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Anti-CGRP therapies for migraine
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Anti-CGRPs in migraine

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Last updated:22nd Oct 2023
Published:4th May 2023
Anti-CGRP therapies for migraine Learning Zone
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What are three key things patients would like doctors to do differently when managing migraine? In the video below, two patients living with migraine contribute their valuable insights to this important question.

The trigeminovascular hypothesis of migraine pathophysiology

Accumulating evidence points to the trigeminovascular system as the biological substrate from which nociceptive transmission originates and produces migraine pain1,2.

The original trigeminovascular hypothesis proposed that migraine relies on1:

  • Activation and sensitisation of first-order trigeminovascular neurons (Figure 1, Step 1)
  • Innervation of the meninges and its vessels (Figure 1, Step 1)
  • Release of vasoactive peptides, including calcitonin gene-related peptides (CGRP), and local inflammation

These core processes sensitise and activate second-order neurons in the brain stem, then third-order neurons in the thalamus (Figure 1, Step 3)2,3.

Finally, nociceptive signals reach multiple cortical areas, which control conscious perception of migraine pain and associated symptoms (Figure 1, Step 4)2,3.

Production of migraine pain through the trigeminovascular pathway

Figure 1. Production of migraine pain through the trigeminovascular pathway (Adapted3). Used with permission under the Creative Commons CC-BY-NC-ND license. Au, auditory; Ect, ectorhinal; Ins = insula; M1/M, motor cortices; PAG, periaqueductal gray; PB, parabrachial nucleus; PtA, parietal association; RS, retrosplenial; S1/S2, somatosensory cortices; SSN, superior salivatory nucleus; TCC, trigeminal cervical complex; T, trigeminal ganglion; VC, visual cortices; V1, ophthalmic branch of trigeminal nerve; V2, maxillary branch of trigeminal nerve; V3, mandibular branch of trigeminal nerve.

The biological mechanisms that produce migraine pain are not fully known: some evidence suggests a peripheral origin at the level of perivascular trigeminal afferents2; other evidence suggests central dysfunction of neurons in the brain stem and diencephalon2

A clinical model of migraine

Signalling molecules recruited in the production of migraine pain, which are vasodilators and widely distributed in the trigeminovascular system, include4:

  • CGRP
  • Pituitary adenylate cyclase-activating peptide-38 (PACAP)
  • Nitric oxide

Experimental studies using this clinical model over three decades of research show that migraine pain can develop in patients with migraine when they are exposed to these molecules, compared to healthy persons who report moderate or no headache4. For example, in two experimental studies, intravenous injection of CGRP caused migraine in patients diagnosed with the disease, but not in healthy people5,6.

Calcitonin gene-related peptide in migraine pathophysiology

CGRP is a peptide neurotransmitter, and one of the most potent vasodilators of intracranial blood vessels2. CGRP is a blood-brain barrier impermeant neuropeptide with a serum half-life of 7–10 minutes7. It diffuses widely from its release site8. There is no reuptake system8.

The CGRP receptor complex is located in the trigeminal ganglion in all investigated species (Figure 2)9.

CGRP and CGRP receptors in the trigeminovascular system

Figure 2. CGRP and CGRP receptors in the trigeminovascular system (Adapted10). CGRP, calcitonin gene-related peptide.Blue dots, CGRP; yellow dots, CGRP receptor.

CGRP expression in trigeminal ganglion

The activation of CGRP and CGRP receptors in the trigeminal ganglion is compatible with CGRP release from C-type sensory neurons, and CGRP actions on Aδ-type sensory neuron receptors and satellite glial cells, which modify pain transmission and sensitivity within the ganglion (Figure 3)11. This expression pattern of CGRP could contribute to migraine pathophysiology and are targets of anti-CGRP treatments10.

Relationship between cells and fibres within the trigeminal ganglion that express CGRP or the CGRP receptor

Figure 3. Relationship between cells and fibres within the trigeminal ganglion that express CGRP or the CGRP receptor (Adapted10). CGRP, calcitonin gene-related peptide. Blue dots, CGRP.

