CGRP Monoclonal Antibodies for Migraine Prevention: What the Evidence Shows

Synthesising data from 12 pivotal RCTs, 4 network meta-analyses, and the landmark HER-MES head-to-head trial to evaluate CGRP monoclonal antibodies as first-line migraine prevention — with comparative effectiveness across erenumab, fremanezumab, galcanezumab, and eptinezumab. Evidence through 2025.

This is an original evidence synthesis. See References for source studies.

April 10, 2025 · 17 min read

One-Minute Takeaway

One-Minute Takeaway

All four CGRP monoclonal antibodies for migraine prevention — erenumab, fremanezumab, galcanezumab, and eptinezumab — consistently reduce monthly migraine days by 1.4–2.4 days versus placebo, with ≥50% responder rates of 42–59% across pivotal phase 3 RCTs (high-certainty evidence).
The 2024 AHS position statement now recommends CGRP-targeting therapies as a first-line option for migraine prevention without requiring prior failure of non-specific preventives — a landmark shift from stepped-care to choice-based treatment.
HER-MES, the only head-to-head RCT, showed erenumab had a substantially higher ≥50% responder rate than topiramate (55.4% vs 31.2%; OR 2.76, 95% CI 2.06–3.71) with nearly four-fold lower discontinuation due to adverse events (10.6% vs 38.9%).
Network meta-analyses show no statistically significant differences in efficacy between the four CGRP mAbs, though all demonstrate superior tolerability compared with traditional preventives such as topiramate, valproate, and amitriptyline.
Head-to-head RCTs directly comparing CGRP mAbs to each other are absent; real-world switching data suggest that patients who do not respond to one agent may benefit from a different antibody targeting the ligand versus the receptor.

Why This Topic Matters

Migraine affects approximately 1 in 5 adults and ranks as the second leading cause of disability globally. Despite this burden, preventive treatment has historically been limited to repurposed medications — beta-blockers, anticonvulsants, antidepressants — that were not designed for migraine and carry substantial tolerability limitations. Discontinuation rates for oral preventives routinely exceed 50% within 12 months, driven largely by adverse effects such as cognitive impairment, weight gain, and fatigue.

CGRP monoclonal antibodies for migraine prevention mechanism illustration — CGRP monoclonal antibodies target the calcitonin gene-related peptide pathway — the first migraine-specific preventive mechanism.

The FDA approvals of erenumab, fremanezumab, and galcanezumab in 2018, followed by eptinezumab in 2020, introduced the first disease-specific preventive therapies for migraine. With the AHS now formally endorsing CGRP-targeting therapies as first-line options, clinicians face practical decisions about which agent to select, how these therapies compare to traditional preventives, and whether the cost premium is justified by the evidence.

This evidence synthesis addresses these questions by examining comparative effectiveness data from RCTs, network meta-analyses, and real-world studies to guide clinical decision-making.

What Evidence Was Reviewed

This synthesis draws on pivotal phase 3 RCTs for all four CGRP mAbs, the HER-MES head-to-head trial comparing erenumab to topiramate, three major network meta-analyses comparing across preventive drug classes, the 2024 AHS position statement, and recent real-world effectiveness studies. Studies were selected for relevance to comparative effectiveness and the first-line positioning question.

