Switching of monoclonal antibodies against calcitonin gene-related peptide in chronic migraine in clinical practice: a case series

Abstract

A multicentre case series of patients with chronic migraine (CM) treated with monoclonal antibodies directed against calcitonin gene-related peptide (CGRP-mAbs) switching were developed. The effectiveness and safety of CGRP-mAbs switching as a preventive treatment for CM in clinical practice were recorded. Effectiveness was measured by ≥50% reduction of monthly migraine days in respect to baseline and reduction in pain intensity. Safety was analysed through adverse events (AEs) and treatment discontinuations. Seven patients were included. The reason for switching was non-response in all cases. Two patients presented a response to the first CGRP-mAb, but the effect was lost after 3 months. The remaining five patients were non-responders. Response to the second CGRP-mAb was observed in three patients, one of them for >3 months. Less than half of the patients previously treated with a CGRP-mAb responded to switching with a second CGRP-mAb. AEs were rare, with no treatment discontinuations.

Background

Migraine is a neurologic disorder defined as recurrent headache attacks lasting 4 to 72 hours and of moderate/severe pain intensity. It usually manifests as pulsatile and unilateral pain accompanied by nausea, vomiting, photophobia and phonophobia. According to the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria, chronic migraine (CM) diagnosis requires at least 15 days of headache per month (≥8 of them with migraine characteristics) for more than 3 months.¹ Migraine is the second most prevalent neurological disease and one of the most disabling, affecting 15% of global population and predominantly women.^{2 3}

In patients with CM refractory to conventional treatment with β-blockers and topiramate or another neuromodulator—or if these drugs are contraindicated or not tolerated—treatment with botulinum toxin A is recommended.³ New monoclonal antibodies (mAbs) for the prevention of CM and episodic migraine have been authorised by the European Medicines Agency (EMA) since 2018. These mAbs are directed against the calcitonin gene-related peptide (CGRP) pathway, either against its ligand (galcanezumab, fremanezumab) or its receptor (erenumab).⁴ Several clinical trials (CTs) support their efficacy and safety compared with placebo.^5–7 Nowadays, there is an absence of comparative head-to-head trials among CGRP-mAbs. However, indirect comparisons and network meta-analyses have been developed.^{8 9}

On the other hand, evidence about switching from one CGRP-mAb to another is very limited, as are the data for concomitant use with botulinum toxin A.¹⁰ There are a few case reports suggesting a possible benefit in switching, but no conclusive recommendations about therapeutic decision-making can be established.^{11 12} Likewise, switching CGRP-mAbs is not authorised in many countries. Clinical practice guidelines have not yet provided any recommendations in this regard.³ Therefore, it seems necessary to develop scientific evidence in order to optimise the preventive treatment of CM and contribute to improving the quality of life of patients.

Case presentation

Patients from several hospitals treated with CGRP-mAbs switching as a preventive treatment for CM were analysed.

Investigations

A multicentric case series review was conducted. Patients from two different hospitals, diagnosed with CM according to ICHD-3 criteria and treated with switching of two CGRP-mAbs between August 2018 and May 2021, were included.¹ Electronic medical records and prescription software were used to obtain the following information: gender, age, previous migraine treatment, CGRP-mAb used and dosage, duration of treatment, reason for switching, and monthly migraine days. Seven patients were enrolled: five women and two men, with a mean age 45 (25–70) years.

The effectiveness and safety of CGRP-mAbs switching as a preventive treatment for CM in clinical practice were evaluated. Effectiveness endpoints were the reduction ≥50% of monthly migraine days from baseline and the reduction in pain intensity. Any subjective assessment of pain improvement by the patient was accepted as a reduction in pain intensity. Patients who did not meet either of these criteria were considered non-responders. Two periods with respect to baseline were established to measure effectiveness endpoints: at 3 months and at 6 months of CGRP-mAb treatment. To measure safety, adverse events (AEs) and treatment discontinuations associated with AEs were recorded.

Treatment

The mean number of previous treatments was six (range 4–10). The most frequent prior therapies were botulinum toxin A (n=7), topiramate (n=5), flunarizine (n=5), amitriptyline (n=4), propranolol (n=4), and zonisamide (n=3). All patients received at least four doses of botulinum toxin A 195 IU every 3 months before treatment with CGRP-mAbs. The mean number of botulinum toxin A administrations was seven (4–16).

