3.6 CGRP Monoclonal Antibodies

This is the most consequential and most confusing section, and it is where the trial-vs-community gap is widest. (Editor’s note: the registry-level trial-by-trial view, including erenumab/CHERUB01, is tabulated in Part VII, §5.1.1; the contested CGRP biology is in Part II, §3.4.)

3.6.1 CGAL: galcanezumab in episodic CH — the one positive trial

Goadsby PJ, Dodick DW, Leone M, et al. Trial of Galcanezumab in Prevention of Episodic Cluster Headache. N Engl J Med 2019;381(2):132–141, DOI 10.1056/NEJMoa1813440, NCT02397473. peer-reviewed

Item	Detail
n	106 randomised (49 galcanezumab, 57 placebo)
Dose	300 mg SC at month 0 and month 1 (note: 300 mg, not the 120 mg migraine dose)
Primary endpoint	Mean change in weekly attack frequency, weeks 1–3
Result	−8.7 ± 1.4 vs −5.2 ± 1.3; difference 3.5 (95% CI 0.2–6.7), p=0.04
Mean % reduction	52% vs 27%
Week-3 ≥50% responders	71% vs 53%, p=0.046, OR 2.4 (95% CI 1.0–5.7)
Adverse events	43% vs 33%; no serious AEs; injection-site pain 8%
Recruitment	Halted early due to enrolment difficulty

Read the confidence intervals. The primary difference CI is 0.2 to 6.7 — the lower bound almost touches zero. The responder OR CI is 1.0 to 5.7 — the lower bound is 1.0. This is a trial that scraped over the significance line, in a population smaller than planned, in episodic CH only.

Critically: the effect converged with placebo after week 4 — by week 5 the odds ratio was 0.3 (i.e. numerically favouring placebo). The drug’s apparent benefit is concentrated in the first three weeks, in a condition where episodic bouts spontaneously remit. This is the single most important caveat about CGAL and it is rarely mentioned.

Regulatory divergence — a genuine conflict. The FDA approved galcanezumab (Emgality) 300 mg for episodic CH in the US on the basis of this trial. The EMA rejected it, stating superiority “not convincingly demonstrated.” preprint / trial Two competent regulators looked at the same single trial and reached opposite conclusions. That should tell you how marginal the result is.

Note also that PMC8748342’s summary table lists galcanezumab for episodic CH as “120 mg s.c. once monthly” with evidence level +. This appears to be an error — CGAL used 300 mg, and 120 mg is the migraine dose. A patient or prescriber relying on that table would underdose by 60%. Flagged as a documented discrepancy in a peer-reviewed review.

3.6.2 The chronic CH galcanezumab trial — the failure

Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia 2020;40(9):935–948, DOI 10.1177/0333102420905321, PMID 32050782, NCT02438826. peer-reviewed

• n=237 (117 galcanezumab 300 mg monthly, 120 placebo)
• Weekly attack frequency change: −5.4 vs −4.6, p=0.334
• Primary AND key secondary endpoints not met

Larger trial, longer treatment, same drug, same dose — and it failed outright in chronic CH.

An important factual correction that circulates wrongly: the chronic trial was completed, not stopped for futility. This was explicitly corrected in the literature by Wenzel R, et al., Neurol Sci 2020;41:2641, PMID 32266593, PMC7419360. peer-reviewed If you see “the chronic trial was stopped for futility,” that is wrong.

Why did it fail in chronic CH? Competing hypotheses

None of these are established. All are labelled as hypotheses.

