KOLAKOWSKI ET AL 2026 EFFICACY
(2026)Objective
To systematically evaluate the efficacy and effectiveness of anti-CGRP monoclonal antibodies (galcanezumab, eptinezumab, fremanezumab, erenumab) in preventing episodic and chronic cluster headache attacks.
Study Summary
• Galcanezumab 300 mg and eptinezumab 400 mg were each individually superior to placebo in eCH; only galcanezumab 300 mg significantly reduced mean weekly attack frequency at week 4 (p=0.04)
• No significant benefit was demonstrated for any anti-CGRP mAb in chronic cluster headache (cCH) (OR=1.07, 95% CI 0.78–1.48, p=0.68)
Intervention
Anti-CGRP monoclonal antibodies — galcanezumab 300 mg s.c. monthly, eptinezumab 400 mg i.v., fremanezumab 675 or 900 mg s.c., or erenumab 280 mg s.c. (280 mg loading, then 140 mg at week 4) — compared to placebo in adults with episodic or chronic cluster headache.
Inclusion Criteria
Adults ≥18 years with eCH or cCH (ICHD-3beta or ICHD-3 criteria); received any anti-CGRP or anti-CGRP receptor mAb; all study designs (RCTs, case series, case reports); published through June 29, 2025.
Study Design
Arms: Anti-CGRP mAbs: galcanezumab 300 mg (n=166), fremanezumab 675/900 mg (n=281), eptinezumab 400 mg (n=102), erenumab 280 mg (n=41) vs Placebo (n=590) — from 6 randomized controlled trials (randomized total n=1081); 506 additional patients from non-randomized studies
Patients per Arm: CGRP antagonists (randomized trials): n=491 as reported; Placebo: n=590; Non-randomized studies: n=506; Overall total: n=1587
Outcome
• Only galcanezumab 300 mg significantly reduced mean weekly attack frequency in eCH at week 4 (−8.7 vs −5.2 attacks/week, p=0.04); no other agent was superior to placebo on this measure
• cCH: no significant benefit for any anti-CGRP mAb (OR=1.07, 95% CI 0.78–1.48, p=0.68); heterogeneity was low to moderate (I²=24%, τ²=0.04)
Bottom Line
Anti-CGRP mAbs provide a statistically significant but modest benefit in episodic cluster headache, with galcanezumab 300 mg and eptinezumab 400 mg outperforming placebo; however, no benefit was demonstrated in chronic cluster headache, and positive results should be interpreted cautiously given endpoint heterogeneity, trial-to-real-world discrepancies, and the modest magnitude of effect.
Major Points
- Anti-CGRP mAbs significantly increased the ≥50% responder rate versus placebo in eCH at week 4 (OR=1.65, 95% CI 1.07–2.55, p=0.02) based on meta-analysis of 6 randomized placebo-controlled trials
- Galcanezumab 300 mg individually outperformed placebo in eCH ≥50% responder rate (71% vs 53%, p=0.046; OR CI 1.00–5.05, p=0.05) and was the only agent with a significant reduction in mean weekly attack frequency at week 4 (−8.7 vs −5.2 attacks/week, p=0.04)
- Eptinezumab 400 mg (ALLEVIATE trial) showed individual superiority over placebo in eCH ≥50% responder rate (67% vs 51%, p=0.02; OR CI 1.12–3.43) but not in weekly frequency reduction
- Fremanezumab (675 mg and 900 mg) and erenumab did not reach statistical significance versus placebo in eCH on either primary or secondary outcomes; both fremanezumab trials were terminated early due to interim futility
- No significant benefit was demonstrated for anti-CGRP mAbs in cCH in the meta-analysis (OR=1.07, 95% CI 0.78–1.48, p=0.68); no individual agent outperformed placebo on weekly frequency reduction in cCH
- Heterogeneity across randomized trials was low to moderate (I²=24%, τ²=0.04)
- 25 studies were included: 6 double-blind placebo-controlled RCTs, 9 non-randomized prospective studies, and 10 retrospective case series/case reports, totaling 1587 patients
- Real-world (non-randomized) data suggested higher response rates than controlled trials, representing a reverse efficacy-effectiveness gap potentially due to lack of placebo control and different conceptualizations of therapeutic success
Study Design
- Study Type
- Systematic review and meta-analysis
- Randomization
- No
- Blinding
- Not applicable (meta-analysis); included studies ranged from double-blind placebo-controlled RCTs to retrospective case reports
- Sample Size
- 1587
- Follow-up
- Varied across included studies (1 week to over 1 year); primary analysis focused on outcomes at 4 weeks post-administration
- Countries
- Switzerland
Primary Outcome
Definition: ≥50% responder rate — proportion of patients achieving ≥50% reduction from baseline in weekly cluster headache attack frequency, assessed at the time point closest to 4 weeks after drug administration; meta-analysis of randomized placebo-controlled trials, subgrouped by eCH and cCH
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo | Anti-CGRP mAbs (pooled) | 1.65 (1.07–2.55 (eCH); 0.78–1.48 (cCH)) | 0.02 (eCH); 0.68 (cCH) |
Limitations & Criticisms
- Small number of RCTs (n=6) limits meta-analysis statistical power
- Significant heterogeneity in study design, endpoint timing, and outcome reporting across included studies
- Two fremanezumab trials (NCT02945046 for eCH, NCT02964338 for cCH) terminated early due to interim futility analyses, potentially biasing results toward the null
- Lack of published categorical data for mean weekly frequency reduction prevented direct p-value calculation; indirect assessments were used instead
- The ≥50% responder rate endpoint may not adequately capture the full therapeutic impact in cluster headache, and endpoint selection remains contested
- Discrepancy between real-world data (suggesting greater efficacy) and RCT results raises questions about the adequacy of controlled trial methods in CH
- European regulatory authorities (EMA) did not approve galcanezumab for CH, citing insufficient efficacy compared to verapamil
- Other potentially relevant outcomes (acute abortive treatment use, PGI-I scores, attack duration and intensity) were not systematically reported across studies, precluding pooled analysis
Citation
Kolakowski L, Kleinsorge MT, Wegener S, Pohl H. Efficacy and effectiveness of anti-CGRP monoclonal antibodies treatment in the prevention of cluster headache attacks: A systematic review and meta-analysis. Cephalalgia. 2026;46(4):1-15. doi:10.1177/03331024261434209