CGRP Antibody (Anti-CGRP Monoclonal Antibody)

Key Points at a Glance

Highlights of This Disease

• CGRP antibodies are monoclonal antibodies targeting the neuropeptide CGRP, which plays a central role in the pathophysiology of migraine.
• Currently, four types (erenumab, fremanezumab, galcanezumab, and eptinezumab) are approved, and RCTs have demonstrated their efficacy in preventing episodic and chronic migraine.
• In 2024, the American Headache Society recommended them as a first-line option without requiring failure of other preventive drug classes.
• Quadrant-specific changes in the retinal nerve fiber layer (RNFL) have been reported in migraine patients compared to healthy individuals, and anti-CGRP antibody administration may improve retinal vascular perfusion.
• Adverse events are generally mild to moderate, but inflammatory complications (such as Susac syndrome) and risk of visual impairment in patients with pre-existing vascular disease have been reported.
• In migraine patients with idiopathic intracranial hypertension (IIH), papilledema may recur even after headache resolution, necessitating continued ophthalmic surveillance.

1. What are CGRP antibodies?

CGRP (calcitonin gene-related peptide) is a neuropeptide produced by neurons in the trigeminal ganglion. Its effects on intracranial blood vessels and the trigeminal system are closely linked to the pathophysiology of migraine. Anti-CGRP monoclonal antibodies (CGRP antibodies) are a class of preventive migraine medications that target CGRP itself or its receptor.

Expression of CGRP in the trigeminal ganglion was confirmed over 30 years ago³⁾. For small-molecule CGRP receptor antagonists (gepants), olcegepant (intravenous) first demonstrated efficacy for acute migraine in 2004³⁾. Monoclonal antibody preparations have been approved sequentially since 2018⁸⁾.

Migraine affects approximately 1.02 billion people worldwide and is the second leading cause of disability globally^3,8). Conventional migraine preventives (beta-blockers, antiepileptics, tricyclic antidepressants, etc.) reduce monthly migraine days by 50% or more in fewer than 45% of patients³⁾. CGRP antibodies are the first migraine-specific preventive drug class to address this treatment gap.

There are currently four approved anti-CGRP antibodies. They are classified into two groups based on their target of action.

CGRP Receptor Target

erenumab: A humanized monoclonal antibody that binds to the CGRP receptor.

Administered subcutaneously at 70 mg or 140 mg once a month.

CGRP Ligand Target

fremanezumab: A fully humanized IgG2Δa. Administered subcutaneously at 225 mg once a month or 675 mg every 3 months.

galcanezumab: Initial dose 240 mg, then 120 mg subcutaneously once monthly.

eptinezumab: 100–300 mg intravenously every 3 months.

Gepants (small-molecule CGRP receptor antagonists) include ubrogepant and rimegepant for acute treatment, and rimegepant and atogepant for preventive treatment^4,7).

In 2024, the American Headache Society (AHS) stated that the evidence for CGRP-targeted therapies is “overwhelmingly greater than any other preventive treatment approach” and recommends them as first-line for migraine prevention without requiring prior failure of other preventive drug classes⁴⁾.

Q How are CGRP antibodies different from conventional migraine preventives?

A

Conventional drugs (e.g., beta-blockers, antiepileptics) were developed for indications other than migraine, and fewer than 45% of patients achieve ≥50% symptom reduction³⁾. In contrast, CGRP antibodies are the first migraine-specific preventive drug class targeting the core pathophysiology (excess CGRP in the trigeminovascular system), and in 2024 the AHS recommends them as first-line even without prior failure of other preventives⁴⁾.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The main indication for CGRP antibodies is migraine, and the typical symptoms of migraine targeted for treatment are as follows.