1. CGRP may not be the driver in chronic CH. A prospective controlled study (n=297, Cephalalgia 2024) found plasma CGRP is LOWER in CH patients than in controls — the opposite of the assumption underpinning the whole drug class. peer-reviewed This directly undercuts the mechanistic rationale. Note this conflicts with older data showing elevated CGRP in the external jugular vein during attacks and elevated interictal CGRP during bouts in episodic CH (PMC4646474). peer-reviewed Possible reconciliation: CGRP elevation may be attack-associated and episodic-bout-associated rather than a chronic-state feature. Contested.
2. PACAP (pituitary adenylate cyclase-activating polypeptide) may be the more relevant target in CH than CGRP. preprint / trial — hypothesis stage.
3. Regression to the mean in episodic CH. The episodic trial’s effect was concentrated in weeks 1–3 and vanished by week 5. Bouts end on their own. Chronic CH has no bout to end, so no spontaneous-remission tailwind for the drug to ride. Under this reading, CGAL’s positive result may be substantially an artefact of episodic natural history — and the chronic failure is the more honest measurement of the drug. This is a hypothesis, but it fits the data uncomfortably well.
4. Dose/exposure: the same 300 mg dose that worked marginally in episodic may be insufficient for a continuously active pathophysiology. Unresolved.

3.6.3 Fremanezumab — both trials terminated

Fremanezumab was trialled in both episodic and chronic CH. Both trials were terminated early for futility. The chronic trial was NCT02964338 (EU CTR 2016-003278-42). There is no journal publication of the results. preprint / trial

This is a meaningful and under-discussed fact: a full anti-CGRP ligand antibody programme in CH was abandoned, and the data were never published in the peer-reviewed literature. Publication bias in this field runs in the direction you would expect.

3.6.4 Eptinezumab: ALLEVIATE and CHRONICLE

ALLEVIATE — failed

Jensen RH, Tassorelli C, Tepper SJ, et al. Eptinezumab for the Preventive Treatment of Episodic Cluster Headache: The ALLEVIATE Randomized Clinical Trial. JAMA Neurol 2025;82(7):706–714, DOI 10.1001/jamaneurol.2025.1317, NCT04688775. peer-reviewed

• n=231, eptinezumab 400 mg IV
• Primary endpoint, change in weekly attacks weeks 1–2: −4.0 vs −4.6; difference 0.7 (95% CI −1.3 to 2.6), p=.50
• FAILED. Stopped for futility at interim analysis.

Note the direction: the placebo group did numerically better than the drug group.

A documented discrepancy worth knowing about

In 2024, Lundbeck issued a press release stating that “VYEPTI met its primary endpoint” in cluster headache (Lundbeck newsroom, 2024). preprint / trial The peer-reviewed publication a year later reports a failed primary endpoint (p=.50) and a trial stopped for futility. I have not been able to reconcile these two statements from the material gathered — the press release may refer to a different analysis, a different endpoint definition, or a different study population. This is flagged as a documented discrepancy between a company communication and the subsequent peer-reviewed publication, not as an established finding of misrepresentation. Contested / unresolved. It is, however, an excellent reason to treat pharmaceutical press releases about CH as advertising until the paper appears.

CHRONICLE — open-label, no control

Tassorelli C, Jensen RH, Goadsby PJ, et al. Lancet Neurol 2025;24(5):429–440, DOI 10.1016/S1474-4422(25)00065-1, PMID 40252664, NCT05064397. peer-reviewed Open-label, n=131, 400 mg IV every 12 weeks over 60 weeks. TEAEs 81%; 4 withdrawals; no treatment-related serious adverse events; “consistent improvements” in attack frequency — but there is no placebo control, so the efficacy statement carries essentially no weight. The study is a safety/tolerability result, and on that narrow question it is reassuring.

A German-language summary of CHRONICLE is available at Thieme. peer-reviewed (German-language source.)

3.6.5 The 2026 meta-analyses: do they genuinely conflict?

Two meta-analyses published within months of each other in 2026 appear to reach opposite conclusions. They do partially conflict — but the conflict is smaller and more interesting than it looks.

