Cgrp Monoclonal Antibodies: Key Lessons from Real World Evidence

Introduction

Methods

Results

Study Characteristics

The search strategy identified 55 articles that met the criteria for full-text review, covering studies conducted ranged from 2019 to 2024 (Figure 1). Most investigation were carried out in Europe (43/55, 78.1%), followed by Asia (7/55, 12.7%) and the US (1/55, 1.8 %) with 7.2% (4/55) being international. Within Europe, 72% (31/43) of the studies were conducted in Italy, 4.6% (2/43) across the Netherlands, United Kingdom, Switzerland, Germany, Greece and Denmark, and 2.3% (1/43) were in Spain and Poland (Figure 2). The majority of the studies (29/55, 52.7%) were single-center, while 47.2% (26/55) were multicenter (Figure 3).The most common study design was prospective cohort studies (42/55, 76.36%) followed by retrospective cohort ones (13/55, 23.64%) (Figure 4). The duration of the studies varied, with 32.7% (18/55) lasting 12 weeks, 36.3% (20/55) lasting 24 weeks, 23.6% (13/55) lasting 48 weeks or more for, and 7.2% (4/55) categorized under other durations (Figure 5). The primary endpoint was effectiveness in 89% (49/55) of the studies, quality of life/disability in 9% (5/55), and other endpoints in 1.8% (1/55) (Figure 6). Erenumab was the most extensively studied anti-CGRP mAb, followed by galcanezumab and fremanezumab. Several studies considered more then one anti-CGRP mAb ( Figure 7) [8,9,10,11,12,13,14,15,16,17,18,19,20,21].

Study design and enrollment inclusion criteria varied across the different real-world studies, reflecting the diversity of clinical practice. Additionally, the studies exhibited heterogeneity in sociodemographic and clinical details, as well as in the primary and secondary efficacy endpoints. Consequently, the following clinical details and their corresponding ranges exclusively pertain to the studies that included these aspects. While most studies provided distinct effectiveness results for patients with EM and those with CM, some studies did not specify outcomes based on migraine frequency.

Erenumab

We identified 18 RWE studies including 6,113 patients, predominantly females (76.2%), diagnosed with either EM (n=1095) or CM (n=5018), with a mean age ranging from 43 to 53 years (Table 1) [4,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. One study specifically focused on patients older than 65 years [35]. Most of these investigations were prospective (n=15) [4,22,23,25,26,27,28,29,30,31,35,36,37] with 3 being retrospective (Figure 3), [24,28,38].

Twelve were conducted across multiple centers [4,23,25,28,29,30,32,33,34,36,37,38]. whilst 6 were single-center studies [22,24,26,27,31,35].

Fourteen studies took place within a single country [4,22,23,24,25,26,27,29,30,31,32,34,35,37], while 4 were international [28,33,36,38]. The duration of these studies varied, with 1 lasting 2 months [22], 6 enduring>3 months [23,24,28,32,33,37], 6 extending to 6 months [25,26,27,29,34,35], 2 for 12 months [4,30], and 3 for more than 12 months [31,36,38].

Table 1. Erenumab in RWE studies.

Table 1. Erenumab in RWE studies.

