Preventive treatment with erenumab heralds new era of migraine management
High dropout rates with oral migraine preventive medications (OMPMs) represent an unmet need in migraine care. The development of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) receptor heralds a new era for migraine prevention. At a recent virtual symposium, Professor Michel Lantéri-Minet of Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, France, and Dr Charles Hua-Chiang Siow of Mount Elizabeth Novena Specialist Centre, Singapore, discussed the role of erenumab, a fully human immunoglobulin G (IgG)-2 mAb, in migraine care.
Unmet needs in migraine care
“Patients referred to headache clinics due to frequent primary headache episodes are at a much higher risk of medication overuse [MOU] than those in the general population [50 percent vs 1–2 percent]. This risk could be reduced when preventive medication is initiated and the intake of acute headache medication is limited,” said Lantéri-Minet. [Lancet Neurol 2019;18:891-902]
None of the currently available OMPMs were designed specifically for migraine. Previous studies showed that persistence of OMPM use was poor among patients with chronic migraine (CM), with a sizeable decrease in persistence of initial prophylaxis after 1 month of treatment, mostly due to a lack of efficacy (episodic migraine [EM], 36.8–47.6 percent; CM, 39.2–48.2 percent) and treatment-related side effects (EM, 34.8–49.0 percent; CM, 34.2–53.2 percent). This is of concern since guidelines recommend continuation of OMPM therapy for ≥6–12 months prior to evaluation for treatment discontinuation. [Cephalalgia 2017;37:470-485; Headache 2013;53:6446-55]
The use of injectable IgG-2 mAb erenumab (70 mg or 140 mg) as preventive treatment for migraine is recommended by current international guidelines and is indicated for prophylaxis of migraine in adults with ≥4 migraine days per month. [Headache 2019;591-518, J Headache Pain 2019;20:6; Erenumab prescribing information]
CGRP: An emerging treatment target in migraine
The trigeminovascular system, consisting of trigeminal ganglia, branches of trigeminal nerves and cerebral blood vessels, is involved in the regulation of cranial blood flow and transmission of pain. Erenumab acts by targeting CGRP receptors in the trigeminal ganglion, trigeminal nucleus caudalis, and the dural vasculature, thereby antagonizing the accumulation of cAMP and preventing the induction of vasodilation, oedema and dural mast cell degranulation, and thus neurogenic inflammation and sensitization of nociceptive neurons. [J Nurse Pract 2019;15:717-724; J Anaesthesiol Clin Pharmacol 2020;36:104-109; Annu Rev Pharmacol Toxicol 2015;55:533-552]
“Compared with other mAbs, erenumab has a lower risk of immunogenicity and a higher specificity of CGRP receptor binding, with neglectable affinity on other calcitonin family receptors,” explained Lantéri-Minet.
Phase II study
In a phase II study, 667 patients with CM (with or without aura; history of MOU permitted) were randomized (3:2:2) to receive subcutaneous placebo, erenumab 70 mg or erenumab 140 mg, every 4 weeks for 12 weeks. [Lancet Neurol 2017;16:425-434]
Treatment with erenumab 70 mg or 140 mg resulted in a significant reduction of monthly acute migraine–specific medication days (MSMDs) vs placebo over the last 4 weeks of treatment (-3.5 days and -4.1 days vs -1.6 days; both p<0.0001).
“Of note, a larger treatment effect of erenumab [70 mg and 140 mg] vs placebo was seen in adults with vs without MOU [with MOU, -5.4 days and -4.9 days vs -2.1 days; both p<0.001] [without MOU, -2.1 days and -3.6 days vs -1.2 days; p<0.05 and p<0.001, respectively]. Erenumab thus offers even greater benefit in patients with MOU,” said Siow. (Figure 1) [Neurology 2019;92:e2309-e2320]
In the phase III STRIVE trial, 995 patients (mean age, 40.9 years) with EM (with or without aura) and concomitant use of OMPMs at stable doses were randomized (1:1:1) to receive erenumab (70 mg or 140 mg) or placebo, every 4 weeks for 24 weeks. [N Engl J Med 2017;377:2123-2132]
In the trial, 42.4 percent of patients were currently using or had previously used migraine preventive medication, and 38.7 percent had discontinued its use because of lack of efficacy or unacceptable side effects.
Significantly more patients treated with erenumab 70 mg or 140 mg achieved ≥50 percent reduction from baseline in mean monthly migraine days (MMDs) (ie, ≥50 percent responder rate) in months 4–6 compared with placebo recipients (43.3 percent and 50.0 percent vs 26.6 percent; both p<0.001). (Figure 2)
“In the difficult-to-treat subgroups, namely, patients with ≥1 and ≥2 treatment failures [TFs], erenumab 70 mg and 140 mg also demonstrated benefit vs placebo in ≥50 percent responder rate [≥1 TFs, 38.6 percent and 39.7 percent vs 17.5 percent; both p=0.001] [≥2 TFs, 26.5 percent vs 36.2 percent vs 11.1 percent; both p<0.05],” said Siow. (Figure 2) [Cephalalgia 2019;39:817-826]
In the subsequent phase IIIb LIBERTY trial, 246 patients with EM and 2–4 preventive TFs were randomized (1:1) to receive erenumab 140 mg (via two 70 mg injections) or placebo, every 4 weeks for 12 weeks. [Lancet 2018;392:2280-2287]
At baseline, 39 percent, 38 percent and 23 percent of patients had attempted two, three or four previous unsuccessful preventive migraine treatments, respectively.
“At week 12, the ≥50 percent responder rate was considerably higher with erenumab vs placebo [30 percent vs 14 percent; odds ratio (OR), 2.7; 95 percent CI, 1.4 to 5.2; p=0.002], but the effect of erenumab was observed from week 4 onwards [week 4, 23 percent vs 5 percent; OR, 5.9; 95 percent CI, 2.3 to 14.9; p<0.001] [week 8, 31 percent vs 12 percent; OR, 3.3; 95 percent CI, 1.7 to 6.4; p<0.001],” said Siow. (Figure 3)
Apart from significant reductions in MMD (p=0.004) and MSMDs (p<0.001), erenumab treatment also led to significant reductions in mean scores on subdomains of the Migraine Physical Function Impact Diary (MPFID) (MPFID-physical impairment; -1.9 vs 1.6; 95 percent CI, -5.7 to -1.2; p=0.003) (MPFID-everyday activities, -3.4 vs 0.6; 95 percent CI, -6.1 to -1.7; <0.001) and a significant improvement in ≥75 percent and 100 percent responder rates (≥75 percent responder rate, 12 percent vs 4 percent; OR, 3.2; 95 percent CI, 1.1 to 9.0; p=0.025) (100 percent responder rate, 6 percent vs 0 percent) compared with placebo at weeks 9–12.
Erenumab was well tolerated in the LIBERTY trial, with comparable rates of adverse events (AEs) and serious AEs vs placebo. Injection site pain (6 percent vs 6 percent), nasopharyngitis (4 percent vs 2 percent), and back pain (4 percent vs 10 percent) were the most frequent treatment-emergent AEs.
“Unmet needs exist with current migraine preventive medications. Erenumab, the first US FDA-approved CGRP mAb for migraine prevention, has a specific mode of action, and is highly effective with a good safety profile,” Lantéri-Minet concluded.