Meta-analysis A — network meta-analysis, negative

Muneer et al. Neurol Sci 2026;47(6):488, DOI 10.1007/s10072-026-09078-1, PMID 42118310. peer-reviewed 5 RCTs, ~1000 patients. Outcome: weekly attack frequency. Result: no agent statistically significant. Galcanezumab −0.81, fremanezumab pooled −0.27, eptinezumab −0.17 weekly attacks; fremanezumab 675/225 mg +0.71 (numerically worse than placebo).

Meta-analysis B — systematic review and meta-analysis, positive in episodic only

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):3331024261434209, DOI 10.1177/03331024261434209, PMID 41961550. PROSPERO CRD420250609351. peer-reviewed (Swiss group — Zurich.)

Searched Embase, Medline, Cochrane CENTRAL, Web of Science; 734 records → 25 articles, 1,587 patients; RoB 2 and ROBINS-I; random-effects, odds ratios. Primary emphasis: ≥50% responder rate closest to 4 weeks (chosen because it was reported in almost all studies).

Population	Effect	95% CI	p
Episodic CH	OR 1.65	1.07–2.55	0.02 — significant
Chronic CH	OR 1.07	0.78–1.48	0.68 — not significant

Galcanezumab 300 mg and eptinezumab 400 mg were both identified as more effective than placebo on the ≥50% responder endpoint in episodic CH. For weekly attack frequency at week 4, a significant mean reduction was seen only for galcanezumab 300 mg (p=0.04) — effect size and CI not stated in the abstract.

Adjudication

They agree completely on chronic CH: no effect. OR 1.07 (0.78–1.48), p=0.68 in one; no significant agent in the other. For a chronic daily patient, both 2026 meta-analyses say the same thing, and it is not encouraging.

They disagree on episodic CH — but on different endpoints. Meta-analysis A used weekly attack frequency (a continuous measure) and found nothing. Meta-analysis B used ≥50% responder rate at 4 weeks (a dichotomised measure) and found OR 1.65. Meta-analysis B also found weekly attack frequency significant for galcanezumab specifically (p=0.04), which is closer to A’s endpoint and closer to A’s galcanezumab point estimate of −0.81.

So the conflict is partly a genuine disagreement about galcanezumab in episodic CH, and partly an endpoint-selection artefact. Responder-rate analyses are more sensitive to a small subgroup of strong responders; continuous mean-difference analyses are diluted by non-responders. Both are defensible; they answer slightly different questions. B also included non-randomised evidence (case series, case reports) alongside RCTs, which A did not — a further source of divergence, and a reason to weight A more heavily for a strictly causal question.

My reading, stated as a judgement rather than a finding: anti-CGRP mAbs probably produce a real but modest benefit in a minority of episodic CH patients, concentrated early, and probably produce nothing detectable in chronic CH. Both meta-analyses are consistent with that. Neither meta-analysis reports NNT. Meta-analysis B reports no adverse-event data, no GRADE assessment and no certainty-of-evidence rating at abstract level.

3.6.6 The real-world data — where the community and the trials diverge hardest

Lamas Pérez R, Millán-Vázquez M, González-Oria C, et al. Cephalalgia 2024;44(3):3331024231226181, DOI 10.1177/03331024231226181, PMID 38501892. Seville, Spain. peer-reviewed (Spanish research team; published in English.)

n=21 refractory chronic CH — exactly the population the RCT said galcanezumab doesn’t help — treated off-label at 240 mg:

• Median monthly attacks 60 → 31 at 1 month, p=0.003
• ≥50% reduction: 47.6% at 1 month, 46.6% at 3 months
• ≥75% reduction: 19% at 1 month, 26.6% at 3 months
• Adverse events 52%, mostly mild

A ~47% responder rate in refractory chronic CH, from the drug that failed its chronic RCT. This is the crux of the trial-vs-real-world gap. Both cannot be straightforwardly true. Candidate explanations: (a) open-label expectation effects in an uncontrolled study — the most likely single explanation; (b) regression to the mean, since patients start the drug when they are at their worst; (c) a genuine responder subgroup that a 3-month parallel-group RCT diluted; (d) the different dose (240 mg vs 300 mg) — unlikely to explain a benefit at a lower dose. Note that the 2026 Kolakowski meta-analysis explicitly acknowledges that “some non-randomised trials reported findings suggesting an effect in chronic cluster headache” while its own pooled randomised estimate was null (PMID 41961550). peer-reviewed The field is aware of this tension and has not resolved it. Contested.