CGRP expression in trigeminal nerves

The intimate relationship between C- and Aδ-fibres within the trigeminal nerves indicates that CGRP signalling occurs between these fibre types, which are known to contribute to pain production, and the CGRP receptors in Schwann cells suggests neuron-glia interaction (Figure 3)12.

CGRP expression in trigeminal peripheral targets

The cerebrovascular trigeminal nerves are important for sustaining blood flow to the brain. CGRP increases cerebral blood flow by dilating cerebral arterioles. This is important for protecting brain circulation by counteracting cerebral artery constriction13.

CGRP expression in trigeminal central targets

CGRP is generously supplied in the central terminals of primary trigeminal afferents. CGRP-positive axons terminate in the spinal trigeminal nucleus in the brainstem and, in the spinal cord, in C1 and C2, including in laminae I and II (dorsal horn)14,15. At these sites, trigeminal input is communicated to second-order neurons of the pain pathway that project through the brainstem and midbrain to cortical regions involved in pain production16,17.

Since the trigeminal ganglion is critical to the trigeminovascular pain pathway, blocking CGRP transmission within the trigeminal ganglion seems sufficient to abort or prevent migraine, and its associated symptoms10

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CGRP mechanism of action and pharmacodynamics

“Now, we luckily have a selective treatment that blocks CGRP as a ligand, or that blocks the CGRP receptor. By stopping the pathway, we stop the CGRP-mediated migraine headache.” Learn more about CGRP inhibitors for migraine from Professor Zaza Katsarava (Department of Neurology, Evangelical Hospital, Germany) in the video below.

Knowledge of the pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology, discussed in the previous section, led to the development of two treatment classes that inhibit the function of CGRP in migraine: monoclonal antibodies (mAbs) and small-molecule antagonists (gepants)18-30.

There are four approved CGRP-targeted mAbs18-25, eptinezumab, erenumab, fremanezumab, galcanezumab, and four gepants26-30, ubrogepant, rimegepant, atogepant, and zavegepant.

  • Erenumab, a human monoclonal antibody, is 5,000-fold more selective for the human CGRP receptor than other related receptors in the calcitonin receptor family31
  • Although the gepants are chemically unrelated to one another, they share a common mechanism of action26-30

Summaries of the mechanism of action and pharmacodynamics of CGRP-targeted mAbs (Table 1) and gepants (Table 2) are shown below18-30.

Table 1. Calcitonin gene-related peptide monoclonal antibodies mechanism of action and pharmacodynamics18-25. CGRP, calcitonin gene-related peptide; IV, intravenous; SC, subcutaneous.

Name Mechanism of action​ Pharmacodynamics​
Eptinezumab (IV)​ Binds to CGRP ligand and blocks its binding to the receptor​ Unknown
Erenumab (SC)​ Binds to the CGRP receptor and antagonises CGRP receptor function​ Administration of erenumab (140 mg IV, single-dose) with sumatriptan (12 mg SC, given as two 6 mg doses separated by one hour) had no effect on resting blood pressure compared with sumatriptan alone​
Fremanezumab (SC)​ Binds to CGRP ligand and blocks its binding to the receptor​ Unknown
Galcanezumab (SC)​

Table 2. Calcitonin gene-related peptide small molecule antagonists (gepants) mechanism of action and pharmacodynamics26-30. CGRP, calcitonin gene-related peptide; IN, intranasal; PO, oral delivery.

Name Mechanism of action Pharmacodynamics
Ubrogepant (PO) CGRP receptor antagonist At a dose 5 times the maximum recommended daily dose, ubrogepant does not prolong the QT interval to any clinically relevant extent
Rimegepant (PO) Unknown
Atogepant (PO) At a dose 5 times the maximum recommended daily dose, atogepant does not prolong the QT interval to any clinically relevant extent
Zavegepant (IN) Unknown

A closer look at the anti-CGRP mechanism of action

Monoclonal antibodies that target CGRP (eptinezumab, fremanezumab, galcanezumab) bind and deactivate CGRP released by trigeminal sensory nerve fibres32. Antibodies (erenumab) or gepants (ubrogepant, rimegepant, atogepant, zavegepant) that target the CGRP receptor act by preventing access of CGRP to its canonoical receptor33.