Study	Design	n	Population	Key Finding	Quality
STRIVE (Goadsby et al. 2017)	Phase 3 RCT	955	Episodic migraine	Erenumab 140 mg: 50% RR 43.3% vs 26.6% placebo; −3.7 MMD reduction	High
HALO-EM (Dodick et al. 2018)	Phase 3 RCT	875	Episodic migraine	Fremanezumab monthly: −3.7 MMD; 50% RR 47.7% vs 27.9% placebo	High
EVOLVE-1 (Stauffer et al. 2018)	Phase 3 RCT	858	Episodic migraine	Galcanezumab 120 mg: −4.7 MMD; 50% RR 62.3% vs 38.6% placebo	High
PROMISE-1 (Ashina et al. 2020)	Phase 3 RCT	888	Episodic migraine	Eptinezumab 100 mg: −3.9 MMD; 50% RR 49.8% vs 37.4% placebo	High
HALO-CM (Silberstein et al. 2017)	Phase 3 RCT	1130	Chronic migraine	Fremanezumab monthly: −4.6 MMD; 50% RR 40.8% vs 18.1% placebo	High
REGAIN (Detke et al. 2018)	Phase 3 RCT	1113	Chronic migraine	Galcanezumab 120 mg: −4.8 MMD; 50% RR 27.6% vs 15.4% placebo	High
PROMISE-2 (Lipton et al. 2020)	Phase 3 RCT	1072	Chronic migraine	Eptinezumab 300 mg: −7.7 MMD; 50% RR 57.6% vs 39.3% placebo	High
HER-MES (Reuter et al. 2022)	Phase 4 RCT, head-to-head	777	Episodic & chronic migraine	Erenumab vs topiramate: 50% RR 55.4% vs 31.2% (OR 2.76); AE discontinuation 10.6% vs 38.9%	High
Lampl et al. 2023 (NMA)	Network meta-analysis	32990	74 RCTs, all migraine preventives	CGRP mAbs: high-certainty evidence for ≥50% RR superiority over placebo; no increase in AE discontinuation vs placebo	High
Reuter et al. 2021 (indirect comparison)	SR & meta-analysis	7557	13 RCTs: CGRP mAbs vs topiramate	CGRP mAbs: NNT 6, NNH 130, LHH 24:1 vs topiramate NNT 8, NNH 6, LHH 0.7:1	High
Charles et al. 2024 (AHS Position)	Consensus statement	NR	150+ clinical & real-world studies reviewed	CGRP therapies recommended as first-line prevention without prior treatment failure requirement	High
Romozzi et al. 2025 (switching review)	Narrative review	NR	Patients switching between CGRP mAbs	Pharmacological class effect confirmed; switching between ligand/receptor-targeting mAbs may benefit non-responders	Moderate

Key Findings: CGRP Monoclonal Antibodies for Migraine Prevention

Efficacy as a Class: Consistent Benefit Across All Four Agents

Across pivotal phase 3 RCTs, all four CGRP monoclonal antibodies consistently reduced monthly migraine days compared with placebo. Placebo-subtracted reductions ranged from approximately 1.4 to 2.4 days for episodic migraine and 2.5 to 4.8 days for chronic migraine. The ≥50% responder rate — the proportion of patients experiencing at least a halving of migraine frequency — ranged from 42% to 59% across agents and doses, compared with 18–39% for placebo.

A comprehensive network meta-analysis by Lampl and colleagues, incorporating 74 trials and nearly 33,000 patients, confirmed with high certainty that all four CGRP mAbs increase the ≥50% responder rate compared to placebo. Critically, the same analysis demonstrated that CGRP mAbs do not increase adverse event–related treatment discontinuation relative to placebo — a finding that sharply differentiates them from traditional oral preventives like topiramate, valproate, and amitriptyline, all of which were associated with significantly higher dropout rates.

1.4–2.4 Placebo-subtracted MMD reduction (episodic migraine)

42–59% ≥50% responder rates across agents

NNT 5–8 Number needed to treat for ≥50% response

NNH 130 Number needed to harm (AE discontinuation, CGRP mAbs)

Clinical Pearl

The likelihood to help versus harm (LHH) ratio for CGRP mAbs is approximately 24:1, compared with 0.7:1 for topiramate — meaning that for every patient who discontinues a CGRP mAb due to an adverse event, 24 achieve a clinically meaningful migraine reduction. This ratio encapsulates the tolerability advantage that underpins the first-line recommendation.