• Headache attacks: Unilateral, pulsating, moderate to severe headache lasting 4–72 hours, aggravated by routine physical activity.
• Photophobia: A major accompanying symptom of migraine, which may also appear in the prodromal phase³⁾.
• Phonophobia, nausea, and vomiting: Occur in association with the headache.
• Visual aura: Scintillating scotoma (fortification spectra), flashes of light, zigzag patterns, shimmering scotoma, etc., slowly progress over 5–20 minutes and resolve within 60 minutes³⁾.
• Prodromal symptoms: Several days before headache onset, marked fatigue, mood changes, yawning, gastrointestinal symptoms, and sensitivity to light and sound may appear³⁾.
• Postdromal symptoms: After headache resolution, fatigue, difficulty concentrating, photophobia, nausea, and speech difficulty may persist³⁾.

Clinical Findings

The possibility that anti-CGRP antibodies may also affect the retina has been reported in studies using optical coherence tomography (OCT).

In a retrospective study comparing migraine patients (16 patients, 32 eyes) and healthy controls (10 subjects, 20 eyes), the following differences were observed before anti-CGRP antibody administration¹⁾.

• Nasal RNFL thinning: 79.9±12.8 μm (healthy: 90.2±14.4 μm, p=0.01)
• Temporal RNFL thickening: 74.2±10.3 μm (healthy: 68.9±4.7 μm, p=0.03)

Changes after 6 months of treatment with anti-CGRP antibodies (fremanezumab 50%, galcanezumab 25%, erenumab 25%) were as follows¹⁾.

The following shows changes in key clinical parameters from the same study.

Parameter	Baseline	6 months	p value
Monthly migraine days (MMD)	15.6±3.8	5.4±1.5	<0.0001
MIDAS	65.6±49.6	13.7±10.8	<0.0001
HIT-6	68.6±3.9	58.6±3.4	<0.0001
Monthly analgesic use days	17±7.8	4.8±1.9	<0.0001

After 6 months, the temporal superior RNFL significantly increased (p=0.02), and the peripapillary inferior hemifield and inferotemporal RPC vessel density also significantly increased (p=0.03, p=0.02)¹⁾. In repeated measures ANOVA with monthly migraine days as a covariate, only the change in temporal superior RNFL was significant (F=13.69, p=0.001)¹⁾.

Q Does migraine affect the eyes?

A

OCT studies have reported thinning of the nasal RNFL and thickening of the temporal RNFL in migraine patients, indicating retinal structural changes different from healthy individuals¹⁾. Additionally, after 6 months of anti-CGRP antibody treatment, the temporal superior RNFL and RPC vessel density significantly increased, suggesting that endogenous CGRP may be involved in retinal vascular perfusion¹⁾.

3. Causes and Risk Factors (CGRP and Migraine Pathophysiology)

The main pathophysiology of migraine is activation of the trigeminovascular system (TVS). The previously proposed vascular theory that intracranial vasodilation is the direct cause of pain is now rejected³⁾.

Neurons in the trigeminal ganglion produce CGRP, and intracranial vascular tissues express CGRP receptors (G protein-coupled). The following three pathways have been shown for CGRP to trigger migraine.

1. Vasodilation pathway: Activation of adenylyl cyclase → increase in cAMP → relaxation of cerebral vascular smooth muscle → vasodilation
2. Neurogenic inflammation pathway: Release of neurokinin A and substance P → neurogenic inflammation around the dura mater
3. Sensitization pathway: Central and peripheral sensitization via the cAMP cascade

Exogenous administration of CGRP reproduces migraine-like symptoms, and intracranial CGRP levels are confirmed to be significantly elevated during migraine attacks.

Prevention and Daily Care

To reduce the frequency of migraine attacks, it is important to identify and avoid triggers. Common triggers include lack of sleep, excessive stress, irregular meals, certain foods (such as excessive alcohol or caffeine), and sudden weather changes. Keeping a headache diary can help you identify your own triggers.

4. Diagnosis and Examination Methods

Diagnostic Criteria for Migraine

For the diagnosis of migraine without aura, at least 5 attacks are required, and each attack must meet the following criteria³⁾.