Figure 4 shows targets for CGRP-related migraine treatments in a CGRP-containing trigeminal nerve that innervates a smooth muscle cell10.

Targets for CGRP-related migraine treatments in a CGRP-containing trigeminal nerve varicosity innervating a cerebrovascular smooth muscle cell

Figure 4. Targets for CGRP-related migraine treatments in a CGRP-containing trigeminal nerve varicosity innervating a cerebrovascular smooth muscle cell (Adapted10). CGRP, calcitonin gene-related peptide; 5-HT, 5-hydroxytryptamine receptor. Blue dots, CGRP.

Inhibition of CGRP-mediated dilation of cerebral arteries?

A hypothesised mechanism of anti-CGRP treatments is inhibition of CGRP-mediated dilation of cerebral arteries, located on the pial surface of the brain. However, the endothelium in these vessels limits molecules passing from the vessel lumen to the abluminal (outer) layers of the vascular wall that contain the smooth muscle and CGRP nerve endings. Does access to the vessel wall determine the effect of CGRP?

The hypothesis was experimentally evaluated in rat cerebral arteries34,35. These studies found that CGRP relaxed the artery only when applied to the abluminal surface of the vessel (Figure 5, top)34,35.  Therefore, circulating CGRP receptor antagonists and antibodies against CGRP and the CGRP receptor cannot cross the endothelial barrier to access targets in the cerebrovasculature. Although CGRP is a powerful vasodilator when administered to the abluminal side of arteries, it seems to have no effect when restricted to the lumen (Figure 5, bottom)34,35.

Access to the vessel wall of cerebral arteries contributes to the effect of CGRP

Figure 5. Access to the vessel wall of cerebral arteries contributes to the effect of CGRP (Adapted10). CGRP, calcitonin gene-related peptide.

Questions remain about how CGRP transmission in the trigeminal ganglion causes migraine, but the approval of effective treatments that act on this target is a milestone for patients

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Play this video to learn the pharmaceutical treatments that two migraine patients have used to improve or prevent migraine, or its associated symptoms. Have these patients benefited from anti-CGRP therapies for migraine? Watch the video for more.

Professor Zaza Katsarava (Department of Neurology, Evangelical Hospital, Germany), observes, “As a headache scientist, as a clinician, treating migraine patients for many years, I can clearly state that the anti-CGRP antibodies are a gamechanger because they are very effective and well tolerated.” In this interview, Professor Katsarava recalls patient observations about the effectiveness of the anti-CGRP antibodies for migraine.

Anti-CGRP monoclonal antibodies and small-molecule antagonists for migraine

There are four CGRP-targeted monoclonal antibodies (mAb) (Table 3) that are US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved for migraine18-25. Four small-molecule CGRP-antagonists, called gepants, are also FDA indicated for migraine26-28,30 (Table 4). Rimegepant is the only EMA approved gepant for migraine29.

  • Anti-CGRPs are comparably effective, well-tolerated for the prevention of both episodic and chronic migraine36, and benefit patient quality of life37
  • Real-world data are needed to evaluate tolerability and long-term safety, due to limited published 6-month follow-up data38
  • Clinical use of mAbs for migraine is currently limited by high costs and regulatory restrictions that require failure of at least two other preventive medications39

Table 3. Calcitonin gene-related peptide (CGRP) monoclonal antibodies approved for migraine18-25. IV, intravenous; QLT, quarterly; QM, monthly; SC, subcutaneous. *Start with 240 mg loading.

Name Target Dose Frequency
Eptinezumab (IV) α-, β-CGRP ligand​ 100 mg
300 mg		 QLT
QLT
Erenumab (SC) CGRP receptor​ 70 mg
140 mg		 QM
QM
Fremanezumab (SC) α-, β-CGRP ligand 225 mg
675 mg		 QM
QLT
Galcanezumab (SC) α-, β-CGRP ligand 120 mg* QM

Table 4. Calcitonin gene-related peptide (CGRP) small molecule antagonists (gepants) approved for migraine26-30. IN, intranasal; PO, oral delivery; PRN, as needed; QD, daily; QoD, every other day. *As an abortive agent; †As a preventive agent.