Author/ Year	N° pts	Observation period	Study Type/Center/National-International	Primary endpoint	Secondary endpoints	Results	Safety findings
Barbanti et al, 2019 [22]	HFEM/CM: 13/65	8 weeks	P S N=Italy	Change in MMD at weeks 5-8 vs baseline	Change in MAI, >50%, >75% and 100% RR and any variation in VAS and HIT-6 scores.	Primary endpoints: HFEM: MMD -7; CM: MH9,7Ds – 15. Secondary endpoints: HFEM: MAI – 7; VAS -7; HIT-6 -30; ≥ 50% ≥ 75% and 100% R were 100%. CM: MAI − 15, VAS − 3, and HIT-6 – 12.8, ≥ 50% R 87.5%, ≥ 75% R 37.5%.	One AE (injection-site erythema) in a single patient (1.3%).
Barbanti et al, 2020 [23]	HFEM/CM: 103/269	12 weeks	P M (n=9) N=Italy	Change in MMD at weeks 9-12 vs baseline in HFEM and CM.	Change in MAI, >50%, >75% and 100% RR and any variation in VAS and HIT-6 scores.	Primary endpoints: HFEM: MMD -4.5; CM: MMD -9.3. Secondary endpoints: HFEM: VAS -1.9; HIT -10.7; MAI from 12.0 (IQR 10.0–14.0) to 5.0 (IQR 3.0–7.0); RR: ≥50% 59.4%; ≥75% 16.8% and 100% 1. CM: VAS -1.7 ± 2.0; HIT -9.7; MAI from 20.0 (IQR 15.0–30.0) to 8.0 (IQR 5.0–15.0; RR: ≥50% 55.5%; ≥75% 22.4% and 100% 1.1%.	Constipation (8.8%), usually rated as mild; severe in one case and classified as a SAE.
Scheffler et al, 2020 [24]	EM/CM: 26/74	12 weeks	R S N=Germany	RR >50%	% of conversion CM →EM; improvement of intensity and duration of pain; % AEs	Primary endpoints: EM: 57.7%; CM: 41.9%. Secondary endpoints: 53% CM → EM; 70.5% and 58.9% improvement of intensity and duration of pain respectively.	AEs: 42%: 23.8% constipation, 23.8% injection side skin symptoms or itching; 16.7% fatigue or a feeling of exhaustion 9.5% insomnia.
Ornello et al, 2020 [25]	CM: 91	24 weeks	P M (n=7) N=Italy	% of conversion to EM from baseline to months 4–6 of treatment and during each month of treatment.	Change in MHD, AMD and NRS.	Primary endpoints: 12.1% discontinuation before month 6 due to ineffectiveness, 68.1% CM →EM. Secondary endpoints: MHD from 26.5 (IQR 20–30) to 7.5 (IQR 5–16; p < 0.001), AMD from 21 (IQR 16–30) to 6 (IQR 3–10; p < 0.001) and NRS from 8 (IQR 7–9) to 6 (IQR 4–7; p < 0.001). Significant decreases both in converters and in non-converters.	1 pt discontinued the treatment before month 6 for AE.
Russo et al, 2020 [26]	CM: 90 (failure to ≥4 migraine preventive medication classes)	24 weeks	P S N=Italy	> 30% reduction in MHD, after ≥3 months of therapy switched to monthly erenumab 140 mg	Disease severity, migraine-related disability and impact and validated questionnaires to explore depression/anxiety, sleep, and QoL. Pain Catastrophizing Scale, Allodynia Symptom Checklist-12 and MIGraine attacks-Subjective COGnitive impairments scale (MIG-SCOG).	Primary endpoints: after 3 doses of 70 mg 70% R, 30% switched to 140 mg; after 6 doses 29% R. After 3 doses MHD -9.7 (p<0.001) and after 6 doses -12.2 (p<0.001). RR: ≥50% of MHD after 3 and 6 doses: 53% and 70%; Secondary endpoints: pain severity, migraine-related disability, and impact on daily living, QoL, Pain Catastrophizing and allodynia (all p<0.001) scales, quality of sleep, symptoms of depression or anxiety (p<0.05) but not MIG-SCOG also improved.	No new AE was reported.
Lambru et al, 2020 [27]	CM: 162	24 weeks	P S N=UK	Change in MMD at weeks 24 vs baseline	RR: 30%, 50%, 75%; % stopped MO HIT-6 score	Primary endpoints: MMD: -7.5 (p<0.001); MHD: -6.8 (p<0.001); Secondary endpoints: RR: 60%, 38%, 22%; MO: 54% →25 %; HIT-6: -7.5 (p=0.01).	At least one AE reported by 48% at month 1, 22% at month 3 and 15% at month 6. The most frequent AEs: constipation 20% and cold/flu-like symptoms 15%.
Barbanti et al, 2021 [4]	HFEM/CM: 60/182	48 weeks	P M (n=15) N=Italy	Change in MMD and MHD at weeks 45-48 vs baseline.	Change in MAI >50%,>75%, 100%, RR and any variation in VAS and HIT-6 scores at weeks 45-48.	221 considered for effectiveness, 242 for safety. Primary endpoints: HFEM: MMD -4.3; CM: MHD -12.8 Secondary endpoints: HFEM: VAS -1.8; HIT-6 -12.3; MAI from 11.0 ([IQR] 10.0–13.0) to 5 (IQR 2.0–8.0); RR: ≥50% 56.1%; ≥75% 31.6%; 100% 8.8%; CM: VAS -3.0; HIT-6 - 13.1; MAI from 20.0 (IQR 15.0–30.0) to 6.0 (IQR 3.8–10.0) RR: ≥50% 75.6; ≥75% 44.5%; 100% 1.2%. 83.6% CM → EM.	AEs: 18.6% usually mild. The most common: constipation 10.3%, injection site erythema 3.3%. 1.2% patients experienced SAEs: 1) Paralytic ileus (treatment related) 2) Non-ST segment elevation myocardial infarction (not related) 3) Myocardial infarction (not related).
Ornello et al, 2021 [28]	HFEM/CM: 374/1036	12 weeks	R M (n=16) I=Italy, UK, Germany, Czech Republic, Russian Federation, Australia.	RR: 0–29%, 30–49%, 50–75%, and ≥75% Comparison between men and women		Primary endpoints: RR≥75%: 20.2%; RR:50–74%: 20.7%; RR:30–49% 15.3%; RR:0–29%: 31.4; Secondary endpoints: gender did not influence the efficacy of outcomes.
de Vries Lentsch et al, 2021 [29]	HFEM/CM: 54/46	24 weeks	P M (n=2) N=Netherlands	MMD after 6 months vs baseline.	AMD, RR, well-being and coping with pain.	Primary endpoints: MMD: -4.8 (p <0.001); Secondary endpoints: AMDs (p <0.001) in all months; RR ≥50%: 36% in ≥3/6 months, and 6% in all 6 months; RR ≥30% 60% and 24%, respectively. Well-being (p<0.001) and coping with pain (p<0.001).	AEs: 93%. Most common: abdominal complaints 72%, including constipation 65%, fatigue 43% and injection site reactions (27%).
De Matteis et al, 2021 [30]	HFEM+CM:32	52 weeks 8-weeks follow-up after treatment completion	P M (n=2) N=Italy	RR and change in MMD during weeks 1-4 after treatment completation as vs baseline and the last 4 weeks of treatment.	RR and changes in MMD AMD, NRS in who did not restart treatment during weeks 5-8 after treatment completion vs last 4 weeks of treatment and with baseline	Primary endpoints: RR >50%: 56%; RR 50-75%: 34%; RR 75-100%: 22%; MMD: -19 (p<0.001) last 4 weeks of treatments, -15 (p<0.001) weeks 1-4 after treatment completation; Secondary endpoints: AMD, NRS: during the last 4 weeks of treatment (p<0.001); weeks 1-4 after completion (p<0.001) lower than baseline (MMD and AMDs p<0.001, NRS p=0.005). 56% RR ≥ 50% from baseline. At week 4 after treatment completion, 31% restarted treatment due to disease rebound.	NA
Andreou et al, 2022 [31]	CM: 135	2 years	P S N=England	Sustained effectiveness in 24 months of treatment	MMD, HIT-6 at month 6, 12, 18	Primary endpoints: RR:30%: 23%; RR:50% and 75%: 16% and 8% respectively. Secondary endpoints: MMD: (p<0.001) HIT-6: (p<0.001) at all timepoints.	NA
Pensato et al, 2022 [32]	CM+MOH: 149 (previously failed onabotulinum toxin A)	12 weeks	P M (n=5) N=Italy	RR 50%, 75%	MHD, MAI, CM →EM	Primary endpoints: RR >50%: 51%; RR >75%: 20%. Secondary endpoints: MHD: -11.3 (p<0.001) MAI: -29.3 (p<0.001) CM → EM: 64%	No SAEs observed.
Ornello et al, 2022 [33]	HFEM+CM: 1215	9-12 weeks	P M (n=16) I=Italy, UK, Germany, Czech Republic, Russian Federation, Australia.	RR: 0-29%, 30-49%, 50-74%, and ≥75% at weeks 9-12 vs baseline.For each response category median MMD and HIT-6 at baseline and at weeks 9-12.	Categorization of residual MMD at weeks 9-12: 0-3, 4-7, 8-14, ≥15. 4 categories of HIT-6: ≤49, 50-55, 56-59, and ≥60. Calculations in men and women.	Primary endpoints: RR 0-29%: 31.4%; RR 30-49%:15.3%; RR 50-74%: 32.6% and RR ≥75%: 20.7%. Secondary endpoints: 0-3 residual MMD: 20.2%, 4-7: 36.5%, 8-14: 24.6%, ≥15: 18.7%. of R (4-7 MMD) 50-74 %: 62.1% and (8-14) 23.7%; of R (0-3) ≥75%: 74.2% (4-7) 25.8%. No differences in gender for residual MMD; HIT-6 distribution less favorable in women in the 0-29% (p=0.004) and in the 30-49% (p=0.003) response categories.	NA
Gantenbein et al, 2022 [34]	EM+CM: 172	24 weeks	P M (n=13) N=Switzerland	Impact on QoL, migraine-related impairment and treatment satisfaction HIT-6, mMIDAS, Impact of Migraine on Partners and Adolescent Children (IMPAC), TSQM-9 (Treatment Satisfaction Questionnaire for Medication) after 6 months		HIT-6 -7.7 (p <0.001), the mMIDAS - 14.1 (p<0.001), MMD -7.6 (p<0.001) and AMD - 6.6 (p<0.001). IMPAC: -6.1 (p<0.001). Mean effectiveness of 67.1, convenience of 82.4 and global satisfaction of 72.4 of patients in the TSQM-9.	99 AEs and 12 SAEs observed in 62 and 11 patients, respectively. All SAEs as not related to the study medication.
Cetta et al, 2022 [35]	15 over 65 (O65) and 15 under 65 (U65), matched for sex HFEM/CM:12/18	24 weeks	P S N=Italy	Change in MHD and MMD vs baseline between young and elder migraine patients	MAI, AMDs, HIT-6, MIDAS, NRS, and ASC-12 after 3 (M3) and 6 (M6) months of treatment.	Primary endpoints: baseline MHD and MMD of both groups: 20. Mean age was 70 (65-76) and 45 (19-55) in the O65 and U65 group, respectively. At M3 and M6 no statistical differences between groups. Secondary endpoints: at M3 and M6, reduction of all clinical features under examination, without statistically significant differences between the 2 groups.	Similar proportion of AEs (M3 and M6, p= 1.0) in each group.
Troy et al, 2023 [36]	CM: 177	17-30 months	P M (n=4) I=Ireland, UK, USA	PROM/QoL outcomes over a period 17–30 months. .	HIT-6, MIDAS, MSQ before starting treatment and at intervals of 3–12 months after starting treatment.	Primary endpoints: 61.6% significant improvement after 6–12 months. 54.8% on treatment (median of 25 months). Secondary endpoints: from baseline to 25-30 months: HIT-6: -14; MIDAS: -101 MSQ: -30	38.4% stopped during the first year, due to lack of efficacy and/or possible AEs.
Pilati et al, 2023 [37]	CM: 88 (CM+MO: 84)	12 weeks	P M (n=6) N=Italy	Variation in MEQ, PSQI, SCI, (Sleep Condition Indicator) ESS, MIDAS, HIT-6 at T3 and later vs baseline	Changes in MMD, DSMs, RR 30%, 50%, 75%, and 100% after the first dose;	Primary endpoints: MEQ morningness → intermediate: p < 0.05; PSQI score > 5 at baseline in 64% of patients and no variation at follow up. SCI significant increase at T3 (p = 0.0144) not confirmed during later (p<0.05). ESS no statistical significance during follow ups At T3 MMD: -10.6 (p<0.001) in patients receiving 70 mg and -16.4 (p<0.001) in 140 mg (p<0.001). A significant difference between T3 and T9 (p=0.014) not confirmed in T3 vs. T12 (p = 0.766). Secondary endpoints: after the first dose of 70 and 140 mg (T1), RR >30%: 13% and 18%; RR >50%: 29% and 34%; RR> 75%: 13% and 26% and RR 100% 0% and 3% respectively. MIDAS and HIT-6 during all the evaluations vs baseline (p < 0.05).	10 different AEs in 37.5%. The most common: constipation in 10.2%. No AE led to withdrawal. 5.7% complained of insomnia.
Buture et al, 2023 [3 8]	82 New Daily Persistent Headache and Persistent Post-Traumatic Headache	over a two to three years	R M (n=3) I= Ireland, UK, USA	Improvement of QoL after 30 months vs baseline		Primary endpoints: significant improvements in QoL in 1/3 over a period of 11–30 months, with a 35% persistence after a median of 26 months of treatment.

