Our study pooled five randomized clinical trials evaluating the safety and efficacy of erenumab for the treatment of episodic migraine. Our analysis showed that erenumab was efficacious and safe for the treatment of migraine. Furthermore, our study pooled both direct and indirect evidence with the Bayesian network meta-analysis method and demonstrated 140 mg erenumab outperforms 70 mg erenumab in multiple efficacy endpoints while related to the same risk for developing adverse events. In addition, our study demonstrated that 70 mg and 140 mg erenumab were associated with significantly reduced migraine frequency and improved functional outcome in patients with prior migraine treatment failures. The heterogeneity was low across all the primary outcomes, indicating a high level of clinical evidence. It is the first meta-analysis comparing the safety and efficacy of different doses of erenumab and the first meta-analysis to demonstrate the safety and efficacy of erenumab in patients with ≥ 2 prior migraine treatment failures.
Targeting CGRP is considered a breakthrough in migraine therapy in the past decades. Serum CGRP levels are elevated during migraine attacks[12]. Meanwhile, the infusion of human CGRP could induce headaches and migraine in migraineurs[13]. These evidences showed that CGPR might play an essential role in migraine attacks. CGRP receptors are widely distributed in both the central and peripheral nervous systems[14]. Since CGRP antagonists have a limited ability to cross the blood-brain barrier (BBB) and there is no increase in BBB permeability during a migraine attack[15], the brainstem, which has a high level of CGRP receptor expression and defective BBB, was considered the target of action of CGRP receptor antibodies[16]. Drugs targeting CGRP were developed based on the role of CGRP in the pathogenesis of migraine, which is highly selective for migraine treatment. CGRP antagonists and CGRP receptor monoclonal antibodies are mainly used as migraine prevention, and small-molecule CGRP antagonists are mainly used for acute management of migraine.
Although current evidence suggests the effectiveness of CGRP monoclonal antibodies in migraine treatment is not dramatically increased compared with traditional therapy, the monoclonal antibodies targeting CGRP and its receptors have their unique advantages in migraine treatment. Low compliance in patients with migraine with chronic prophylactic medication use is frequently reported[17]. Erenumab has been designed and modified to extend its circulating half-lives[18]. In clinical practice, it could be given once per month, which could potentially increase compliance among migraineurs. A cost-analysis based on US societal perspective Markov health state transition model has demonstrated the use of erenumab was associated with reduced migraine-related direct and indirect costs compared with supportive care[19].
As CGRP ligand could dilate blood vessels, the potential risk on the cardiovascular system caused by CGRP targeted therapies attracts much attention. A study conducted on human isolated cranial arteries has found that the use of erenumab was not associated with direct vasoconstriction and did not influence the effect of endogenous or exogenous vasoactive compounds[20]. A 12-week trial conducted by Tepper et al. confirmed that erenumab did not affect the blood pressure and 24-hour blood pressure changes in healthy volunteers[21]. No significant difference was found in the emergence of vascular adverse events between the erenumab group and the placebo group in the short-term migraine treatment phase[22]. In addition, a study conducted in patients with stable angina has found that the use of erenumab had no effect on exercise time[23]. Although these studies have demonstrated CGRP targeted therapies are not likely to induce severe adverse events caused by vasoconstriction, CGRP may play a more critical role in the change of vascular tension in hypertensive rats than in normotensive rats[24]. Hence, future researches are still needed to evaluate the long-term use of erenumab in patients with cardiovascular risk or hypertension.
Our study mainly pooled short-term placebo-controlled trials for episodic migraineurs. Erenumab also showed its effect on chronic migraine patients[25]. So far, a handful of studies have been conducted to evaluate the long-term use of erenumab. An open-label study evaluating long-term safety and efficacy of erenumab in patients with episodic migraine found that erenumab use is related to improved function and a favorable safety and tolerability profile[26]. The long-term adverse effects of erenumab include injection-site reactions, constipation, and muscle spasm[27]. In another similar long-term study, erenumab was found to be safe and well-tolerated, and the adverse events were considered consistent with shorter-term placebo treatment[28]. Furthermore, evidence suggests that the long-term use of erenumab increased the conversion from chronic migraine to episode migraine[29], especially 140 mg dose[30]. Besides, a previous study reported that erenumab use was associated with a higher response rate in patients who had a high susceptibility to migraine induction by CGRP[31].
As a preventive therapy, erenumab is likely to be prescribed for long term use. Thus, the cross-talk of erenumab with other commonly-used drugs is another concern for physicians. From the pharmacokinetics perspective, as mAbs are eliminated via catabolic pathways, they may not compete directly with other small molecule drugs that are mainly eliminated via hepatic, renal, or biliary processes[32]. A study conducted in 2017 found that subcutaneous erenumab did not influence the effect of estrogen/progestin combination oral contraceptives among healthy females[33]. A placebo-controlled trial investigating co-administration of erenumab 140 mg and sumatriptan 12 mg have found no additional effect on averages of mean arterial pressure or on the pharmacokinetics of sumatriptan[34].
Optimal management of chronic migraine patients with concurrent overuse of acute medications poses a challenge for clinicians[35]. Results from clinical trials have demonstrated that erenumab is effective in patients with medication overuse[36–38]. In a post-hoc analysis, erenumab showed comparable efficacy between medication over-users and the non-medication overuse group[39].
Preventive treatment of migraine is an essential component of migraine management. To date, multiple drugs have been applied to the preventive treatment of migraine, including beta-blockers, topiramate, amitriptyline, and onabotulinumtoxinA[40]—however, none of these drugs highly selective to pharmacological targets on the migraine pathogenesis pathway which would lead to disturbing adverse events. Propranolol and timolol are the only beta-blockers approved by the FDA for migraine prevention[41]. Frequently reported adverse events for beta-blockers include fatigue, exercise intolerance, and orthostatic hypotension. Besides, beta-blockers are contraindicated in patients with decompensated heart failures and patients with asthma. Valproate and topiramate are frequently used as migraine preventive therapy. Previous evidence suggests about 50% of patients who received valproate and topiramate achieve a 50% reduction in headache frequency[42]. However, for the safety outcomes, the use of valproate and topiramate is related to increased adverse events. Commonly reported adverse events for valproate including nausea, fatigue, tremor, weight gain, and hair loss, and topiramate commonly causes paresthesias, fatigue, cognitive impairment, taste perversion, weight loss, and nephrolithiasis[43]. When compared with valproate and topiramate, erenumab is related to comparable efficacy outcomes and is not associated with increased risk for developing adverse effects. Amitriptyline is the only tricyclic antidepressant shown to be effective for migraine prevention in clinical trials, but it often causes sedation, dry mouth, and weight gain[44]. To sum up, although no clinical trial has been conducted to evaluate the safety and efficacy of erenumab versus other traditional methods, current evidence indirect comparison suggests erenumab outperform these traditional migraine preventive drugs[45]. Pericranial intramuscular injections of onabotulinumtoxinA (Botox) is another FDA-approved novel therapy for the prevention of headaches in adults with chronic migraine[46]. However, until now, the effectiveness of Botox in episodic migraineurs remains uncertain on account of the low quality of limited evidence[47].
Our study had a few limitations. First, although our study included five multicenter randomized trials that have a low risk for bias, the heterogeneity of overall functional improvement in the pair-wise meta-analysis was considerably high, indicating a low level of clinical evidence. Second, all the included clinical trials were limited to short-term use; further pooled analysis based on long-term, or real-world studies are needed. Third, our analysis of 70 mg erenumab in patients with previous treatment failure only includes one trial with an insufficient sample size. Further studies are still needed to provide more robust evidence.