3.6.7 What the community says about Emgality — in detail

From three r/clusterheads threads. community report throughout.

Doses used are far above label

Reported: “3 × 100 mg monthly”, “three injections each month”, “three Emgality shots per month”, “300 mg each month, all at once”, “three injections at the start of a cluster” (Emgality for chronic CH thread; How long for Emgality to kick in). One patient noted the regular migraine dose “worked but wore off after two weeks” and moved to 300 mg dosing. Several described the effect “wearing off towards the end of the month.”

This end-of-month wearing-off pattern is reported repeatedly and has no counterpart in the trial literature, which used monthly dosing and did not report within-cycle fluctuation. If real, it argues for more frequent dosing or higher trough levels — an entirely untested hypothesis generated by patients. Worth noting as a legitimate research question that came from the community, not the clinic.

Time to effect — much longer than trials suggest

Trials measured the primary endpoint at weeks 1–3. Patients report:

“Truthfully I’d say it was in month three or so that I noticed a change in the intensity and a small change in frequency.” (r/clusterheads)

Others: “the pain was gone after a week”; “a difference within a few days”; one commenter asserted it “may take up to five months for chronic sufferers to achieve full benefit” (no source cited). One reported headaches WORSENING for a couple of weeks after starting before benefit arrived (r/clusterheads).

Divergence: CGAL’s whole positive result lives in weeks 1–3. Much of the community reports benefit arriving at months 3–5. If the community is right, CGAL measured the wrong window. If the trials are right, the late “responses” are regression to the mean or bout cycling. Unresolved, but the disagreement is stark.

Effectiveness in chronic CH — bimodal and often time-limited

Reported outcomes from one thread of ~12 participants (r/clusterheads):

Reported outcome	Count
No benefit at 6 months	1
No benefit at 7 months	1
Worked ~6 months then stopped completely	1
Worked 6–12 months then stopped	1
Worked 12 months (then refills discontinued)	1
Worked 2 years then stopped after daylight saving began	1
Ongoing benefit	2

“I was chronic, and Emgality has helped me return to a normal lifestyle.” — headaches went from multiple daily at 8–10/10 to 4–5/10

“It worked well for roughly six months, achieving over 90% effectiveness.” — and this from someone who said it was “the only preventive that provided more than 10–20% efficacy during nearly seven years of chronic illness,” before ceasing to work entirely

“I tried the 6-month course, but it caused hair loss and didn’t help my chronic headaches.”

“starting was tough—my headaches actually worsened for a couple of weeks—but since then I haven’t had any cluster attacks, except when I miss an injection.”

Two patterns here have no trial correlate whatsoever and deserve flagging as unexplained:

1. Tachyphylaxis. Multiple independent reports of excellent response for 6–24 months followed by complete and permanent loss of effect. The trials ran 3 months (chronic) and 8 weeks (episodic) — structurally incapable of detecting this. The Seville real-world study ran 3 months. Nobody has looked. Unknown, and important.
2. One patient reported Emgality stopped working “after daylight saving time began” (r/clusterheads). community report — n=1, almost certainly coincidence. Recorded only because CH has a documented seasonal/circadian structure (§4.1: peaks in March/April and September/October/November, i.e. around the equinoxes and around DST transitions in both hemispheres), which makes it the one coincidence in this chapter with a non-absurd mechanism. Unverified, almost certainly noise, but noted.