Name Target Dose Frequency
Ubrogepant (PO) CGRP receptor 50 mg
100 mg		 PRN*
Rimegepant (PO) CGRP receptor 75 mg PRN*
QoD†
Atogepant (PO) CGRP receptor 10 mg
30 mg
60 mg		 QD†
Zavegepant (IN) CGRP receptor 10 mg PRN

Efficacy data for anti-CGRP monoclonal antibodies for migraine

Eptinezumab

Eptinezumab is the first and only CGRP-mAb to be available in an intravenous (IV) formulation21,22. The most common adverse effects for this drug are nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, and bronchitis21,22. Table 5 shows selected phase 3 clinical trial efficacy data for migraine40-42.

Table 5. Selected eptinezumab randomised controlled phase 3 trial efficacy data40-42. All eptinezumab treatments were given intravenously. CM, chronic migraine; EM, episodic migraine; MBS, most bothersome symptom; MMD, mean monthly migraine day. *P-values are results compared against placebo.

Name Inclusion criteria Study period Primary endpoint*
PROMISE-1 EM 3 months
n = 888		 MMD reduction:
Placebo: −3.2
30 mg: −4.0 (P=0.0046)
100 mg: −3.9 (P=0.0182)
300 mg: −4.3 (P=0.0001)
PROMISE-2 CM 12 weeks
n = 1,072		 MMD reduction:
Placebo: −5.6
100 mg: −7.7 (P<0.0001)
300 mg: −8.2 (P<0.0001)
RELIEF CM Acute treatment
n = 480		 Time to headache pain freedom:
Placebo: 9 h
100 mg: 4 h (P<0.001)
Time to absence of MBS:
Placebo: 3 h
100 mg: 2 h (P<0.001)

Erenumab

Erenumab was the first CGRP targeted mAb to receive FDA approval18. The most common adverse effects for this drug are injection site reaction, nasopharyngitis, upper respiratory tract infection, fatigue, and constipation18,23. Table 6 shows selected phase 3 clinical trial efficacy data for migraine31,43-45.

Table 6. Selected erenumab randomised controlled phase 3 trial efficacy data31,43-45. CM, chronic migraine; EM, episodic migraine; MMD mean monthly migraine day. *P-values are results compared against placebo.

Name Inclusion criteria Study period Primary endpoint*
STRIVE EM and ≤2 prior classes of failed preventive treatments 4−6 months
n = 955		 MMD reduction:
Placebo: −1.8
70 mg: −3.2 (P<0.001)
140 mg: −3.7 (P<0.001)
ARISE EM and ≤2 prior classes of failed preventive treatments 3 months
n = 577		 MMD reduction:
Placebo: −1.8
70 mg: −2.9 (P<0.001)
LIBERTY EM and 2−4 prior classes of failed preventive treatments 3 months
n = 246		 50% or greater reduction rate of MMD:
Placebo: 14%
140 mg: 30% (P=0.002)
EMPOwER EM and ≤2 prior classes of failed preventive treatments 3 months
n = 900		 MMD reduction:
Placebo: −3.1
70 mg: −4.2 (P=0.002)
140 mg: −4.8 (P<0.001)

Fremanezumab

Fremanezumab is a IgG2, humanised CGRP mAb20,24. The most common adverse effect for this drug are injection site reaction20,24. Table 7 shows selected phase 3 clinical trial efficacy data for migraine46-48.

Table 7. Selected fremanezumab randomised controlled phase 3 trial efficacy data46,47. All fremanezumab treatments were given intravenously. Fremanezumab 225 mg dosages were given monthly, 675 mg dosages were given every 3 months. CM, chronic migraine; EM, episodic migraine; MHD, monthly headache day; MMD, mean monthly migraine day. *P-values are results compared against placebo.