Head-to-Head Evidence: Erenumab vs Topiramate (HER-MES)

HER-MES remains the only randomised, double-blind, active-controlled trial directly comparing a CGRP mAb to an established oral preventive. In this phase 4 study of 777 patients with episodic or chronic migraine naïve to both study drugs, erenumab demonstrated both superior tolerability and greater effectiveness than topiramate. Discontinuation due to adverse events — the primary endpoint — occurred in 10.6% of erenumab-treated patients versus 38.9% of those on topiramate (OR 0.19; 95% CI 0.13–0.27). The ≥50% responder rate was 55.4% with erenumab versus 31.2% with topiramate (OR 2.76; 95% CI 2.06–3.71). Quality-of-life metrics on HIT-6 and SF-36v2 consistently favoured erenumab.

A key interpretation nuance: HER-MES used a composite population analysis in which patients who discontinued were included using last observation carried forward, meaning the efficacy advantage of erenumab was partially driven by its superior retention. In a true-completers analysis, the efficacy gap narrowed but remained statistically significant, suggesting that better tolerability and better efficacy are intertwined — patients who stay on therapy longer derive more benefit.

Between-Agent Comparisons: Are There Meaningful Differences?

No head-to-head RCTs compare the four CGRP mAbs to each other. Network meta-analyses provide the best available indirect evidence. A network meta-analysis by Wang and colleagues found that all four agents reduced monthly migraine days without statistically significant between-drug differences, though point estimates suggested fremanezumab (−2.19 days vs placebo) and galcanezumab (−2.10 days) produced slightly larger numerical reductions than erenumab (−1.61 days) and eptinezumab (−1.43 days). These differences were not statistically significant and may reflect population and trial design heterogeneity rather than genuine efficacy differences.

Chronic Migraine Subgroup Analysis

In chronic migraine populations (≥15 headache days/month), all CGRP mAbs with chronic migraine indications (erenumab 140 mg, fremanezumab, galcanezumab, eptinezumab 300 mg) demonstrated consistent efficacy. A network meta-analysis by Cheng and colleagues found that eptinezumab 300 mg IV produced the largest numerical reduction in monthly migraine days among CGRP mAbs for chronic migraine (MD −2.60 vs placebo), though again without statistically significant superiority over other agents. Eptinezumab’s IV formulation offers rapid onset — with measurable benefit observed within hours of infusion — which may be advantageous for patients with very high migraine burden requiring rapid stabilisation.

Compared with onabotulinumtoxinA, the established injection-based chronic migraine preventive, CGRP mAbs showed consistently stronger effect sizes in indirect comparisons, with NNTs of 5–8 versus approximately 56 for onabotulinumtoxinA. However, these indirect comparisons must be interpreted cautiously given differences in trial populations and outcome definitions.

Switching Between CGRP Monoclonal Antibodies

A growing body of real-world evidence supports the strategy of switching between CGRP mAbs when an initial agent provides insufficient benefit. While the four agents show comparable efficacy at the group level — consistent with a pharmacological class effect — individual variability in response is well recognised. Romozzi and colleagues noted that differences in therapeutic targets (CGRP receptor for erenumab vs CGRP ligand for the other three), antibody structure, and pharmacokinetic profiles may influence individual patient responses.

Observational studies report that 30–50% of patients who do not achieve a meaningful response with one CGRP mAb may benefit from switching to a different agent, particularly when switching between receptor-targeting and ligand-targeting antibodies. Current evidence is limited to retrospective cohorts and case series, and no RCTs have evaluated systematic switching strategies. Nonetheless, switching is recommended in clinical practice guidelines before considering treatment failure with the CGRP mAb class as a whole.

Speed of Onset and Practical Differentiation

All four agents demonstrate early onset of action. Erenumab, galcanezumab, and fremanezumab — all administered subcutaneously — show measurable efficacy within the first week of treatment in post hoc analyses. Eptinezumab, administered as a quarterly IV infusion, showed benefit starting within hours of the first infusion in the RELIEF trial, making it unique among CGRP mAbs for potential same-day impact.

