This is the first large, independent, prospective analysis evaluating the effectiveness and tolerability of erenumab in real-world CM patients with and without MOH, refractory to medical treatments. Refractory CM is a very disabling migraine variant; it often represents a medical challenge for headache specialists and poses substantial burden on healthcare service utilisation . The vast majority of patients treated in this audit would largely meet the recently EHF updated criteria for refractory CM since they failed all the drug classes with evidence in migraine prevention including injectable treatments and often non-invasive neuromodulation approaches, had severe migraine symptoms and reported high levels of headache-related disability . Furthermore, a significant proportion of patients displayed a chronic daily headache pattern at baseline.
The results of this report suggested that over a period of six months, erenumab was well tolerated and effective in preventing migraine symptoms. Compared to baseline, erenumab led to a significant improvement across all the efficacy outcomes, which was sustained throughout the six months and led to a relevant reduction in headache-related disability. Our efficacy outcomes were less impressive than the ones of a recent real-life open-label study conducted predominantly CM patients . Indeed, at month 6, 69% and 62% of patients obtained respectively at least 30% and 50% reduction in MMD. Similar outcomes were observed in the BoNT/A non-responder subgroup analysis. Possible explanation for the outcome differences between studies may include patients selection. In the Italian study, patients failed 2–4 treatments, hence were considered difficult-to-treat, whereas in our study most patients failed all established treatments, hence were more refractory to medical treatments. Furthermore, the increased proportion of responders at month 6 in the Italian study may have been influenced by the fact that non-responders could have discontinued the treatment earlier, whereas in our analysis, all patients, apart from those who discontinued because of adverse events, continued for the trial for six month, even if they did not respond at month 3.
The month-3 reduction in MMD with erenumab 70 mg reported in our analysis was similar to the main endpoint of the pivotal phase 2 CM clinical trial both when the whole study population was considered but also when the subgroup of patients who failed at least two preventive treatments was analysed [18, 19]. Furthermore, the 50% response rate with erenumab 70 mg in the overall Phase 2 trial population was 40% and in the subgroup analysis of patients with at least two prior treatment failures was 35.6%, very similar to the 35% response rate found in our patients. At month 6, a progressive improvement in most of the efficacy measures was observed in our patients, possibly due to the longer exposure to erenumab, but perhaps also due to the increased dose which may have enhanced the clinical improvement in some of our patients. A similar effect was reported in the 1-year open-label extension of the pivotal phase 2 clinical trial . However, in that study, the withdrawal of treatment non-responders may have biased the results by impacting positively on the outcomes, whereas in our audit all patients were treated for at least six months unless they decided to discontinue it due to side effects.
Reduction of at least 30% in monthly migraine frequency is considered a clinically meaningful change especially in the refractory migraine population [21, 22]. If this cut-off was applied after three months treatment in our refractory patients, almost half of the patients (49%) would qualify for treatment continuation with erenumab. However, a small proportion of patients who did not obtain a 30% reduction in MMD at month 3, met the 30% threshold for treatment continuation at month 6, suggesting that highly refractory CM may benefit from a six month treatment, similarly to BoNT/A recommended regimen, to include those with a delayed response.
Along with the uncertainty about the optimal trial duration in refractory CM, it is also unclear whether the 140 mg erenumab dose is clinically superior to the 70 mg dose. In patients who switched from 70 mg to 140 mg, we observed a greater improvement in MMD and MHD. Furthermore a significant minority of non-responders after three monthly 70 mg erenumab injections, became responders once they were switched to the 140 mg dose, indicating a degree of superiority of the dose of 140 mg compared to the 70 mg. Similar findings emerged from the post hoc analysis of the pivotal erenumab CM study, which pointed towards a slight superiority of 140 mg dose in patients who failed two or more preventive treatments compared to those who were naïve or failed one treatment only , even when they had MOH . Moreover, during the 1-year open-label treatment extension of the parent study, erenumab 140 mg showed greater clinical benefit compared to the 70 mg dose in a number of outcomes including reduction in MMD, 50%–75%–100% responder rates and reduction in days of use of abortive migraine medications . Our data along with the post-hoc analysis of the pivotal CM trial, suggest that erenumab 140 mg dose may provide greater and more sustained efficacy compared to the 70 mg dose in the difficult-to-treat CM population.
