The impact of CGRPergic monoclonal antibodies on prophylactic antimigraine therapy and potential adverse events

ABSTRACT

Migraine is a prevalent medical condition and the second most disabling neurological disorder. Regarding its pathophysiology, calcitonin gene-related peptide (CGRP) plays a key role, and, consequently, specific antimigraine pharmacotherapy has been designed to target this system. Hence, apart from the gepants, the recently developed monoclonal antibodies (mAbs) are a novel approach to treat this disorder. In this review we consider the current knowledge on the mechanisms of action, specificity, safety, and efficacy of the above mAbs as prophylactic antimigraine agents, and examine the possible adverse events that these agents may trigger. Antimigraine mAbs act as direct scavengers of CGRP (galcanezumab, fremanezumab, and eptinezumab) or against the CGRP receptor (erenumab). Due to their long half-lives, these molecules have revolutionized the prophylactic treatment of this neurovascular disorder. Moreover, because of their physicochemical properties, these agents are hepato-friendly and do not cross the blood-brain barrier (highlighting the relevance of peripheral mechanisms in migraine). Nevertheless, apart from potential cardiovascular side effects, the interaction with AMY₁ receptors and immunogenicity induced by autoantibodies against mAbs could be a concern for the safety of long-term treatment with these molecules.

KEYWORDS:

• CGRP
• eptinezumab
• erenumab
• fremanezumab
• galcanezumab
• migraine
• monoclonal antibodies
• pain
• trigeminovascular system

Article highlights

• Globally, migraine is one of the most prevalent medical conditions and the second most disabling neurological disorder. Its pathophysiology has been strongly linked with a dysfunction of the CGRPergic neurotransmission in the trigeminovascular system.

• Consequently, drugs that specifically target CGRPergic neurotransmission are considered potential antimigraine drugs.

• Current specific antimigraine pharmacotherapies can be divided into: (i) acute abortive drugs, e.g. ergots, triptans, gepants, and ditans; and (ii) prophylactic drugs, e.g. CGRPergic monoclonal antibodies (mAbs).

• The triptans (5-HT_1B/1D receptor agonists with pEC₅₀ values between 6.50 and 8.50 for 5-HT_1F receptors, such as sumatriptan and second-generation triptans) and ditans (5-HT_1F receptor agonists, such as lasmiditan) indirectly inhibit the release of CGRP from the trigeminovascular system, whereas the gepants (CGRP receptor antagonists) and mAbs were designed to directly target the CGRPergic transmission.

• In the case of mAbs, these agents act as direct scavengers of CGRP (galcanezumab, fremanezumab, and eptinezumab) or against the CGRP receptor (erenumab). Moreover, according to current randomized clinical trials (RCT’s) conducted in patients with episodic and chronic migraine, these mAbs possess a good safety and efficacy profile.

• Indeed, considering the chemical nature of mAbs, these molecules are devoid of liver toxicity and seem to exert their actions outside the central nervous system (CNS).

• In any case, since CGRP may play a role in modulating the cardiovascular and other systems (e.g. gastrointestinal and cutaneous), there may still be some concerns about the use of anti-CGRP molecules with a long half-life.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was supported by the Consejo Nacional de Ciencia y Tecnología (219707 to C.M.V., and A1-S-23631 to A.G-H.) and the SEP-Cinvestav Research Support Fund (Grant No. 50 to C.M.V.).