Name Inclusion criteria Study period Primary endpoint*
HALO-CM CM and <2 prior classes of failed preventive treatments 3 months
n = 1,130		 MMD reduction:
Placebo: −2.5
225 mg: −4.6
675 mg: −4.3
(P<0.001, for both)
HALO-EM EM and <2 prior classes of failed preventive treatments 3 months
n = 875		 MMD reduction:
Placebo: −2.2
225 mg: −3.7
675 mg: −3.4
(P<0.001, for both)
FOCUS EM and 2−4 prior classes of failed preventive treatments 3 months
n = 462		 MMD reduction:
Placebo: −0.6
225 mg: −4.1
675 mg: −3.7
(P<0.0001, for all)

Galcanezumab

In 2019, Galcanezumab was the first CGRP targeted mAb FDA approved for episodic cluster headache19,25. The most common adverse effects for this drug are nasopharyngitis, injection site pain or reaction19,25. Table 8 shows selected phase 3 clinical trial efficacy data for migraine49-52.

Table 8. Selected galcanezumab randomised controlled phase 3 trial efficacy data49-52. All galcanezumab treatments were given as monthly subcutaneous injections. CM, chronic migraine; EM, episodic migraine; MHD, monthly headache day; MMD, mean monthly migraine day. *P-values are results compared against placebo.

Name Inclusion criteria Study period Primary endpoint*
EVOLVE-1 EM and ≤2 prior classes of failed preventive treatments 4−6 months
n = 858		 MMD reduction:
Placebo: −2.8
120 mg: −4.7
240 mg: −4.6
(P<0.001, for both)
EVOLVE-2 EM and ≤2 prior classes of failed preventive treatments 3 months
n = 915		 MMD reduction:
Placebo: −2.3
120 mg: −4.3
240 mg: −4.2
(P<0.001, for both)
REGAIN CM and ≤3 prior classes of failed preventive treatments 3 months
n = 1,113		 MHD reduction:
Placebo: −2.7
120 mg: −4.8
240 mg: −4.6
(P<0.001, for both)
CONQUER EM and 2−4 prior classes of failed preventive treatments 3 months
n = 462		 MMD reduction:
Placebo: −1.0
120 mg: −4.1 (P<0.0001)

Efficacy data for small-molecule anti-CGRP antagonists for migraine

Ubrogepant

Ubrogepant was the first gepant to receive FDA approval for the acute treatment of migraine26. The most common adverse effects for this drug are nausea and somnolence26. Table 9 shows selected phase 3 clinical trial efficacy data for migraine53,54.

Table 9. Selected ubrogepant randomised controlled phase 3 trial efficacy data53,54. All ubrogepant treatments were given as oral formulations. MBS, most bothersome symptom. *P-values are results compared against placebo.

Name Inclusion criteria n Primary endpoint*
ACHIEVE-1 2–8 migraine attacks per month 1,672 2-h headache pain freedom:
Placebo: 11.8%
50 mg: 19.2% (P=0.002)
100 mg: 21.2% (P<0.001)
2-h absence of MBS:
Placebo: 27.8%
50 mg: 38.6% (P=0.002)
100 mg: 37.7% (P=0.002)
ACHIEVE-2 2–8 migraine attacks per month 1,686 2-h headache pain freedom:
Placebo: 14.3%
25 mg: 20.7% (P=0.03)
50 mg: 21.8% (P=0.01)
2-h absence of MBS:
Placebo: 27.4%
25 mg: 34.1% (P=0.07)
50 mg: 38.9% (P=0.01)

Rimegepant

Rimegepant was originally developed for acute treatment of migraine27,29. Common adverse effects for this drug are dizziness, nausea, and urinary tract infections27,29. Table 10 shows selected phase 3 clinical trial efficacy data for migraine55,56.

Table 10. Selected rimegepant randomised controlled phase 3 trial efficacy trial55,56. All rimegepant treatments were given as oral formulations. MBS, most bothersome symptom. *P-values are results compared against placebo.