The duration of the migraine among participants ranged from 5 to 33 years, with baseline values of MMD/MHD spanning from 9.4 to 26, NRS score from 6.8 to 10, HIT-6 from 64.2 to 67.8, and MIDAS from 77.5 to 130.5. At baseline, the MAI ranged from 11.6 to 26.7, with the proportion of subjects experiencing medication overuse varying from 52% to 95%. The average number of prior therapeutic failures spanned for 3.6 to 6.9 (Table 1). Only one study conducted a comparative analysis of outcomes between men and women [28].

Between 11% and 74% of patients required a dose escalation from 70 mg to 140 mg, with the latter usually being more effective. Changes in MMD, MHD, NRS, MAI, MIDAS and HIT-6, as well as >50%, >75% and 100% response rates are detailed in Table 5. Three study reported >30% response [26,27,33]. Treatment with erenumab led to a transition form CM to EM in 22%-83% of individuals, and from medication overuse to no medication overuse in 25% to 71.9% of patients. Some studies also evaluated patient reported outcomes, assessing aspects such as disability, quality of life, quality of sleep, pain catastrophizing, impact of migraine on partners and adolescent children, treatment satisfaction and subjective cognitive impairment during migraine attacks [26,34,36].

RWE studies have consistently reported overall good safety and tolerability profiles for erenumab. The proportion of patients reporting adverse events (AEs) ranged from 7.8% to 93% (median 23.5%). The most frequently reported AEs were constipation (median 15.2%), fatigue (median 16.7%), and injection site erythema (median 13.5%) (Table 6). Five serious AEs were reported, accounting for 0.08% of cases. Among these, three were treatment-related: paralytic ileus in one patient and severe constipation in two patients, totaling 0.05%. The other two cases, myocardial infarction, were not treatment-related. The discontinuation rate ranged from 0% to 40% (Table 6).

a) 

Fremanezumab

We identified 8 relevant articles focusing on fremanezumab in RWE studies, involving 1,776 patients (701 with EM and 1,075 with CM; 397 males and 1,379 females; medication overuse: 579), with a mean age ranging from 38.5 to 49.5 years (Table 2) [6,39,40,41,42,43,44,45]. Among these studies, 7 were prospective and 1 was retrospective (Figure 3). Of the prospective studies, 2 were conducted at single centers [43,44], while 5 were multi-center studies. The retrospective studies was multi-center [40]. The durations of the studies varied, with 3 lasting 3 months [39,42,43], 3 lasting 6 months [40,41,44], and 2 extending to 12 months [6,45].

Table 2. Fremanezumab in RWE studies.

Table 2. Fremanezumab in RWE studies.

Author/ Year	N° pts	Observation period	Study Type/Center/ National-International	Primary endpoint	Secondary endpoint	Results	Safety findings
Barbanti et al, 2022 [39]	67 (HFEM/CM: 21/46)	12 weeks	P M (n=9) N=Italy	Change in MMD for HFEM and MHD for CM at weeks 9–12 vs baseline.	Change in MAI, NRS, HIT-6 and MIDAS and ≥ 50%, ≥ 75% and 100% RR at the same time intervals.	Primary endpoints: MMD: -4.6 (p<0.05) MHD: -9.4 (p<0.001). Secondary endpoints: MAI:-5.7 (p<0.05), -11.1(p<0.001); NRS: -3.1, -2.5 (p<0.001) MIDAS: -58.3 (p<0.05), -43.7 (p<0.001) in HFEM and CM respectively; HIT-6: -18.1(p<0.001) in HFEM. The ≥ 50%, ≥ 75% and 100% RR at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM	5.7% reported TEAEs: 1 injection site erythema (1.9%), 1 abdominal pain (1.9%) and 1 neck pain and somnolence (1.9%)
Driessen et al, 2022 [40]	1003 (HFEM/CM: 416/587)	24 weeks	R M (n=421 clinicians: 240 neurologists, 80 general practitioners, 36 pain management specialists, 21 psychiatrists, 38 PAs or NPs, and 6 other headache specialists) N=Netherland	Changes in MMD and MHDs at month 6	NA	MMD/MHD: −7.7 and −10.1 in HFEM and CM respectively; −10.8 in the MO sub-group; −9.9 in the MDD subgroup, −9.5 in the GAD subgroup, and -9.0 in the prior exposure to a different CGRP mAb subgroup.	NA
Barbanti et al, 2023 [41]	410 (HFEM/CM: 214/196)	24 weeks	P M (n=28) N=Italy	Change in MMD and MHD at weeks 21–24 vs baseline	Changes in MAI, NRS, HIT-6, MIDAS and ≥50%, ≥75%, and 100% RR at weeks 21–24 vs baseline.	Primary endpoints: MMD: -6.9 (p<0.001) MHD: -14.2 (p<0.001) Secondary endpoints: ≥50%, ≥75% and 100% responders: HFEM: 75.0, 30.8 and 9.6%; CM: 72.9, 44.8 and 1%; NRS: -3.4, -2.7; MAI: -8.0, -15.1; HIT: -6, -8.0; -20.9, -24.3; MIDAS: -55.0, -72.6 respectively in HFEM and CM.	NA
Argyriou et al, 2023 [42]	204 (HFEM/CM:107/97)	12 weeks	P M (n=6) N=Greece	A minimum 50% decrease in MHD at T1 vs T0 and the percentage of 30%, 75%, and 100% reduction in mean MHD	Changes in mean MHD, migraine severity, mean days with intake of any acute headache medications, MIDAS, HIT-6, EQ-5D and QOL	Primary endpoints: reduction MHD: 83.5% HFEM and 62.6% CM patients . Secondary endpoints: MHD: -6.5, -9.4 respectively in HFEM and CM; p<0.001 in migraine severity, mean days with intake of any acute headache medications, MIDAS, HIT-6, EQ-5D and QOL	25% of patients (n=26) experimented treatment-associated toxicity, 43.8% (n=21) erenumab versus 16.3% (n=7) galcanezumab versus 15.4% (n=2) fremanezumab
Cullum et al, 2023 [43]	91 (HFEM/CM:-/91)	12 weeks	P S N=Denmark	Reduction ≥30% in MMD from baseline to weeks 9–12.	Responders ≥50 and ≥75% and proportion of patients reporting AEs.	Primary endpoints: MMD: -7.3; MHD: -8.2. ≥30% RR: 65% Secondary endpoints: ≥50 and ≥75% RR: 51% and 24%	NA
Suzuki et al, 2023 [44]	127 (HFEM/CM:54/73)	24 weeks	P S Japan	Change MMD/MHD and responders at 6 months	Predictors of responder at 6 months	Primary endpoints: MMD: −6.9 MHD: −9.7 ≥50%, ≥75% and 100% responders: HFEM: 90.4, 36.5 and 9.6%; CM: 52.2, 14.9 and 1.5% Secondary endpoints: higher percentage of nausea at baseline were associated with a≥50% MMD reduction at 6 months.	NA
Caponetto et al, 2023 [45]	83 (HFEM/CM:16/67)	52 weeks	P M (n=17) Italy	Change MMD, MHD, RR and persistence in medication overuse at 3-6 and 12 months	Change in MAI, MIDAS andHIT-6 at 3-6 and 12 months	Primary endpoints: MMD: -5, -6 and -6.5 (p<0.001) MHD: -11, -13 and -15 (p<0.001) ≥50%, ≥75% and 100% responders at 12 months: HFEM: 78.6, 35.7% and 14.5; CM: 75.9%, 37% and 56% Secondary endpoints: MAI: -6, -7.5 and -7; -14, -15 and -15.5; HIT-6: -11, -20 and -18.5; -11, -12.5 and -15; MIDAS: -18, -18 and -18; -48, -52 and – 53.5 respectively in HFEM and CM.	AEs 9.6% Discontinued for tolerability 1 pts (1.2%) local allergic reaction at site injection, constipation: 7.2%, injecion site reactions 3.6%
Barbanti et al, 2024 [6]	130 (HFEM/CM: 49/81)	48 weeks	P M (n=26) N=Italy	Change in MMD and MHD at weeks 45-48 vs baseline	Changes in MAI, NRS, HIT-6, MIDAS and ≥50%, ≥75%, and 100% RR at weeks 45-48 vs baseline. ≥50%, ≥75%, and 100% RR in patients with psychiatric comorbidities and MO.	Primary endpoints: MMD: -6.4(p<0.001) MHD: -14.5 (p<0.001) Secondary endpoints: ≥50%, ≥75% and 100% responders: HFEM: 75.5%, 36.7%, and 2%; CM: 71.6%, 44.4%, and 3.7%; pts with psychiatric comorbidities: 60.5%, 37.2%, and 2.3%; CM with MO: 74.2%, 50%, and 4.8%; CM with MO and psychiatric comorbidities: 60.9%, 39.1%, and 4.3%. NRS: -3.4, -3.4; MAI: -6, -16.5; HIT-6: -16.9, -17.9; MIDAS: -50.4, -76.6 respectively in HFEM and CM.	TEAEs occurred in 7.8% (6/130) of patients treated with fremanezumab for at least 48 weeks