• Duration: 4 to 72 hours
• Headache characteristics: At least 2 of the following 4 items (unilateral, pulsating, moderate to severe, aggravated by routine physical activity)
• Associated symptoms: Photophobia and phonophobia, or nausea and/or vomiting

The aura of migraine with aura consists of fully reversible neurological symptoms (visual, sensory, speech/language, motor, or brainstem symptoms) that develop gradually over ≥5 minutes and each symptom lasts 5–60 minutes³⁾.

Red flags (SNOOP10)

If any of the following warning signs are present, further investigation to rule out secondary headache is necessary³⁾.

• Systemic symptoms (fever, weight loss)
• Focal neurological signs
• Sudden severe headache (thunderclap headache)
• First onset at age 50 or older
• Progressive worsening
• Painful ocular symptoms with autonomic symptoms
• After head trauma
• Immunosuppression or HIV status
• Headache after analgesic overuse or new medication

OCT/OCT-A

OCT/OCT-A is used to evaluate retinal structural and vascular changes in migraine patients. It enables quantitative assessment of quadrant-specific RNFL changes (nasal thinning and temporal thickening) and changes in vascular perfusion after treatment ¹⁾. Currently, its use is primarily research-based, but its significance as a diagnostic aid in neuro-ophthalmology is gaining attention.

5. Standard Treatment

Anti-CGRP Antibodies (Migraine Preventive Treatment)

All four anti-CGRP antibodies have demonstrated efficacy in preventing episodic and chronic migraine in RCTs ³⁾, reducing monthly migraine days by 1–2.8 days and monthly migraine hours by 22.7–30.4 hours. Meta-analyses show no significant differences in safety or efficacy among the four agents.

The administration methods for each drug are shown below.

Drug name	Dose	Dosing interval and route
erenumab	70 or 140 mg	Once monthly, subcutaneous injection
fremanezumab	225 mg or 675 mg	Once monthly or every 3 months, subcutaneous injection9)
galcanezumab	Initial 240 mg, then 120 mg	Once monthly, subcutaneous injection
eptinezumab	100–300 mg	Every 3 months, intravenous administration

Fremanezumab is a fully humanized IgG2Δa that binds to the CGRP ligand, and its efficacy was validated in the phase 3 placebo-controlled HALO CM (chronic migraine) and HALO EM (episodic migraine) trials (12 weeks) ⁹⁾. The FOCUS trial confirmed efficacy even in patients with an inadequate response to 2–4 classes of preventive medications ⁹⁾.

The half-life is long, ranging from several weeks to several months, and it does not cross the blood-brain barrier. Because it is metabolized into peptides and amino acids, the risk of drug interactions and liver toxicity is low. Safety during pregnancy has not been established.

Gepants (small molecule CGRP receptor antagonists)

• Acute treatment: ubrogepant, rimegepant⁷⁾
• Preventive treatment: rimegepant, atogepant⁴⁾

Application to migraine with IIH

The use of erenumab for migraine-like headache associated with idiopathic intracranial hypertension (IIH) has been reported.

Efficacy

Open-label trial (55 patients): Moderate to severe headache days decreased by 71%, total headache days decreased by 45% (from baseline to 12 months). Analgesic use days also significantly decreased³⁾.

Case series (7 patients): Erenumab showed marked efficacy for migraine-like headaches persisting after resolution of papilledema ⁶⁾.

Cautions

Recurrence of papilledema: In an open-label trial, papilledema recurred without headache in 7 cases ³⁾. In a case series, papilledema reappeared while headache remained controlled in cases with recurrent intracranial hypertension ⁶⁾.

Need for monitoring: Improvement in headache does not indicate resolution of papilledema. Continued ophthalmologic surveillance is essential ⁶⁾.

