of treatment, patients already displayed a significant reduction of the MDM, PM, NDM, HIT-6, and MIDAS scores compared to the baseline (Figure 1). This result also confirms in a population of CM and MOH sufferers the rapid onset of action of galcanezumab, which has been already assessed among episodic migraineurs (Iagarshi et al., 2021) as well as CM sufferers who had failed multiple preventive medications (Schwedt et al., 2021), with a clinically meaningful improvement even after the first week of treatment (Kuruppu, North, et al., 2021). Moreover, the improvement in patients' disability has been specifically assessed in CM sufferers (Ford et al., 2021). However, despite the habitual rapid onset of action of galcanezumab, not all patients experience a rapid response (Goadsby et al., 2019). However, the 50% of patients who do not respond after the first and second months may respond within the 3rd month, at least in episodic migraine (Goadsby et al., 2019). Hence, a follow-up of at least 3 months is warranted. The rapid onset of action of galcanezumab is linked to the early reach of the peak serum (5 days) (Kuruppu, North, et al., 2021) and the initial administration of a double loading dose of 240 mg instead of the 120 mg dose used for the other injections. About the last point, it has been proved that the reduction of the free CGRP is dose-and time-dependent for galcanezumab, with a higher dose determining a higher reduction (Kielbasa & Helton, 2019). This could also explain why, after the great improvement in the first 3 months of treatment, the effect of galcanezumab stabilizes over time (Pozo-Rosich et al., 2022), thus ruling out the existence of a tolerance effect. In this sample, an amelioration of anxious and depressive symptoms was observed. Smitherman et al. (2020) indicated that CM sufferers with comorbid anxiety and depression responded to the 240 mg dose but not to the 120 mg one, thus necessitating additional interventions. In our study, patients were screened for anxious and depressive symptoms using the HADS score, but a few scored more than 11 points, the threshold for mild depression and anxiety (Bjelland et al., 2022).
Due to this, our results are poor compared to the ones obtained by  (Table 2). In particular, a higher MDM, a higher NRS score at the baseline, and a higher number of failed preventive treatments in the past were independent predictors of CM persistence after 1 year of treatment. A higher number of migraine days per month has been associated with a lower response to anti-CGRP mAbs in CM (Caronna et al., 2021;Iannone et al., 2022). Moreover, in a similar population from our center, a higher number of failed preventive treatments were associated with a lower response toward erenumab (Baraldi et al., 2021). Pain intensity has not been linked to the response to the anti-CGRP mAbs, but pain catastrophizing has been linked to the response to the anti-CGRP mAbs (Silvestro et al., 2021). Many biochemical mechanisms may explain a lower response to the anti-CGRP mAbs and occur peripherally since anti-CGRP mAbs do not pass the blood-brain barrier (BBB) (Kielbasa & Helton, 2019). In particular, galcanezumab binds the 61% of the free CGRP at the steady state (Kielbasa & Helton, 2019). Hence, a considerable amount of the free CGRP may be able to bind and activate its receptors. Additionally, due to the calcitonin peptide family, other peptides, such as amylin, adrenomedullin-1, and adrenomedullin-2, may bind to the CGRP receptors and activate them, even if less potently (Edvinson et al., 2022). On the other hand, the abovementioned peptides may activate their receptors and offset the blocking effect of anti-CGRP mAbs on CGRP signaling (Rees et al., 2022). Considering this, how can it be biologically explicable that the MDM, the pain intensity, and the preventive treatment failed in the past influence the response to anti-CGRP mAbs? It has been proven that CM complicated with MOH is associated with higher CGRP levels in the peripheral blood, which restore after the successful withdrawal of the overuse of painkillers (Greco et al., 2020). Hence, it is not unreasonable to think that a higher MDM at the baseline may be associated with higher CGRP levels and, consequently, a lower response to anti-CGRP mAbs. These data may also explain why in our previous article, the number of migraine days per month was not associated with the response to erenumab, since it acts on the CGRP receptor rather than on the ligand (Sacco et al., 2019). Pain intensity is associated with higher CGRP levels in somatic pain (Schou et al., 2017), but no study has linked higher CGRP levels with the intensity of a migraine attack.
It could be possible that the recurrence of high-intensity attacks may determine higher CGRP levels. Furthermore, the failure of many preventive treatments in the past may indicate a more resistant form of migraine. Even if this category displays a worse response to anti-CGRP mAbs, they respond well (Kuruppu, Tobin, et al., 2021)

. A study from
Tassorelli's group demonstrated that patients with anxiety disorders are less likely to respond to anti-CGRP mAbs (Bottiroli et al., 2021), confirming the results obtained in another study among CM sufferers treated with galcanezumab in 2020 (Smitherman et al., 2020). Pain and depression are processed by the same brain areas, thus determining a possible overlapping between the two conditions (Zheng et al., 2022), and this may explain why the two conditions are often correlated. Moreover, stating the incapability of the anti-CGRP mAb to cross the BBB and to reach the abovementioned areas, it should be arguable that depressive symptoms may be refractory toward anti-CGRP mAbs (Irimia et al., 2021). In our study, we did not find an independent effect of anxiety or depression on the response to galcanezumab. Still, the percentage of patients suffering from anxiety and depression was meager at the baseline not allowing a reliable comparison. After 1 year of treatment, the three-month suspension determined a worsening in the MDM, PM, NDM, NRS score, HIT-6, and MIDAS score. This confirmed that the data indicate the worsening of migraine after 3 months of suspension (Raffaelli et al., 2022;Vernieri, Brunelli, et al., 2021). It seems that migraine worsening after the suspension of galcanezumab spread slower than with erenumab, probably because of the higher half-life of the first mAb (27 vs. 21 days) (Kielbasa & Helton, 2019). Migraine worsening indicates that, despite their good effectiveness, anti-CGRP mAbs are not disease-modifying agents (Vernieri, Brunelli, et al., 2021). Some oral preventive treatments have been shown to reduce the number of migraine days per month for several months after treatment cessation (Diener et al., 2007;Wöber et al., 1991). The explanation of this prolonged effect may be searched in the central action of these drugs. On the contrary, galcanezumab acts outside the BBB (Kielbasa & Helton, 2019), so it can only lead to peripheral neuronal network changes that poorly interfere with the central mechanisms of pain chronicity, that is, central sensitization (Mungoven et al., 2021). Interestingly, despite the worsening, patients resulted less impaired after the 3-month stop compared with the baseline. This indicates that a 3-month period is not enough to lose all the benefit of anti-CGRP mAbs, and a return to the baseline situation may require more than 3 months of suspension. Galcanezumab was also well-tolerated with a few AEs, mostly mild. No serious AEs were registered, apart from a transitory ischemic attack, which led to treatment discontinuation (Table 3). The most common AE was constipation, according to the action of galcanezumab, even on the β-isoform of the CGRP, mainly expressed at the intestinal level (Holzer & Holzer-Petsche, 2022). Our study has some limitations, such as the lack of a control group and the low sample size. The low number of patients who returned at the control visit after the suspension of galcanezumab did not allow us to make a reliable comparison with the same before suspension. Anyhow, a general worsening was seen. Despite this, the analyzed sample was composed only by severely impaired patients with CM and MOH, followed by a long period of time and this is-to our knowledge-the first study exploring the galcanezumab effectiveness in a sample composed only by CM and MOH sufferers. Our results confirm this drug's effectiveness and safety even in such a severely impaired population.

DATA AVAILABILITY STATEMENT
The dataset analyzed for this article is available from the corresponding author upon reasonable request.