Name Inclusion criteria n Primary endpoint*
NCT03237845 2–8 migraine attacks per month 1,186 2-h headache pain freedom:
Placebo: 12.0%
75 mg: 19.6% (P<0.001)
2-h freedom from MBS:
Placebo: 25.2%
75 mg: 37.6% (P<0.001)
NCT03461757 2–8 migraine attacks per month 1,811 2-h headache pain freedom:
Placebo: 11.0%
75 mg: 21.0% (P<0.001)
2-h freedom from MBS:
Placebo: 27.0%
75 mg: 35.0% (P<0.001)

Atogepant

Atogepant was developed as a preventive therapy for migraine28. The most reported adverse events in phase 3 clinical trials were nausea, constipation, and upper respiratory tract infection57,58. Table 11 shows selected phase 3 clinical trial efficacy data for migraine57,58.

Table 11. Selected atogepant randomised controlled phase 3 trial efficacy data57,58. All atogepant treatments were given as oral formulations. EM, episodic migraine; MMD, mean monthly migraine day. *P-values are results compared against placebo.

Name Inclusion criteria n Primary endpoint*
NCT02848326 EM and ≤2 prior unsuccessful preventive treatments​ 834 MMD reduction:
Placebo: −2.9
10 mg: −4.0 (P=0.024)
30 mg: − 3.8 (P=0.039
60 mg: −3.6 (P=0.039)
30 mg twice daily:
−4.2 (P=0.0034)
60 mg twice daily:
−4.1 (P=0.0031)
NCT03777059​ EM and <4 prior unsuccessful preventive treatments​ 910 MMD reduction:
Placebo: −2.5
10 mg: −3.7
30 mg: −3.9
60 mg: −4.2
(P<0.001, for all)

Zavegepant

One challenge for peptides as medicines is their suboptimal bioavailability59. Subcutaneous injection can lead to poor patient adherence and injection site reactions59. Concerns have been raised about the risks of continuous CGRP blockade in mAb injection59.

The nasal mucosa is a less demanding physiological barrier than subcutaneous or intravenous administration59. Intranasal delivery recruits the olfactory and trigeminal pathways; lower doses can be administered, and dosage volume is relatively small59. Improved patient adherence, tolerability, and a rapid onset of action are clinical benefits of nasal delivery59.

US FDA approved in March 2023, the third-generation gepant zavegepant nasal spray is indicated for the acute treatment of migraine in adults, with or without aura30. The most common adverse reactions are taste disorders, nausea, nasal discomfort, and vomiting30. Table 12 shows selected phase 3 clinical trial efficacy data for migraine30.

Table 12. Selected zavegepant randomised controlled phase 3 trial efficacy data30. All zavegepant treatments were given as intra-nasal formulations. MBS, most bothersome symptom. *P-values are results compared against placebo.

Name Inclusion criteria n Primary endpoint*
NCT04571060 2–8 migraine attacks per month 1,405 2-h headache pain freedom:
Placebo: 14.9%
10 mg: 23.6% (P<0.001)
2-h freedom from MBS:
Placebo: 31.1%
10 mg: 39.6% (P<0.001)
NCT03872453 2–8 migraine attacks per month 1,673 2-h headache pain freedom:
Placebo: 15.5%
10 mg: 22.5% (P<0.011)
2-h freedom from MBS:
Placebo: 33.7%
10 mg: 41.9% (P<0.016)

Since polypharmacy is associated with improved patient adherence, concurrent use of CGRP-targeted mAb and gepants, or use of CGRP-targeted mAbs with other drugs, such a onabotulinumtoxinA, is under investigation60

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Although monoclonal antibodies (mAb) targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) have shown efficacy in randomised clinical trials for migraine, as demonstrated in the previous section, no head-to-head comparisons with established treatments have been published for episodic migraine prophylaxis.

Based on published data, this downloadable infographic aims to show differences in benefit-risk ratios between anti-CGRP mAbs, topiramate and propranolol for episodic migraine prophylaxis.

Selecting anti-CGRP mAbs for episodic migraine prophylaxis

Download infographic

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