Cautions and side effects in treatment

• Inflammatory complications: In a case series of 8 patients, autoimmune hepatitis, Susac syndrome (including retinal artery branch occlusion), and psoriatic arthritis were reported in close temporal association with anti-CGRP antibody administration ²⁾.
• Caution for pre-existing vascular disease: A case has been reported where a Behçet’s disease patient developed permanent bilateral vision loss along with BD relapse after receiving erenumab⁵⁾. The FDA prescribing information also warns about use in patients with pre-existing vascular disease⁵⁾.
• Papilledema in IIH patients: Papilledema may recur even when headache is absent, and continued ophthalmologic surveillance is necessary, especially during weight fluctuations^3,6).
• Safety during pregnancy: Safety during pregnancy has not been established.

Q Is there a difference in efficacy among the four anti-CGRP antibodies?

A

Meta-analyses have not shown significant differences in safety or efficacy among the four agents. Erenumab targets the CGRP receptor, while the other three target the CGRP ligand, differing in mechanism of action, but no clear difference in clinical outcomes has been demonstrated to date. Route of administration (subcutaneous vs. intravenous) and dosing interval (monthly vs. every 3 months) serve as practical criteria for selection.

Q Can CGRP antibodies be used for headaches in idiopathic intracranial hypertension (IIH)?

A

In an open-label trial of 55 IIH patients, erenumab reduced moderate-to-severe headache days by 71% ³⁾. However, papilledema recurred in some cases even after headache resolution, indicating that headache improvement does not imply control of intracranial pressure. Continued ophthalmologic surveillance is essential ⁶⁾.

Q What are the side effects to watch for with CGRP antibodies?

A

Adverse events are generally mild to moderate. However, case reports of inflammatory complications (autoimmune hepatitis, Susac syndrome, psoriatic arthritis) exist ²⁾, and in patients with pre-existing vascular diseases (e.g., Behçet disease), a risk of permanent visual impairment has been reported ⁵⁾. In patients with vascular disease, the appropriateness of administration must be carefully assessed.

6. Pathophysiology and Detailed Mechanisms

CGRP is a neuropeptide produced in pseudounipolar neurons of the trigeminal ganglion, and its role was discovered over 30 years ago ³⁾. Intracranial blood vessels express CGRP receptors (G protein-coupled), establishing neurovascular signaling with trigeminal ganglion neurons.

During migraine attacks, CGRP is released from trigeminal nerve endings. The three pathophysiological pathways triggered are as follows:

1. Vasodilation: Adenylate cyclase is activated, increasing cAMP, which relaxes cerebral vascular smooth muscle, leading to vasodilation.
2. Neurogenic inflammation: Release of neurokinin A and substance P induces sterile inflammation around the dura mater.
3. Central and peripheral sensitization: Peripheral sensitization of the trigeminal nerve and central sensitization of the trigeminal nucleus occur via the cAMP cascade. This contributes to cutaneous allodynia and persistence of headache.

Anti-CGRP antibodies inhibit these three pathways by binding to the CGRP ligand or CGRP receptor. Since they do not cross the blood-brain barrier, their main effects are exerted peripherally (around trigeminal nerve endings and dural blood vessels).

CGRP also has anti-inflammatory and immunomodulatory effects, influencing the function of NK cells, dendritic cells, and bone marrow myeloid progenitor cells ²⁾. When inhibitory control over these cells is removed by CGRP inhibition, a pro-inflammatory response may be triggered ²⁾. This has been suggested as the pathological mechanism for inflammatory complications (see “Precautions and Side Effects in Treatment” section).

Regarding effects on the retina, it has been shown that activation of endogenous CGRP and its receptors may be involved in quadrant-specific RNFL changes and vascular perfusion changes in migraine patients ¹⁾. In IIH patients, it has been suggested that CGRP may function as a mechanistic driver of headache ⁶⁾.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For Patients: Please Read Carefully

The following information is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Monitoring Treatment Effects with Retinal OCT/OCT-A

A retrospective study by Cesareo et al. (2025) reported that after 6 months of anti-CGRP antibody treatment, vascular perfusion in the superficial capillary plexus and radial peripapillary capillaries (RPC) increased, and the temporal superior RNFL significantly improved (p=0.02)¹⁾.

