Severe acute allergic reaction after switching anti-calcitonin gene-related peptide monoclonal antibodies: A case report

Abstract

Background

Anti-calcitonin gene-related peptide monoclonal antibodies (CGRP-mAbs) are widely used for migraine prevention and are generally considered safe, with rare severe allergic reactions. Switching between CGRP-mAbs is a common strategy for non-responders, although allergic cross-reactivity remains a theoretical concern. We report a rare case of a severe allergic reaction following switching from fremanezumab to galcanezumab.

Case presentation

A 68-year-old woman received fremanezumab for migraine prophylaxis. Due to the deterioration of migraine days, the CGRP-mAb was switched from fremanezumab to galcanezumab. Following the galcanezumab injection, the patient experienced skin rash and dyspnea.

Discussion

The present case describes a severe allergic reaction after switching CGRP-mAbs. Given the potential for allergic reactions, further research on similar cases and rigorous investigations are required to assess the safety and risks associated with switching CGRP-mAbs.

Graphical abstract

This is a visual representation of the abstract.

Introduction

Treatment with anti-calcitonin gene-related peptide monoclonal antibodies (CGRP-mAbs) for migraine prophylaxis is considered safe and has significantly reduced headache-related disabilities, including symptoms during the interictal phase.^1-3 Randomized controlled trials of CGRP-mAbs have shown that severe allergic side effects are rare; however, careful administration is required.^4,5 Allergic reactions may not be limited to a single specific drug; rather, they may occur in response to other drugs that share similar mechanisms of action. In the case of CGRP-mAbs, switching between agents is often considered a viable option for non-responders^6-14; however, severe allergic reactions following this switch have not been previously reported. Here, we report a case of a severe allergic reaction after switching from fremanezumab to galcanezumab.

Case presentation

A 68-year-old woman was referred to a neurologist complaining of increased frequency of headaches. She also had a history of hyperthyroidism, mammary cancer (cT1cN0M0 luminal B), bronchial asthma, and food allergies. Episodic headache with visual aura began at 30 years of age. During the periods of headaches, the patient had nausea and photophobia. The headache was preceded by a visual aura lasting for approximately 30 min. Therefore, she was diagnosed with migraine with aura. The patient experienced migraine attacks for 15 or more days per month for at least 3 months, with at least 8 of those days meeting the criteria of chronic migraine, based on the International Classification of Headache Disorders, 3rd edition. Because the number of monthly migraine days (MMDs) increased regardless of prophylactic treatment with sodium valproate 200 mg/day, the patient was administered fremanezumab 225 mg monthly. The MMDs decreased from 12 to 6 days after 1 month of fremanezumab administration, and sodium valproate oral medication was discontinued. However, the severity of the headache increased 6 months after fremanezumab administration. Due to the deterioration of frequencies, galcanezumab was administered to reduce MMDs. There were no side effects 30 min after the injection of galcanezumab (240 mg); however, immediately after she left the hospital, she experienced a sudden diffuse nettle rash with dyspnea (Figure 1). She used the medicine she had brought with her on the spot. Two puffs of beta-agonist relieved her dyspnea, and an anti-inflammatory ointment was administered to reduce the skin rash, which disappeared after treatment.

Figure 1.

Skin rash observed in the upper arm after administration of galcanezumab (arrows).

Following the severe allergic reaction to galcanezumab, the patient was reluctant to try any new medications. However, alternative preventive medications, such as beta-blockers, antiepileptics (e.g. topiramate), calcium channel blockers, and antidepressants (e.g. amitriptyline), were considered. Through a shared decision-making process, the patient ultimately elected to resume the original prophylactic therapy, which, despite its modest effectiveness, offered a known and acceptable safety profile. Unfortunately, the administration of gepants was not feasible in this case, as it has not been approved for clinical use in Japan. The patient was re-administered sodium valproate (200 mg/day). No obvious allergic reactions have occurred since then. This case report was prepared in accordance with the CARE guidelines.

Discussion

In this report, we described a severe allergic reaction after switching from fremanezumab to galcanezumab. The allergic reaction corresponded to an immediate-type hypersensitivity reaction (anaphylaxis) characterized by dermatological symptoms (urticaria) and respiratory symptoms (dyspnea), which can be classified as grade 3 regarding the recent proposal. ¹⁵

Given the patient's medical history of bronchial asthma and food allergies, it is plausible that she had a heightened baseline risk of developing hypersensitivity reactions. This case highlights the importance of carefully considering individual allergic predispositions when prescribing anti-CGRP-mAbs. Both fremanezumab and galcanezumab are mAbs targeting the CGRP ligand, whereas erenumab is distinct in that it binds to the CGRP receptor. Notably, erenumab, a fully human mAb, has been associated with a relatively low incidence of anti-drug antibodies and neutralizing antibodies in previous studies. While a reduced immunogenic response does not necessarily imply a decreased risk of hypersensitivity reactions, the low immunogenicity profile of erenumab may have contributed to its selection in clinical scenarios where the potential for allergic reactions was a concern. ¹⁶ Although erenumab may have been a preferable choice due to the advantageous difference, erenumab use was not possible in the present case because the medication was not included in the hospital formulary at the time of treatment. From a therapeutic standpoint, switching between different CGRP-targeting mAbs has been shown to be a feasible and potentially effective strategy for patients who do not respond adequately to the initial treatment. Although the efficacy and safety of these switches have been demonstrated in previous studies, careful monitoring remains essential, particularly in patients with known risk factors for allergic reactions.^{6-10,12-14,17} Importantly, no severe allergic reactions were observed in previous studies, indicating that switching between anti-CGRP antibodies is a valid and safe treatment option.

Although anaphylactic reactions associated with anti-CGRP-mAbs have been reported, no report has described allergic hypersensitivity reactions occurring immediately after switching between these agents. Cross-reaction should be one of the possibilities within the agents that share mechanisms^18,19; however, in the present case, it remains unclear whether the allergic reaction was triggered by structural similarities between fremanezumab and galcanezumab, or by galcanezumab itself. ²⁰ Given the potential for hypersensitivity reactions, further accumulation of cases and rigorous investigations are required to assess the safety and risks associated with switching to the alternative anti-CGRP-mAbs.

Conclusion

This report highlights the potential risk of allergic reactions associated with switching to anti-CGRP antibodies. Given the immunogenic variability among biological agents, transitioning from one anti-CGRP-mAb to another may subtly alter the immune response and potentially influence the likelihood of hypersensitivity reactions. Future case studies focusing on the safety implications of such therapeutic switches, particularly in relation to allergic manifestations, are warranted to enhance our understanding and optimize treatment strategies in clinical practice.

Clinical implications

• Switching between CGRP-mAbs is a common strategy for non-responders, though allergic cross-reactivity remains a theoretical concern.

• A case with switching of anti-CGRP-mAbs from fremanezumab to galcanezumab was described, wherein the patient experienced skin rash and dyspnea.

• Further investigations are needed to assess the safety and risks associated with switching CGRP-mAbs.