Side effects patients report that trials don’t emphasise

• Hair loss — reported independently in three separate threads by at least four different people (1, 2, 3). “I started noticing more hair in my comb each morning.” One described “severe hair loss” that vitamins did not help. CGAL reported no serious AEs and 8% injection-site pain; alopecia is not a labelled galcanezumab adverse effect. This is one of the clearest examples in the chapter of a community signal absent from trial data. Whether it is causal is unknown — but four independent reports across three threads is above the noise floor for an anecdotal source, and post-marketing alopecia reports for CGRP mAbs do exist in the wider migraine community.
• Weight gain — reported by at least two people, one estimating 5–10 lb over two years and considering it a fair trade.
• Frequent urination in the first two weeks after injection, described as “pretty ridiculous.”
• Sluggishness in the first few days post-injection.
• Injection-site appearance “like a punched stomach.”

The trial-reported profile (injection-site pain, no serious AEs) and the community-reported profile (hair loss, weight gain, urinary frequency) barely overlap. Trials of 8 weeks to 3 months in ~340 patients total are not powered to detect uncommon or slow-onset effects.

Access is a major, under-documented barrier

UK/NHS (r/clusterheads NHS thread):

“If you want it through the NHS, your neurologist must apply for external funding.”

The neurologist must demonstrate “all other options have been exhausted”; the patient must have tried “nearly every other NHS drug”; and one refractory chronic patient was “only permitted a three-month trial.” No commenter in that thread confirmed successfully obtaining it long-term.

US: “exhausted from battling insurance”; one patient’s refills were discontinued after 12 months despite the drug working, with no reason given — they switched to Qulipta (atogepant), reporting daily clusters fell from four to one or two (r/clusterheads). community report (Atogepant in CH is off-label with no trial evidence; this is a single anecdote.)

Australia: galcanezumab (Emgality) is TGA-approved and PBS-listed, but only for chronic migraine and high-frequency episodic migraine — not for cluster headache (PBS galcanezumab listing; Australian Government Department of Health announcement on expanded Emgality PBS listing). preprint / trial (government/regulatory documents) Migraine Australia describes it as “on PBS for a very limited criteria of people, available through a discount program for others,” and is actively campaigning for expanded criteria (Migraine Australia). community report (patient advocacy organisation) Headache Australia notes the PBAC recommended galcanezumab for chronic migraine in July 2019 after failure of at least three preventives (Headache Australia). community report

Practical implication for an Australian chronic CH patient: there is no PBS pathway for Emgality in cluster headache. Private cost is substantial (the PBS DPMQ for a single 120 mg pen is listed at $523.36 — and the CH dose is 300 mg, i.e. multiple pens). Realistic routes are a compassionate/discount access programme, private purchase, or a specialist arguing the case individually. Given that both 2026 meta-analyses found no significant effect in chronic CH, spending that money on a chronic-CH indication is a decision to make with clear eyes about the evidence.

3.6.8 Summary judgement on CGRP mAbs

Question	Answer	Confidence
Works in episodic CH?	Marginally, early, in a subset	Low-moderate; one trial scraped p=0.04, EMA rejected it, meta-analyses split by endpoint
Works in chronic CH?	No detectable effect in randomised data	Moderate-high; one adequately sized negative RCT plus two concordant 2026 meta-analyses
Real-world chronic response ~47%?	Reported, uncontrolled, plausibly inflated	Low
Tachyphylaxis after 6–24 months?	Repeatedly reported by patients, never studied	Unknown
Hair loss?	Repeatedly reported by patients, not a labelled AE	Unknown
Safe?	Yes, on available data — no treatment-related SAEs across CGAL, chronic trial and CHRONICLE	Moderate-high

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4. Neuromodulation & Procedures

This category covers non-invasive and implanted devices, and surgical procedures, generally reserved for people who have failed multiple preventive drug trials — refractory chronic CH. Response rates here are inflated relative to the general CH population by design, because trial cohorts are pre-selected for having already failed everything else; that caveat applies to every efficacy figure in this section.