Participants’ disease duration ranged from 7 to 29.6 years, Baseline MMD/MHD spanned from 10 to 24.3, NRS from 7.9 to 9.6, MAI from 10 to 12 in EM and 20 to 22.5 in CM. HIT-6 score ranged from 62.4 to 68 in EM and 68.3 to 70 in CM while MIDAS score from 66 to 73.1 in EM and 89.4 to 98 in CM (Table 2). Prior treatment failures among participants ranged from 4.3 to 6. Variations in MMD, MHD, NRS, MAI, MIDAS, and HIT-6 scores, >50%, >75% and 100% response rates and AEs are outlined in Table 5. A proportion of 61.2% to 93.8% of individuals transitioned from CM to EM, while 75% to 96.6% of patients discontinued medication overuse.

AEs, categorized as mild and transient, were observed in a range from 2.4% to 23% of the individuals (with a median of 9.6%) (Table 7). The predominant occurrences included reactions at the injection site (median 4.7%) and constipation (median 2%). The proportion of patients discontinuing the treatment spanned from 2% to 31% (median 9.5%). The reasons for discontinuation included lack of effectiveness (14%), personal reasons (6%), lost to follow-up (6%), AE (2%), pregnancy (1%), lack compliance (1%) and other unspecified reasons (31%) (Table 7).

b) 

Galcanezumab

We identified 15 relevant articles focused on evaluating Galcanezumab in RWE settings (Table 3) [7,46,47,48,49,50,51,52,53,54,55,56,57,58,59].

Table 3. Galcanezumab in RWE studies.

Table 3. Galcanezumab in RWE studies.