The first CGRP-mAb used was galcanezumab 120 mg monthly (with 240 mg induction dose) in six patients and erenumab 70 mg monthly in one patient. These therapies presented a mean duration of 7 (4–10) months. The second CGRP-mAb was erenumab 70 mg monthly in four patients, fremanezumab 225 mg monthly in two cases, and galcanezumab 120 mg monthly (with 240 mg induction dose) in one. The second CGRP-mAb treatments were used for a mean of 6 (3–14) months.

Outcome and follow-up

The reason for switching to a different CGRP-mAb was absence of response to a previous one in all cases. The baseline number of monthly migraine days was ≥8 in all patients. A ≥50% reduction in monthly migraine days from baseline was recorded in two patients with the first CGRP-mAb used at 3 months, who also showed a decrease in pain intensity. The response in these cases was lost after 3 months. The remaining five patients presented no response from baseline. Two patients receiving the second CGRP-mAb achieved a ≥50% reduction in monthly migraine days and a decrease of pain intensity during the first 3 months of treatment. This response was maintained up to 6 months in one of them. Another patient showed only a ≥50% reduction in monthly migraine days for 3 months and after this time there was a loss of response, with no reduction in pain intensity. The remaining four cases obtained no response to second CGRP-mAb and were patients who also failed to respond to the first CGRP-mAb. Individual patient results are detailed in table 1.

Table 1.

Individual results from patients with chronic migraine treated with CGRP mAb switching

Patient		1	2	3	4	5	6	7
Gender		Female	Male	Male	Female	Female	Female	Female
Approximate age (years)		50–55	25–30	45–50	45–50	40–45	65–70	25–30
Baseline migraine days		≥8	≥8	≥8	≥10	≥10	≥8	≥15
Previous treatments		Botulinum toxin A, flunarizine, mirtazapine, propranolol, topiramate (n=5)	Botulinum toxin A, flunarizine, propranolol, topiramate, zonisamide (n=5)	Botulinum toxin A, amitriptyline, atenolol, escitalopram, flunarizine, gabapentin, pregabalin, topiramate, venlafaxine, zonisamide (n=10)	Botulinum toxin A, candesartan, gabapentin, propranolol, venlafaxine, zonisamide (n=6)	Botulinum toxin A, amitriptyline, flunarizine, nadolol, propranolol, topiramate (n=6)	Botulinum toxin A, amitriptyline, duloxetine, pregabalin (n=4)	Botulinum toxin A, amitriptyline, flunarizine, nadolol, topiramate (n=5)
First CGRP mAb		Galcanezumab	Galcanezumab	Galcanezumab	Galcanezumab	Galcanezumab	Galcanezumab	Erenumab
Duration of first CGRP mAb therapy (months)		10	9	9	4	4	6	6
Reduction ≥50% of monthly migraine days with respect to baseline with first CGRP mAb	At 3 months	Yes	No	Yes	No	No	No	No
	At 6 months	No	No	No	Not reached	Not reached	No	No
Reduction in pain intensity with first CGRP mAb	At 3 months	Yes	No	Yes	No	No	No	No
	At 6 months	No	No	No	Not reached	Not reached	No	No
Reason for switching		No response	No response	No response	No response	No response	No response	No response
Second CGRP mAb		Erenumab	Erenumab	Fremanezumab	Erenumab	Erenumab	Fremanezumab	Galcanezumab
Duration of second CGRP mAb therapy (months)		6	7	3	14	7	3	5
Reduction ≥50% of monthly migraine days with respect to baseline with second CGRP mAb	At 3 months	Yes	No	Yes	Yes	No	No	No
	At 6 months	No	No	Not reached	Yes	No	Not reached	Not reached
Reduction in pain intensity with second CGRP mAb	At 3 months	No	No	Yes	Yes	No	No	No
	At 6 months	No	No	Not reached	Yes	No	Not reached	Not reached

CGRP mAb, monoclonal antibodies directed against the calcitonin gene-related peptide pathway.

