Erenumab-aooe was the first of the anti-CGRP mAbs to be approved for the preventive treatment of migraine in adults.21 Erenumab, a completely human immunoglobulin G2 (IgG2) mAb that binds at the CGRP receptor, acts as an antagonist, inhibiting CGRP ligand activation of the receptor.25  Erenumab does not show cross-reactivity at adrenomedullin, calcitonin, and amylin receptors and lacks agonist activity at other CGRP receptor types.25 The drug requires 3 months to reach steady state. 21

STRIVE (Study to Evaluate the Efficacy and Safety of Erenumab [AMG 334] in Migraine Prevention; Identifier: NCT02456740) evaluated the effectiveness of erenumab 70 mg and 140 mg for the management of CM.26 The primary end point was change in mean monthly migraine days (MMD) at 3 months. Prior to treatment, patients had an average baseline of 18 MMD. The results of the trial showed that MMD was reduced by 6.6 days for both the 70-mg and 140-mg doses (Table 2).26

Secondary end points included the ability of erenumab to reduce mean MMD by ≥50% from baseline at the end of the trial.  At 3 months, 41.2% of patients on erenumab 140 mg achieved a 50% reduction in MMD, and 40% of patients on erenumab 70 mg had a 50% reduction in MMD.26 Extension trials have shown promise at the 3-year mark indicating continued improvement with erenumab for the treatment of CM.18,27 

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The efficacy of erenumab in the treatment of EM also was studied at both 70-mg and 140-mg doses in ARISE (Study to Evaluate the Efficacy and Safety of Erenumab [AMG 334] Compared to Placebo in Migraine Prevention; Identifier: NCT02483585). Patients in this trial had a baseline of 8.3 MMD.18 Treatment reduced MMD by 3.2 days at the 70-mg dose and by 3.7 days at the 140 mg-dose compared with baseline MMD.18

At 4 to 6 months on erenumab 140 mg, 50% of patients were able to achieve a ≥50% reduction in MMD; on erenumab 70 mg, 43.3% of patients demonstrated a ≥50% reduction.18 Reduction in the number of acute migraine-specific medication days was demonstrated in both STRIVE and ARISE (Table 3).

Across both CM and EM trials with erenumab, the most frequently reported adverse reaction was injection site irritation, which occurred in 6% of patients receiving 70 mg/mo (n=787) and 5% of patients receiving 140 mg/mo (n=507) compared with 3% of patients receiving placebo (n=890).21 The frequency of complaints of constipation in patients on 70 mg was found to be similar to placebo at 1% compared with 3% for patients on 140 mg.  Cramps and muscle spasms occurred in <1% of patients at the 70-mg dose, 2% at the 140-mg dose, and <1% in patients taking placebo.21


Unlike erenumab, which targets the CGRP receptor, fremanezumab-vfrm is a fully humanized IgG2a δa/κ mAb that selectively targets CGRP ligand isoforms. This agent inhibits activation of the Aδ myelinated afferents in the trigeminovascular system originating from meningeal nociceptors.28 Fremanezumab may be administered either as a single injection of 225 mg/1.5 mL/mo in a prefilled syringe or as 3 single-dose syringes (totaling 675 mg/4.5 mL) every 3 months. Fremanezumab has been approved by the FDA in both dosing strategies for the treatment of migraine in adults (including both CM and EM).22 A trial of fremanezumab in patients with cluster headache failed to meet the primary outcome.29

Fremanezumab requires about 6 months to reach steady state plasma concentrations.22  At the time of publication, an autoinjector, rather than the original prefilled syringe, is under FDA review.

In the HALO trial (Efficacy and Safety of Subcutaneous Administration of Fremanezumab (TEV-48125) for the Preventive Treatment of Migraine; Identifier:  NCT02638103) for EM, the primary end point was change in MMD from baseline during the 12-week period with quarterly or monthly dosing. From a baseline of 8.9 MMD, monthly treatment reduced EM MMD by 3.6 at 12 weeks and 4.9 at 6 months. For quarterly dosing from a similar baseline (9.2 MMD), EM MMD was reduced by 3.9 at 12 weeks and by 5.0 at 6 months.30  

Similarly, in the fremanezumab trial for the prevention of CM (Comparing Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Chronic Migraine, Identifier: NCT02621931), the primary end point was change in MMD from baseline during the 12-week study period with either quarterly or monthly dosing. From a baseline of 16.2 MMD, monthly dosing showed an average reduction of 4.6 MMD; the reduction in MMD for quarterly dosing was 4.3.20

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Unlike erenumab or fremanezumab, galcanezumab-gnlm uses a humanized IgG4 mAb to modify CGRP function. Similar to fremanezumab, galcanezumab binds, inactivates, and depletes or sequesters the CGRP ligand itself. The binding site of fremanezumab represents the domain of CGRP known to interact with the CGRP receptor. Galcanezumab is administered via an autoinjector with a loading dose of 2 injections (total of 240 mg) on the first day followed by subcutaneous injections of 120 mg/mo thereafter.23  Galcanezumab has also emerged as the first CGRP treatment to achieve approval for management of episodic cluster headache in adults.31

The REGAIN trial (Evaluation of Galcanezumab in the Prevention of Chronic Migraine; Identifier:  NCT02614261) evaluated the effectiveness of galcanezumab at both 120-mg and 240-mg doses.32 The primary end point was change from baseline in monthly migraine headache days (MHD) over 3 months. From a baseline of 19.4 MHD, the 120-mg dose decreased MHD by 4.8; however, a higher incidence of drug injection-site reactions and sinusitis was seen at this dose.32

Now used as a loading dose, the higher 240-mg dose was not approved as a monthly dosing regimen. The loading dose was derived from pharmacokinetic modeling indicating that this initial dose would reach steady state rapidly. This dosing approach is unique to galcanezumab in the subcutaneous class.32 From the subcutaneous depot, galcanezumab reaches steady state within 1 week as opposed to the 3 to 6 months required by the other subcutaneous agents.21,22

The EVOLVE-1 (Evaluation of Galcanezumab in the Prevention of Episodic Migraine; Identifier: NCT02614183) study assessed the safety and efficacy of galcanezumab at both 120-mg and 240-mg doses.33 The primary end point was change in MHD over months 1 to 6.  From a baseline of 9.2 MHD, MHD fell 4.7 for the 120-mg dose.33 EVOLVE-2 (Evaluation of Efficacy & Safety of Galcanezumab in the Prevention of Episodic Migraine; Identifier: NCT02614196), which had a similar protocol for EM, had nearly identical findings; only the 120-mg dose was approved.34 

This article originally appeared on Clinical Advisor