Author/ Year	N° pts	Observation period	Study Type/Center/ National-International	Primary endpoint	Secondary endpoint	Results	Safety findings
Takizawa et al, 2021 [46]	52 pts (EM/CM: 25/27)	12 weeks	R S N= Japan	Change in MMD, MHD, 50% RR, 100% RR. NRS, MAI	Changes from baseline in associated symptoms; premonitory symptoms.	Primary endpoints: MMD: - 4.4 (p < 0.001) in EM. MHD: - 7.3 (p < 0.001). MAI in EM: -4 (p < 0.001). MAI in CM: -6 (p < 0.001). The ≥50% and 100% RR: 76.0% and 20.0% in EM and 48.1% and 7.4 %in CM. NRS: -2 in EM; -1 in CM (both p < 0.001) Secondary endpoints: improvement in photophobia, phonophobia, nausea/vomiting 64.9%, 50.0%, 63.9% respectively. Premonitory symptoms at baseline: 46.1%. Afrer 12 weeks 62.5% reported premonitory symptoms without subsequent headache.	Injection site reactions at first, second and third injections: 26.9%, 17.3%,20.0%; constipation: 7.7%; fatigue: 5.8%; burning sensation: 3.8%; lightheadedness: 3.8%; others:19%.
Vernieri et al, 2021 [47]	165 (EM/CM: 33/130)	24 weeks	P M (n=13) N= Italy	Change in MMD (for HFEM) and MHD (for CM) after 6 months.	Changes in NRS, MAI, HIT-6 and MIDAS scores, ≥50% RR, conversion rate from CM to EM and MO discontinuation.	Primary endpoints: MMD - 8 (p< 0.001). MHD: -13 (p < 0.001). Secondary endpoints: NRS: - 2 in EM and – 2 in CM;( p< 0.001). HIT-6: - 14 in EM and -13 in CM (all p< 0.001); MIDAS: - 27 in EM and -54 in CM (p < .001). MAI: -8 in EM; -15 in CM (both p <0.001) ≥50%RRs: 76.5% in HFEM and 63.5% in CM. CM -→ EM: 77.2%. MO discontinuation: 82.0%.	AE: 10.3% non-serious events.
Vernieri et al, 2022 [48]	CM:156	12 weeks	P M (n=14) N= Italy	Consecutive 3-month ≥50% MHD RR.	Persistence of conversion from MO to non-MO and from CM to EM in all 3 months of treatment. Change in MHDs, MIDAS, HIT-6, MAI.	Primary endpoint: persistent ≥50% MHD RR: 41.7% Secondary endpoints: CM→ EM: 55.8%. Conversion from MO to non-MO: 61.8% of patients. MHD: -15 (p <0.001); MIDAS: -43 (p <0.001); HIT-6: -11 (p <0.001); NRS: -2 (p <0.001) MAI: -13 (p <0.001).	NA
Altamura et al, 2022 [49]	CM: 161	52 weeks	P M (n=15) N= Italy	Conversion rate from CM to EM from baseline to 12 months.	MO discontinuation, changes in MAI and monthly NRS.	Primary endpoint: CM →EM: 52.3%. Secondary endpoints: MO discontinuation rate: 82.8%. MAI: -17 (p < 0.000001). NRS: -2 (p < 0.000001).
Fofi et al, 2022 [50]	27 (EM/CM: 14/13)	24 weeks	P S N= Italy	Change in MMD, NRS, MAI, HIT-6 MIDAS and reduction in RSS and improvement in MS after 6 months of treatment.		MMD: -10.2 (p < 0.001); NRS: -2.4 (p < 0.001); MAI: -14.3 (p < 0.001); HIT-6: -14.6 (p < 0.001); MIDAS: -68.4 (p < 0.001); RSS: - 7 (p = 0.027); MS: + 0.29 (p = 0.014).	NA
Silvestro et al, 2022 [51]	43 (EM/CM: 8/35)	24 weeks	P S N= Italy	Change in MHD, NRS, attack duration and whole pain burden score after 3 and 6 months of treatment.	≥50% ≥75% RR; ≥50% reduction of whole pain burden core. change in MIDAS, HIT-6, MAI MSQ, BDI-II, HDRS scores. Proportion of patients converting from CM to EM and from non-responders to responders to pain killers.	Primary endpoints: MHD: -13.1 (T3) and -14.2 (T6) (p < 0.001);NRS: -2.1 score (T3) and -2.7 (T6) (p < 0.001);Headache attack duration (treated): -5.3 hours (T3) and -6.7 hours (T6) (p < 0.001). Whole total pain burden score: -1498 (T3); -1591.3 (T6) (p < 0.001). Secondary endpoints: ≥50% RR: 72.1% (T3), 74.4% (T6). ≥75% RR:44.2% (T3), 55.8% (T6). Reduction of 50% and 75% of the whole total pain burden score: 88.4% (T3), 95.4% (T6) and 76.7% (T3) and 88.4% (T6). MIDAS: -70 (T3) -74.5 (T6) (p < 0.001) HIT-6: -11 (T3); -11.5 (T 6) (p < 0.001) MAI: -15.5 at moths 6 (p < 0.001). MSQ: - 45,71 (T3); -47.14 (T6) (p < 0.001) BDI-II: -5.5 (T3); -5.5 (T6) (p = 0.003) HDRS: -5 (T3); -5 (T6). (p < 0.001). CM -→ EM: 74.3%	Injection site reaction: 23.26%, constipation:16.27%, fatigue: 6.98%, acrocianosys: 2.32%.
Kwon et al, 2022 [52]	87 (EM/CM:22/65)	12 weeks	P S N= Korea	>50% RR at 3 months.	>30%, >75%, and 100% RR, MHD, moderate/severe headache days, MAI, CCD, and HIT-6 and MIDAS scores.	Primary endpoint: >50% RR: 44.8% (54.5% EM and 41.5% CM). Secondary endpoints: >30% RR: EM 59.1%, CM 55.4%; >75% RR: EM 27.3%, CM 27.7%; 100% RR: EM 22.7%, CM 10.8%. MHD: -7.2 (p<0.001). Moderate/severe headache days: -4.3 (p<0.001); MAI: -4.1 (p<0.001); CCD: +7.3 (p<0.001); HIT-6: -4.4 (p<0.001); MIDAS: -32.9 (p<0.001).	Constipation 16.3%, fatigue 7%, acrocyanosis 2.3%
Ashina et al, 2023 [53]	46 (EM/CM: 27/19)	12 weeks	P S N= USA	Effects on premonitory symptoms, and/or occurrence of headache afterexposure to triggers or aura episodes in treatment-responders (≥ 50%), super-responders (≥ 70%), non-responders (< 50%) and super nonresponders(< 30%).		Premonitory symptoms decreased by 48% in responders, 28% in non-responders, 50% in super responders, and 12% in super non-responders. Triggers followed by headache decreased by 38% in responders, 13% in non-responders, 31% in super-responders, 4% in super non-responders.	NA
Guerzoni et al, 2023 [54]	78 CM	64 weeks	P S N= Italy	Change in MMD, MAI after 1 year.	Change in NRS, HIT-6, MIDAS	Primary endpoints: MHD: - 11.5 (p < 0.001); MAI- 30.1 (p < 0.001). Secondary endpoints: NRS: −2.8; HIT-6: -58.4 MIDAS -19.5 (p < 0.001).	NA
Vernieri et al, 2023 [7]	191 (EM/CM:43/148)	52 weeks	P M (n=16) N= Italy	Change in MMD /MHD.	Changes in MAI, NRS MIDAS, HIT-6. >50%, >75%, and 100% RR.	Primary endpoints: MMD: -6.0; MHD: -11.9. (all p < 0.00001) Persistent ≥50% RR: 56.5%. Persistent responders have a higher body mass index (BMI) (p = 0.007), a good response to triptans (p = 0.005) and MMD ≥50% RR at V1 (p < 0.0000001). Secondary endpoints: EM: MAI – 9; NRS: -2; HIT-6 -12.3; MIDAS -37,6. (p < 0.00001). >50%, >75%, and 100% RR /3.8%, 37.2%, 2.3%. CM: MAI: -18.4, NRS: -1.9; in HIT-6 :– 13.7; MIDAS – 57.6. (p < 0.00001). >30%, >75%, and 100% RR. >50%, >75%, and 100% RR 60.5%, 38.1%, 3.4%.	Two pts dropped out for nonserious AEs.
Suzuki et al, 2023 [55]	55 (EM/CM:18/37)	12 weeks	R S N= Japan	Change in MMD; A ≥ 50% RR at month 1,2 and 3. WMDs during month 1.		MMD: − 6.2 at 1 month (p < 0.001), − 6.8 at 2 months (p < 0.001), and − 7.9 at 3 months (p < 0.001). The ≥ 50% RR: 40.0% at 1 month, 41.8% at 2 months, and 50.9% at 3 months. The ≥ 75% RR: 10.9% at 1 month, 14.5% at 2 months, and 27.3% at 3 months. WMDs week 1: - 1.6; week 2: - 1.2, week 3: - 1.0; week 4: - 1.1 (p < 0.001).	NA
Lee et al, 2023 [56]	238 CM	12 weeks	P S N= Korea	Change in MHD, a ≥ 50%, ≥ 75%, ≥ 100% RR at month 3. Comparison of migraine charcteristics, comorbidities, and treatment responses between responder and non-responder groups.		MHD: - 12.7. ≥ 50% RR: 64.3%. ≥ 75% RR: 35.3%. ≥ 100% RR: 3.4%. Responder group features: younger, lower frequency of baseline headache days, more accompanying symptoms such as nausea, vomiting, and photophobia, better triptan response, less depression. Everyday headache (p = 0.017), depression (p = 0.024) and absence of accompanying symptoms (p=0.020) were significantly associated with response.	NA
Schiano di Cola et al, 2023 [57]	54 (EM/CM:17/37)	24 weeks	R S N= Italy	Change in MHD, MMD, NRS, MAI, MIDAS, and HIT-6 at T0, T3 and T6.		MHD -11.2 at T3 and - 11 at T6 (p < 0.001). MMD: - 8.2 at T3 and -7.5 at T6; (p < 0.001). NRS: – 1.6 at T3 and – 1.7 at T6 (p = 0.001). MAI -17.6 at T3 and -17.1 atT6 (p < 0.001). MIDAS: - 71.8 at T3 and – 77.5 at T6 (all p < 0.001). HIT-6: - 9.3 at 3 M and -11.1 at 6 M (all p < 0.001). MIDAS: −74.3% at T3, −80.6% at T6. HIT-6: -24.3% and 29.2% at T3 a T6, respectively.	NA
Schiano di Cola et al, 2023 [58]	47 (EM/CM:17/30)	24 weeks	P S N= Italy	Change in MHD, MMD, NRS, MAI, MIDAS, and HIT-6 scores at T3, and T6.	To evaluate photophobia, photophobia at T3 and T6.	Primary endpoints: MHD T3: -10.6; T6: -11.5 (p < 0.0001). MMD T3: -7.5; T6: -6.6 (p < 0.0001). NRS: - 1.4 both T3 and T6 (p < 0.0001) MAI: -17.5 at T3 and T6. (p < 0.0001). MIDAS T3: -60.5; T6: -64 (p < 0.0001). HIT-6 T3: -9; T6: -9.6 (p < 0.0001). Secondary endpoint: improvement in ictal photophobia: 68.1% more frequent in patients with episodic migraine (p = 0.02) and triptans responders (p = 0.03).	NA
Kim et al, 2023 [59]	104 (EM/CM: 24/80)	12 weeks	R S N= Korea	The ≥ 50% RR in the 3rd month of treatment vs baseline.		The ≥ 50% RR: 55.7%.	NA

The total number of individuals involved was 2,150, comprising 248 with EM and 1,902 with CM. The gender distribution was 844 males and 1,306 females, with a mean age of 44.9 years. Patients with calculated medication overuse were 822. Among the 15 studies, 11 were prospective [7,47,48,49,50,51,52,53,54,56] and 4 were retrospective (Figure 3) [46,55,57,59]. All retrospective studies were single-center, while among the prospective studies, 7 were single-center [50,51,52,53,54,56,58] and 4 were multicenter [7,47,48,49]. The duration of the studies varied, with seven lasting 3 months [46,47,52,53,55,56,59], five lasting 6 months [48,50,51,57,58] and three lasting 12 months or more [7,49,54].