AEs were found in three patients. Injection-site pain occurred in two cases: one with galcanezumab as first CGRP-mAb and one with erenumab as second CGRP-mAb. One patient, who had previously received galcanezumab, developed pruritic erythema during treatment with erenumab as second CGRP-mAb. No AEs were reported by the rest of the patients. No treatment discontinuations associated with AE were collected.

Discussion

CGRP-mAbs appear to be an adequate therapeutic option for migraine prevention in patients with previous standard preventives failure. However, there are few publications about the switching of these drugs and all of them were case series with small sample size.^{11 12} No randomised CTs have been published about this issue. In our study, less than half of the patients treated with the CGRP-mAbs switching responded to both the first and second drug, with non-response to the first mAb being the reason for switching in all cases. Most patients refractory to the first CGRP-mAb also failed to respond to the second one. This seems reasonable due to the similar mechanism of action of the two CGRP-mAbs. During the observation time, few AEs were detected, which in no case led to treatment discontinuation.

Our study presents the limitation of a small sample size, like the aforementioned publications. However, the relatively recent marketing of these drugs, the insufficient scientific evidence to support switching, and the lack of recommendations in clinical practice guidelines make it difficult to find a greater number of patients with CGRP-mAbs switching in clinical practice. Therefore, these data should be interpreted with caution. CTs with larger sample sizes are needed to provide evidence on the possible benefits of switching CGRP-mAbs.

The patients were treated with the erenumab 70 mg regimen according to the physician’s clinical criteria based on the scientific evidence. One CT showed a similar efficacy and safety profile for 140 mg and 70 mg of erenumab.⁵ Thus, the summary of products characteristics of the EMA also recommends the regimen of erenumab 70 mg every 4 weeks.⁴ Taking this into account, and not knowing the long-term adverse effects, health professionals sought the least possible exposure to CGRP-mAbs. The use of the erenumab 140 mg regimen is another option for CM patients refractory to erenumab 70 mg.

Our work showed modest benefits for the second CGRP-mAb after failure of the primary CGRP-mAb in CM, in contrast to other published studies.^{11 12} Some authors suggest that the slightly different mechanism of action of CGRP-mAbs—against the receptor or ligand—could explain a superior benefit observed with the second CGRP-mAb compared with the first. However, these data are not conclusive.¹² Furthermore, the influence of these differences in the mechanism of action on the efficacy and safety of CGRP-mAbs should be considered in future research. For example, erenumab blocks the canonical CGRP receptor and it has no effects on others such as the amylin 1 receptor.¹³ Most of our patients used mAbs against both the receptor and ligand without this leading to a significant improvement in the response. An improved response was only observed in one case with the second mAb by switching the mechanism of action. Considering CGRP-mAbs switching as an exceptional situation, it seems reasonable to select outcomes that provide true benefit to patients with CM. The ≥50% reduction in monthly migraine days and the decrease in pain intensity used as endpoints in our work could be considered more relevant than the endpoints described in these studies. Likewise, the effectiveness of CGRP-mAbs has not been adequate in most of our cases after 3 months. This loss of effect over time has been suggested in previous network meta-analyses.¹⁴ There are also reports in the literature—real world data— describing a benefit of some CGRP-mAbs after 3 months.¹⁵ For this reason, the follow-up of our patients with CM for 6 months with each antibody in a controversial clinical context such as CGRP-mAbs switching can be important.

A few AEs were observed in our study and they were mild-moderate. On the other hand, possible long-term consequences of switching these drugs in terms of safety are still unknown.

The optimisation of preventive treatment in patients with CM is of paramount importance given the socioeconomic impact of this disease.2 3 16 17 The shortage of treatments indicated after CGRP-mAbs is a limitation for clinical decision-making. The development of more scientific evidence on CGRP-mAbs switching could contribute to the optimisation of preventive treatment of CM. CTs are required to establish the adequate therapy after failure of a first CGRP-mAb and to improve the quality of life of patients.

Learning points.

• Data on the switching among CGRP monoclonal antibodies for the treatment of chronic migraine is very limited.

• Less than half of our patients treated with the second CGRP monoclonal antibodies achieved a response.

• Clinical trials are required to recommend an adequate therapy after a first failure of CGRP monoclonal antibody treatment.

Data availability statement

All data relevant to the study are included in the article.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

The authors fulfilled all the ethical and legal criteria to develop this study.