Erenumab has led to a sustained resolution of MOH in a meaningful proportion of patients. Our data were similar to the outcome of the subgroup analysis of 274 CM patients with MOH treated with erenumab or placebo, showing no significant difference in treatment effect between the group with MOH and non-MOH . Given that MOH is frequently diagnosed in tertiary referral clinics, the efficacy of erenumab in this even more complex group of patients, makes it a valuable option also in those patients in whom abortive treatment withdrawal is proven to be difficult to achieve or ineffective.
Erenumab has consistently shown a very favourable safety and tolerability profile across the CM and episodic migraine trials with low discontinuation rates [18, 24,25,26]. In the subgroup analysis of the pivotal phase 2 clinical trial, patients with prior preventive treatment failure treated with erenumab reported a higher proportion of AEs compared to placebo (42–58% depending upon the different doses) . Our refractory group of patients displayed a similar proportion of AEs at month 1 (48%). However, with subsequent treatments, the proportion of patients complaining of AEs diminished substantially, suggesting that longer exposure to erenumab may lead to improved tolerability. Constipation and cold-like symptoms were confirmed to be the most frequent AEs, similarly to the pivotal clinical trials in migraine [18, 24,25,26]. However, the percentage of patients with constipation observed in our study was higher, especially during the first three months of treatment, compared to the one in the clinical trials. A likely explanation may be that we systematically asked about this adverse event every month for the first three months. However, a higher percentage of constipation (13.5%) was also observed in a recent real-life study , suggesting that the real-world population may be more susceptible to medications’ adverse events perhaps in view of their frequent co-morbidities. The discontinuation rate displayed by our patients was greater than the ones reported in previous studies, even when the subgroup analysis of the patients with prior preventive treatments failure was considered [18, 19]. Patients referred to our tertiary Centre have often been previously seen by multiple specialists across the country and tried many pharmacological options. High treatments discontinuation rates in the refractory CM patients may constitute one of the biological aspects of this complex migraine variant, especially in the context of multiple comorbidities, such as irritable bowel syndrome which was reported by a high proportion of our patients and may at least explain discontinuation due to severe constipation.
Hypertension has sparsely been associated to erenumab exposure . In our patient no other causes of hypertension were identified. It is likely that their new-onset hypertension was erenumab-related given that no other causes were identified, the patient was otherwise healthy at baseline and the BP normalised with discontinuation of erenumab. In light of this case, it may be advisable to counsel patients about this possible and likely very rare AE.
The main limitation of this audit is the open label design. However, it is unlikely that the symptoms improvement could be explained by placebo alone. The strengths of this report are the large number of patients with a refractory form of migraine, which reflects the type of complex and difficult-to-treat patients seen in tertiary headache clinics and the prospective and the real-world nature of the analysis, which includes patients not subject to strict inclusion and exclusion criteria.
Recently published position statements and guidelines have debated patients selection and positioning of anti-CGRP MABs within the arsenal of migraine preventive treatments in clinical practice. Despite their meaningful efficacy and good tolerability demonstrated in clinical trials across the spectrum of episodic and chronic migraine, this new class of drugs is costly, hence in clinical practice it may be reserved for the difficult-to-treat/refractory subgroup of CM patients only, which were largely excluded for the clinical trials [28, 29]. Our analysis along with another recent study , provided the first real-world evidence of efficacy of erenumab in such population, supporting its meaningful role even in the complex difficult-to-treat CM population. In conclusion, erenumab was effective in the prevention of migraine symptoms in our refractory CM patients with and without MOH.