Participants exhibited diverse disease durations, spanning from 24 to 30.1 years, with baseline MMD/MHD ranging from 11.2 to 21. The MAI spanned from 12 to 24.7, NRS from 7 to 7.6, MIDAS score from 30 to 96.1, and HIT-6 score from 64.6 to 66.9. Prior treatment failures ranged from 3 to 12 among participants (Table 3). Variations in MMD, MHD, NRS, MAI, MIDAS and HIT-6 scores, >50%, >75% and 100% response rates along with adverse events details are documented in Table 5.A proportion of 52.3% to 77.2% [23,24,30] of individuals transitioned from CM to EM, while 61.8% to 82.0% of patients discontinued medication overuse [48].

AEs, rated as mild and transient, occurred in 0% to 26.9% of the patients (median 2.3%). The most common were injection site reactions (median 8%) and constipation (median 7.7%) (Table 8). No serious AEs were reported nor did any patient discontinue treatment due to adverse events. The proportion of patients discontinuing the treatment ranged from 5.4% to 22.5% (median value: 9.8%). The reason for discontinuation was detailed in only three studies, and in all cases, it was due to a lack of efficacy, ranging from 6.1% to 14.2%. Among patients who discontinued therapy for reasons other than adverse events, no dropouts were reported in the 12-week studies. In the 24-week studies, 9 dropouts were reported in one study and 3 in another [48,54]. In a 1-year study, 1 patient discontinued treatment due to drug unavailability [7].

c) 

RWE studies examining multiple monoclonal antibodies.

Fourteen RWE studies explored more than one anti-CGRP mAb [8-21. Among these, ten studies encompassed erenumab, fremanezumab, and galcanezumab (Table 4), [10,11,13,14,15,21].Two studies focused on both erenumab and galcanezumab [8,9] another on erenumab and fremanezumab [12] and one on galcanezumab and fremanezuma [16]. Of these studies, eight were prospective [8,9,10,11,14,18,19,20,21] and five were retrospective [12,13,15,16,17]; nine were conducted at a single center [8,10,11,12,13,15,16,17,19], and four were multicenter [9,14,15,17,18]. The combined patient cohort across these RWE studies, investigating more than one anti-CGRP mAb, totaled 6,231 globally (females 5,270, males 961; EM: 1786; CM: 4,463; mean age: 46.4).

Table 4. Multiple mAbs in RWE studies.

Table 4. Multiple mAbs in RWE studies.