However, this study has the following limitations: the small sample size of 16 patients (32 eyes), the lack of evaluation during headache attacks, the absence of long-term follow-up data, and the lack of analysis by antibody type. Larger-scale studies are needed to determine whether retinal OCT/OCT-A can serve as a biomarker for evaluating the therapeutic effect of anti-CGRP antibodies and for migraine management ¹⁾.

Non-invasive biomarker using tear CGRP

It has been reported that tear CGRP levels are elevated in migraine patients and decrease after anti-CGRP antibody administration. This non-invasive method of tear collection is attracting attention for biochemical monitoring of migraine, but further research is needed for diagnostic and therapeutic applications.

Application of anti-CGRP antibodies in IIH

Yiangou et al. (2020) reported that administration of erenumab to 7 IIH patients whose papilledema had resolved but who still had migraine-like headaches resulted in marked headache improvement in all cases ⁶⁾. Even in cases where intracranial pressure rose again and papilledema recurred, headache control was maintained.

This finding suggests that CGRP may be a mechanistic driver of IIH-related headaches, but it should be noted that headache control does not replace monitoring of intracranial pressure. Ophthalmic surveillance should be continued, especially during weight fluctuations ⁶⁾.

Elucidation of the Pathophysiology of Inflammatory Complications

Ray et al. (2021) reported 8 cases of autoimmune hepatitis, Susac syndrome, and psoriatic arthritis that occurred in close temporal association with anti-CGRP antibody administration ²⁾.

Based on the immunomodulatory effects of CGRP, it has been hypothesized that CGRP inhibition may unmask pre-existing autoimmune predisposition. Immunological studies are needed to identify which patient groups are at high risk ²⁾.

Safety in Patients with Vascular Disease

Khan et al. (2025) reported a case of a patient with well-controlled Behçet’s disease who developed painless bilateral vision loss 11 days after the second injection of erenumab, resulting in permanent visual impairment despite steroid treatment ⁵⁾.

It has been hypothesized that CGRP may function as a physiological compensatory mechanism for vasoconstriction, and that CGRP receptor inhibition may impair compensatory vasodilation to ischemia caused by BD-related small vessel vasculitis ⁵⁾. Research is needed to clarify the scope of contraindications and precautions in patients with vasculitis and ischemic vascular disease.

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8. References

1. Cesareo M, Martucci A, Bovenzi R, et al. Evaluating the impact of anti-CGRP monoclonal antibodies on retinal features in migraine patients: a retrospective optical coherence tomography study. Ther Adv Neurol Disord. 2025;18:17562864251347277.
2. Ray JC, Allen P, Bacsi A, et al. Inflammatory complications of CGRP monoclonal antibodies: a case series. J Headache Pain. 2021;22(1):121.
3. Mollan SP, Virdee JS, Bilton EJ, et al. Headache for ophthalmologists: current advances in headache understanding and management. Eye (Lond). 2021;35(5):1350-1368.
4. Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine. Headache. 2024;64(4):333-341.
5. Khan FA, Malik A, Nelson E, et al. Permanent visual impairment following a Behçet’s disease flare while on calcitonin gene-related peptide receptor antagonist therapy: a case report. BMC Ophthalmol. 2025;25(1):518.
6. Yiangou A, Mitchell JL, Vijay V, et al. Calcitonin gene related peptide monoclonal antibody treats headache in patients with active idiopathic intracranial hypertension. J Headache Pain. 2020;21(1):116.
7. Digre KB. What’s New in the Treatment of Migraine? J Neuroophthalmol. 2019;39(3):352-359.
8. Frerichs LM, Friedman DI. Galcanezumab for the prevention of migraine. Pain Manag. 2021;11(2):101-112.
9. Friedman DI, Cohen JM. Fremanezumab: a disease-specific option for the preventive treatment of migraine. Emerg Top Life Sci. 2020;4(2):179-190.