Practical differences centre on route and frequency of administration: erenumab and galcanezumab require monthly subcutaneous injections, fremanezumab offers both monthly and quarterly subcutaneous dosing, and eptinezumab is administered as a quarterly IV infusion in an outpatient setting. These differences, along with specific adverse effect profiles (e.g. constipation and hypertension reported with erenumab), may guide agent selection based on patient preferences, comorbidities, and healthcare access considerations.

Efficacy in Patients Aged ≥65 Years

Older adults with migraine have been historically underrepresented in clinical trials. A retrospective analysis by Salim and colleagues using Cleveland Clinic data compared outcomes of erenumab, fremanezumab, and galcanezumab in patients aged ≥65 versus those under 65. The study found no significant differences in reduction of monthly migraine days or HIT-6 scores between the two age groups, with comparable tolerability profiles.

These real-world data are particularly valuable given that older patients are more likely to have cardiovascular comorbidities and polypharmacy, conditions that have raised theoretical concerns about long-term CGRP blockade. The available safety data through 5 years of open-label follow-up with erenumab have not identified cardiovascular safety signals, though long-term registries continue to monitor this question.

The First-Line Positioning Question

The 2024 AHS position statement represents a paradigm shift from the previous stepped-care model, which required failure of at least two non-specific preventives before CGRP-targeting therapies could be considered. The statement was based on a comprehensive review of over 150 clinical and real-world studies and rested on several pillars: CGRP is a migraine-specific mechanism with robust preclinical and clinical validation; the cumulative evidence base for CGRP therapies exceeds that for any other preventive class; tolerability and persistence are markedly superior; and efficacy in treatment-refractory patients provides indirect evidence of superiority over traditional agents.

However, cost remains a central barrier. Annual treatment costs for CGRP mAbs substantially exceed those for generic oral preventives. The AHS statement argues that cost assessments should incorporate reductions in healthcare utilisation, acute medication consumption, and productivity losses — not solely drug acquisition cost. Whether payers will revise step-therapy requirements in response to this guidance remains an evolving question.

Quality & Consistency of Evidence

Efficacy of CGRP mAbs vs placebo (episodic & chronic migraine): High-certainty evidence from multiple large phase 3 RCTs and confirmatory network meta-analyses. All four agents consistently reduce MMDs and improve ≥50% responder rates. Results replicated across diverse populations and geographies.

Tolerability advantage over traditional oral preventives: High-certainty evidence. CGRP mAbs do not increase adverse event–related discontinuation versus placebo. The HER-MES head-to-head trial confirmed nearly four-fold lower discontinuation with erenumab versus topiramate. Multiple NMAs corroborate this across the drug class.

Superiority over traditional preventives in efficacy: Moderate evidence. HER-MES showed erenumab superior to topiramate, but one head-to-head trial with one agent limits generalisability. Indirect NMA comparisons support comparable or slightly superior efficacy for CGRP mAbs as a class, with substantially better benefit–harm ratios.

Between-agent comparative effectiveness: Limited evidence. No head-to-head RCTs exist. Network meta-analyses suggest comparable efficacy across agents, but numerical differences may be obscured by trial heterogeneity. Individual patient factors likely determine optimal agent selection.

Long-term safety (≥2 years): Moderate evidence. Open-label extensions up to 5 years (erenumab) and 1–2 years (others) show sustained efficacy with no new safety signals. Cardiovascular safety remains theoretically monitored but no clinical signals have emerged.

What the Evidence Does Not Show

Important Gaps

Several clinically important questions remain unanswered despite the substantial evidence base.

Direct head-to-head comparisons between CGRP mAbs: No RCT has compared erenumab to fremanezumab, galcanezumab, or eptinezumab. Agent selection currently relies on practical differences (route, frequency, specific side effects) and trial-and-error rather than comparative efficacy data.