Author/ Year/Country	N° pts	Observation period	Study Type/Center/ National-International	Primary endpoint	Secondary endpoint	Results	Safety findings
Caronna et al, 2021 [8]	CM: 139 Erenumab: 96, Galcanezumab: 43	24 weeks	P S N= Italy	Change in MHD in MO e non-MO patients at monts 6; ≥50% RR at monts 6.	To compare pts with and w/o MO resolution at 6 months.	Primary endpoint: MHD MO: − 13.4 (p < 0.0001) MHD non-MO: -7.8 (p < 0.0001) ≥50% RR MO: 63.6% ≥50% RR non- MO: 57.5% Secondary endpoint: pts with ongoing MO at 6 months: higher frequency of MDM (p = 0.020), higher score in a 0–3 pain severity scale (p = 0.020), higer MAI p = 0.049), benzodiazepine use (p = 0.034), more anxiety in BAI (p = 0.020); previous failure to onabotulinumtoxinA (p = 0.048).	NA
Vernieri et al, 2021 [9]	154 Erenumab: 91, Galcanezumab: 63 (EM/CM: 47/107)	52 weeks 8-weeks follow-up after treatment completion	P M N= Italy	Change in MMD in the three months following erenumab and galcanezumab discontinuation (F-UP 1–2-3) after one year of treatment vs baseline.	Changes in MAI, in NRS, and HIT-6 score in F-UP 1–2-3.	Primary endpoint: MMD F-UP 1 EM/CM: - 2/- 5.5 MMD F-UP 2: EM/CM: -0.5/ -4 MMD F-UP 3: EM/CM: -0.5/-4 Secondary endpoints: MAI at F-UP 1 EM/CM: -6/-13 MAI at F-UP 2: EM/CM: -3/-9 MAI at F-UP 3: EM/CM: -2/-6 NRS at F-UP 1 EM/CM: -1.5/-1 NRS at F-UP 2: EM/CM: -1.5/-1 NRS at F-UP 3: EM/CM: -0.5/0 HIT-6 at F-UP 1 EM/CM: -10-5/-7 HIT-6 at F-UP 2: EM/CM: -4/-5 HIT-6 at F-UP 3: EM/CM: -6/-4	NA
Raffaelli et al, 2022 [10]	39 Erenumab: 16, Galcanezuma: 15, Fremanezumab: 8 (HFEM/CM: 14/25)	60 weeks	P S N=Germany	Change in MMD between the last four weeks of treatment discontinuation and weeks 9–12 after restart.	Changes in MHD, MAI, and HIT-6 scores in the same observation period.	Primary endpoint: MMD: -4.5 (p<0.001). Secondary endpoint: MHD -5.4 (p< 0.001) MAI: -3.9 HIT-6: -6 (p<0.001).	NA
Iannone et al, 2022 [11]	CM:203 Erenumab: 96 Galcanezumab : 74Fremanezumab: 33	52 weeks	P S N= Italy	Change in MMD; the ≥ 50%, ≥ 75% and 100% RR in MMD at 12 months. The ≥ 50% reduction in MIDAS score at 12 months.	Clinical predictors of response at 6 months and 12 months.	Primary endopoint: MMD: -8.4 (p< 0.0001) ≥ 50% RR: 36.4% ≥ 75% RR: 15.4% 100% RR: not achived. Reduction ≥ 50% in MIDAS: from 63.5% to 96.1%. Secondary endpoint: association with lower RR at 1 month: duration of chronicization (p = 0.04); elevated number of MMD at baseline (p < 0.0001); association with lower RR at 6 months: duration of chronicization (P = 0.04); MMD at baseline (p < 0.0001); Total Number of Analgesics (p = 0.003).	NA
Nowaczewska et al, 2022 [12]	123 Erenumab: 75, Fremanezumab: 48 (HFEM/CM:36/87)	12 weeks	R S N=Poland	Check if baseline clinical parameters and cerebral blood flow (CBF) measured by transcranial Doppler (TCD) may help predict mAbs efficacy	NA	Baseline Vm (mean velocity) values in middle cerebral artery were significantly lower in good responders vs non-responders. MAbs responsiveness ≥50% was positively associated with unilateral pain localization (p = 0.003) and HIT-6 score (p = 0.036) whereas negatively associated with Vm in right MCA (p = 0.012), and having no relatives with migraine (p = 0.040).	NA
Quintana et al, 2022 [13]	123 (56 Erenumab: 56, Galcanezumab: 38, Fremanezumab: 29 (HFEM/CM:66/57)	24 weeks	R S N=Italy	Reduction in MDM and MAI at 3 and 6 months	Change in HIT-6, MIDAS and Headwork	Primary endpoint: at 3 month Fremanezumab was statistically superior to Erenumab (MMD -16.7 vs -12.9, p<0.02). Secondary endpoint: Erenumab determined a greater improvement in the Headwork vs Fremanezumab (-14.7 vs -8.2, p<0.01)	NA
Barbanti et al, 2022 [14]	864 Erenumab: 639, Galcanezumab: 173, Fremanezumab: 52. (HFEM/CM: 208/565)	≥ 24 weeks N=Italy	P M (n=20) N=Italy	≥ 50% response predictors at 24 weeks	≥ 75% and 100% response predictors at 24 weeks.	Primary endpoint: ≥50% response in HFEM positively associated UP + UAs (p=0.004) and in CM with UAs (p=0.0264), UP + UAs (p=0.012), UP + allodynia (p=0.034) Secondary endpoint: 75% response positively associated with UP + UAs (p=0.006) in HFEM and with UP + UAs (p=0.012) and UP + allodynia (p=0.005) in CM	30% of Erenumab and Fremanezumab patients reported TEAEs (pain and redness at the injection site, constipation)
Varnado et al, 2022 [15]	3082 CGRP mAb versus SOC and 421 Galcanezumab versus SOC EM/CM 1749/ 1333	52 weeks	R S N= USA	To compare real-world treatment patterns for CGRP mAb, specifically galcanezumab versus standard-of-care (SOC) migraine preventive treatments.		Pts stopping SOC:75%. Compared with SOC, the CGRP mAb cohort had higher mean persistence (212.5 vs 131.9 days), adherence (PDC: 55.1% vs 35.2%), and more patients were adherent with PDC ≥80% (32.7% vs 18.7%) (all p <0.001). During 12-month follow-up, fewer patients discontinued CGRP mAb versus SOC (58.8% vs 77.6%, p <0.001).	NA
Katsuki et al, 2023 [16]	8 CM Fremanezumab: 5; Galcanezumab: 3	12 weeks	R S N= Japan	Median of MHD, MAI HIT-6 at 3 months.		Median MHD before, one, and three months: 30, 4 and 1 respectively. Median MAI: 17.5, 1.5, and 0 respectively) Median for HIT-6: 60.5, 45.5, and 44 respectively.	NA
Cantarelli et al, 2023 [17]	104 CM Erenumab: 48, Galcanezumab: 43, Fremanezumab: 13	24 weeks	R S N=Spain	Change in MHD, MIDAS and HIT-6 at weeks 0, 12, and 24 of treatment (at least 50%)	Treatment efficacy: young versus older patients, previous failure to >5 versus <5 drugs	Primary endpoint: reduction form erenumab, galcanezumab and fremanezumab in MHD, MIDAS and HIT-6 at week 12 (p<0.001); MHD at week 24 from Erenumab and Galcanezumab (p <0.001); MIDAS and HIT-6 in the erenumab group (P < 0.001, P = 0.004) and MIDAS in the galcanezumab group (P < 0.001). Secondary endpoints: reduction in MHD >50% at week 12 (P = 0.044) was observed between patients with >5 prior treatment failures with fremanezumab and in MHD >75% at week 24 with galcanezumab (p = 0.038)	NA
Muñoz-Vendrell et al, 2023 [18]	162 Erenumab: 38, Galcanezumab: 85, Fremanezumab: 29 (HFEM/CM: 32/130)	24 weeks	P M (n=18) N=Spain	Change in MMD at 6 months of treatment and the presence of AEs	Change in MMD at 3 months, change in MHD, MAI, frequency of days by intensity, the 30%, 50%, 75% and 100% RR, HIT-6, MIDAS and PGIC at 3 and 6 months.	Primary endpoint: MMD: -10.1 (p=0.0001). Secondary endpoint: MMD: -9.7; MHD: -10.1, -10.5; MAI: -8.8, -9.4 (p<0.001). ≥30%,≥50%,≥75% and 100% RR: 68%, 57%, 33% and 9%.	Injection pain, rash or pruritus: 26 pts, flu-like symptoms: 8 pts, hair loss : 2 pts.
Guerzoni et al, 2023 [19]	233 Erenumab, Galcanezumab, Fremanezumab (HFEM/CM:40/193)	48 weeks	P S N=Italy	Response to anti-CGRP mAbs between women in menopause and those of childbearing age.	Effectiveness of anti-CGRP mAbs between woman with physiological menopause and those with a surgical one and effectiveness different antibodies and the predictors of a 75% response among women in menopause	Primary endpoint: the effectiveness of anti-CGRP monoclonal antibodies is almost the same between women in menopause and women of childbearing age. Secondary endpoint: no predictors of an excellent response apart from a lower AC at the baseline (p= 0.03)	Constipation: erenumab 54.5% for galcanezumab: 40.9%; fremanezumab, 4.5%. Injection site reaction only in 7 pts with galcanezumab.
Barbanti et al, 2023 [20]	771 Erenumab: 527, Fremanezumab: 40, Galcanezumab:5 (HFEM/CM:154/418)	≥24 weeks	P M (n=16) N=Italy	Frequency and characteristics of late responders (>12 weeks)		Late responders: 55.1%. Differed from responders: higher BMI (+0.78, p= 0.024), more frequent treatment failures (+0.52, p= 0.017) and psychiatric comorbidities (+10.1%, p = 0.041), and less common unilateral pain, alone (−10,9%, p = 0.025) or in combination with UAs (−12.3%, p = 0.006) or allodynia (−10.7, p = 0.01).	AEs: 23% constipation (4.4%), fatigue (4.4%) and dizziness (3.3%).
Vernieri et al, 2023 [21]	226 Erenumab: 125, Galcanezumab, Fremanezumab: 101 (HFEM/CM:46/180)	64 weeks	P M (n=10) N=Italy	MMD, MAI, and HIT-6 at baseline, after 90-112 days (Rev-1), after 84-90 days since Rev-1 (Rev-2) and 30 days after the last injection, in the first and the second year after a discontinuation period		MMD (18.1 ± 7.8 vs. 3.4±7.8), MAI (26.7± 28.3 vs.17.7 ±17.2), and HIT-6 scores (63.1 ± 5.9 vs. 67.1 ± 10.3) were lower in the second year than in the pre-treatment baseline (consistently, p<0.0001). Second-year baseline MMD were lower in patients on anti-CGRP mAbs (p = 0.001) and with lower pre-treatment baseline MMD (p ≤ 0.001).	NA

AEs: adverse event AMD: monthly acute medication intake days; BAI: Beck Anxiety Inventory scale; BDI-II - Beck Depression Inventory, Second Edition; BMI: Body mass index; CCD: clear cristal days; CM: chronic migraine; EM: Episodic Migraine; HADS: hospital anxiety and depression scale; HARS - Hamilton Anxiety Rating Scale; HFEM: High Frequency Episodic Migraine; HIT-6: Headache Impact Test; LFEM: Low Frequency Episodic Migraine; MAI: monthly acute medication intake MIDAS: Migraine Disability Assessment Questionnaire; MMD: Monthly migraine days; MOH: medication overuse-headache; MSQ : Migraine-Specific Quality-of-Life Questionnaire; NA: not applicable; NRS: Numerical Rating Scale; PGIC: Patient Global Impression of Change scale; PMI: Monthly painkiller intake; PDC: proportion of days covered; RR: Response rate; SOC: standard of care UMP: unilateral migraine pain; WMD: Weekly migraine days.

Table 5 summarizes changes in MMD, MHD, NRS, MAI, MIDAS, and HIT-6 scores, as well as >50%, >75%, and 100% response rates. Table 9 report information on adverse events.

Table 5. Synopsis of efficacy endpoints among patients receiving erenumab (white rows), galcanezumab (grey rows) or fremanezumab (blu rows) in RWE studies. The data are presented as change from baseline values at different time interval. Where results from more than one RWE study are present, two numerical values separated by a slash indicate the range of variation.

Table 5. Synopsis of efficacy endpoints among patients receiving erenumab (white rows), galcanezumab (grey rows) or fremanezumab (blu rows) in RWE studies. The data are presented as change from baseline values at different time interval. Where results from more than one RWE study are present, two numerical values separated by a slash indicate the range of variation.

	3 months			6 months			12 months
	All	EM	CM	All	EM	CM	All	EM	CM
MMD	-	-2.5/-4.5	-		-4.8/-7.7	-	-	-4.3/-7.8	-
	-	-4.4	-	-	-7.5 -8.2	-	-	-6/-11.5
		-4.6/-7.3	-		-6.9, -7.7	-		-6.4/-6.5	-
MHD	-6.9/-7.9	-	- 4.7/-15	-4	-	-6.8/-19	-	-	-12.8/-21.7
	-	-	-7.3/-15	-10.2/-14.2	-	-11/-14.9	-	-	-10/-11.9
	ù		-8.2/-9.4		-	-9.7/-14.2		-	-14.5/-15
NRS	-	-0.5/-1.9	-1.7/-3		-0.7/-2	-2/-3	-	-0.7/-3	-1.8/-3.6
	-1.6/-2.1	-1/-2	-1	-1.4/-2-7	-2	-2	-	-2	-1.9/-2.8
		-3.1	-2.5		-3.4	-2.7		-3.4	-3.4
MAI	-6.5/-7.6	-5/-7	-12/-15	-1.7	-5/-8	-14/-15	-	-5/-8	-14/-16
	-4.1	-4/-6.5	-4/-15	-14.2/-17.5	-8	-8/-29.7	-	-9	-18.4/-30.1
		-5.7	-11.1		-8	-15.1		-6/-7	-15.5/-16.5
MIDAS	-	-28.5/-48.9	-35.1/-42.1		-32.4/-44.6	-37.1/-45.9	-	-38.3/-47	-44.3/-65.1
	-32.9	-	-14/-71.8	-64/-77.5	-27	-54	-	-9.3	19.5/-57.6
		-31/-53.8	-43.7/-55		-55	-72.6		-18/-50.4	-53.5/-76.6
HIT-6	-7/-8.4	-8.4/-10.7	-9.7/-11.4		-7.1/-13.3	-7.5/-12.7	-	-12.3/-13.7	-13.1/-14
	-4.4	-4	-11	-9.3/-14.6	-63	-50	-	-12.3	-13.7/-58.4
		-10/-18.1	-0.3/-28		-20.9	-24.3	-	-16.9/-18.5	-15/-17.9
>50% RR (%)	41.9/53.3	57.7/59.4	41.9/55.5	-	36/63	22/70	-	56/85	44.5/68
	50.9	41.7/76	48.1/76.5	73.2/95.4	76.7	61.5/74.4	-	73.8	60.5
		43.3/76.5	38.3/58.3		75/90.4*	52.2/76.3		75.5/78.6	71.6/75.9
>75% RR (%)	20.2/20.7	16.8/22.9	20/22.4	-	16.3/38.4	38/42.3	-	31.6/42	31.6/44.5
	27.3	41.7/73.8	27.7/44.2	45.7/55.8	30.2	63.5	-	37.2	38.1
		24/40.2	17/25		30.8/36.5	14.9/44.8*		35.7/36.7	44.4/37
100% RR (%)	-	1/3	1.1/5		4.6	2.8-9	-	8.8	1.2/ 8.5
	-	7/20	3.4/10.8	-	9.3/11.6	4.7	-	2.3	3.4
		9.9	0		9.6	1/1.5		2/14.3	3.7/5.6

All: migraine patients (not specified if episodic or chronic); EM: episodic migraine; CM: chronic migraine; MMD: monthly migraine days; MHD: monthly headache days; NRS: numerical rating scale score; MAI: monthly analgesic intake; MIDAS: migraine disability assessment scale score; HIT-6: headache impact test-6 score; >50% RR: >50% response rate; >75% RR: >75% response rate; 100% RR: 100% response rate.*90.4 controllato- studio giapponese su 130 pz. * errore di trscrizione 44.8, no 4.8 *14.3 controllato – è il long term 52 week Caponetto/Iannone (sono 2 pazienti su 14).

Table 6. Overview of adverse events among patients receiving erenumab in RWE studies.

Table 6. Overview of adverse events among patients receiving erenumab in RWE studies.

		AE type	Frequency range	Frequency <8% (pts n)	Frequency 8-10% (pts n)	Frequency >10% (pts n)
Pts with AEs-	7.8%-93%	- constipation	8.8%-65%	-	1	4
		- injection site erythema	0.8%-27%	1	-	2
		- fatigue	0.8%-43%	1	-	2
		- insomnia	5.7%-9.5%	-	1	-
		- cold/flu-like	5%-15%	-	-	1
		- dizziness	0.6-1.8	1	-	-
		-arthralgia	1.1-1.7	2	-	-
Pts with SAEs	0-1.2%	- paralytic ileus - constipation - myocardial infarction	0.4% 0.8% 0.8%
Pts who discontinued treatment due to AEs	0-1.2%	- paralytic ileus - constipation - myocardial infarction	0.4% 0.8% 0.8%

Table 7. Overview of adverse events among patients receiving fremanezumab in RWE studies.

Table 7. Overview of adverse events among patients receiving fremanezumab in RWE studies.

		AE type	Frequency range	Frequency <8% (pts n)	Frequency 8-10% (pts n)	Frequency >10% (pts n)
Pts with AEs	0%- 26.9%	- injection site reactions	1.1-12.7%	6	1	1
		- constipation	0.7-7.2%	7	-	-
		- dizzines	1.9-4%	2	-	-
		- flu-like simptoms	3.9-4-%	2	-	-
		- fatigue	0.4-3%	2	-	-
		- arthralgia	0-2%	1	-	-
		- nausea	0.2-2%	2	-	-
		- abdominal pain	0-1.9%	1	-	-
		- hair loss	0.2-1%	2	-	-
		- libido loss	0-0.2%	1	-	-
Pts with SAEs	0%	-
Pts who discontinued treatment due to AEs	0-1.2%	- injection site reactions

AEs: adverse events; SAEs: serious adverse events.

Table 8. Overview of adverse events among patients receiving galcanezumab in RWE studies.

Table 8. Overview of adverse events among patients receiving galcanezumab in RWE studies.

		AE type	Frequency range	Frequency <8% (pts n)	Frequency 8-10% (pts n)	Frequency >10% (pts n)
Pts with AEs	0%- 26.9%	- injection site reaction	1%/26.9%	1	-	2
		- constipation	1.1%/16.3%	2	-	2
		- dizziness	<2%/8%	1	1	-
		- flu-like simptoms	0%/<2%	2	-	-
		- fatigue	5.8%/7%	3	-	-
		- arthralgia	0%/2.3%	2	-	-
		- acrocyanosis	0%/2.3%	2	-	-
Pts with SAEs	0%	-
Pts who discontinued treatment due to AEs	0	-

Table 9. Overview of adverse events reported in multiple mAbs REW studies.

Table 9. Overview of adverse events reported in multiple mAbs REW studies.

		AE type	Frequency range
Pts with AEs	0%- 54.5%	- injection site reaction	0%- 30%
		- constipation	0%- 54.5%
		- dizziness	0%-3.3%
		- fatigue	0%-4%
Pts with SAEs	0%
Pts who discontinued treatment due to AEs	0%

Discussion

Conclusion

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