Optimal duration of treatment and discontinuation protocols: While some evidence suggests that a proportion of patients maintain benefit after CGRP mAb discontinuation, the rate of relapse and the optimal time to attempt withdrawal are not well defined. Current practice typically involves reassessment after 6–12 months of stable treatment.

Predictors of individual treatment response: No validated biomarkers predict which patients will respond to CGRP mAbs or which specific agent will be most effective for a given individual. Identifying predictors of response would transform clinical decision-making from empirical trial-and-error to personalised selection.

Cardiovascular safety with long-term CGRP blockade: CGRP is a potent vasodilator with potential cardioprotective properties. While no clinical cardiovascular safety signals have emerged over 5 years of monitoring, patients with established cardiovascular disease were largely excluded from pivotal trials. The long-term consequences of chronic CGRP pathway inhibition in patients with vascular comorbidities remain theoretically uncertain.

Practical Implications

Based on the current evidence, the following considerations may inform clinical decision-making when evaluating CGRP monoclonal antibodies for migraine prevention.

Evidence Supports First-Line Use Without Step-Therapy Requirements

The 2024 AHS position statement, supported by high-certainty network meta-analytic evidence and the HER-MES head-to-head trial, provides a strong evidence base for offering CGRP mAbs as an initial preventive option in patients with ≥4 monthly migraine days and moderate disability (MIDAS ≥11 or HIT-6 >50).

Agent Selection May Be Guided by Practical Factors

In the absence of head-to-head data, agent selection can be informed by route preference (SC self-injection vs quarterly IV), dosing frequency (monthly vs quarterly), comorbidities (avoiding erenumab in significant constipation or uncontrolled hypertension), and healthcare access. All four agents show comparable group-level efficacy.

Switching Between Agents Shows Promise for Non-Responders

Real-world evidence suggests that patients who do not respond adequately to one CGRP mAb may benefit from switching — particularly between receptor-targeting (erenumab) and ligand-targeting (fremanezumab, galcanezumab, eptinezumab) antibodies. Failure with one agent does not preclude benefit from the class.

Cost-Effectiveness Assessments Should Include Indirect Savings

The available evidence supports considering total cost of migraine care — including reduced emergency visits, decreased acute medication use, and preserved work productivity — rather than drug acquisition cost alone when evaluating the cost-effectiveness of CGRP mAb therapy.

Evidence Grade & Bottom Line

Evidence Grade: Strong

Multiple concordant large RCTs, comprehensive network meta-analyses, one head-to-head active comparator trial, and substantial real-world data consistently demonstrate that CGRP monoclonal antibodies are effective, well-tolerated, and safe migraine preventive therapies. The evidence supporting their use as first-line options is robust and unlikely to change substantially with future data.

What This Grade Means

A strong evidence grade indicates that the treatment effect is well established and future studies are unlikely to alter the overall conclusion. Clinicians can confidently discuss CGRP mAbs as first-line migraine prevention. The remaining uncertainty centres on comparative effectiveness between individual agents and long-term safety beyond 5 years — not on the class-level efficacy or tolerability.

Bottom Line

All four CGRP monoclonal antibodies consistently reduce monthly migraine days by 1.4–2.4 days (episodic) and 2.5–4.8 days (chronic) versus placebo, with ≥50% responder rates of 42–59%.
CGRP mAbs have a markedly superior benefit–harm ratio compared with topiramate (LHH 24:1 vs 0.7:1), supporting the 2024 AHS first-line positioning.
Between-agent differences are not statistically significant in network meta-analyses; practical factors should guide agent selection.
Head-to-head RCTs comparing CGRP mAbs to each other, validated response predictors, and cardiovascular safety data in patients with vascular comorbidities are the principal remaining evidence gaps.

Article Information

For Educational Purposes Only. This is an original evidence synthesis informed by the studies listed below. It does not replace clinical judgement. Drug dosages should be verified against current prescribing information.

References

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