"Longitudinal Analysis of Amylin Levels in Migraine Patients Undergoing an Anti- CGRP/CGRPr Treatment"

While the discovery of calcitonin gene-related peptide (CGRP) and its role in migraine has offered important insights into the condition and currently offers an effective pharmacological target for many patients, it fails to explain the variability of this complex disorder (Ashina et al. 2021). Unsurprisingly, some patients do not benefit from the use of anti-CGRP therapies (Caronna et al. 2024), gepants and/or monoclonal antibodies (mAb), raising the question of what else we are missing in the migraine pathophysiology, and whether other targets could complement the current treatment options (Rees et al. 2022).

In this context, different research studies have pointed to a wide range of candidates, though results remain inconclusive (Silvestro et al. 2023). One of the most promising candidates is amylin, a 37-amino acid peptide (Hay 2017), which is a member of the calcitonin family, where CGRP is also found. In fact, the existence of a relationship between CGRP and amylin is well documented, as these two molecules show some promiscuity with each other's receptors. Specifically, the receptor for amylin shares the same affinity for its canonical ligand (CGRPr) as it has for CGRP (Hay et al. 2018). Besides the signalling overlap found between CGRP and amylin there are some other features that indicate a possible implication of this endocrine peptide in migraine. The expression of both ligand and receptor, although it is primarily found in the pancreas, where amylin develops its main function as glucose-lowering hormone (Lutz 2005), is not limited to it. Amylin and its receptor are also expressed in migraine relevant sites, including sensory neurons (Mulder et al. 1995) and the trigeminovascular system (Hendrikse et al. 2019). Moreover, amylin is also implicated in pain processing, a key feature of migraine pathophysiology, despite its precise role within pain mechanisms is poorly understood (Hay et al. 2017). Overall, the knowledge we currently got about amylin, its overlapping signalling, locations, and functions, clearly points to a degree of implication for the molecule or its receptor in the pathophysiology of the migraine attack, although its precise involvement remains undescribed and still has a lot of questions remaining to be answered.

Over the last few years, efforts have been made to advance our knowledge about the relevance of amylin receptor-dependent pathways in migraine (Russo & Hay 2023). Provocation studies in mice support a role of the peptide in inducing cutaneous sensitivity and photophobia (De Logu et al. 2019; Ghanizada et al. 2021), providing proof of principle that amylin and CGRP might have overlapping functional roles. When we focus on humans, a Danish clinical trial study found that the infusion of pramlintide, an amylin receptor agonist used in clinical practise for the treatment of diabetes, in a group of patients diagnosed with migraine without aura provoked immediate headache and migraine-like headache in a very similar proportion and characteristics to the ones produced by the infusion of CGRP in the same subjects (Ghanizada et al. 2021). It also showed that despite a third of patients who developed migraine-like attacks did so with both molecules there was an important proportion who were only sensitive to either amylin or CGRP, but this observation requires further investigation.

Complementary to these data, there is a case-control study which investigated the interictal levels of amylin and CGRP in a group of patients with episodic or chronic migraine (Irimia et al. 2021). The research found both peptide concentrations were increased only in the chronic migraine group when compared to controls and patients with episodic migraine. Although the main aim of this research was to evaluate the usefulness of amylin as a biomarker for chronic migraine it raised the question of whether amylin could be playing a role in migraine chronification, similarly to what has been hypothesized with CGRP (Torres-Ferrús et al. 2023). To this date, there is not any additional study which has confirmed/refuted these findings, so their conclusions should be taken carefully.

Lastly, we have the evidence coming from studies evaluating the impact of mAbs targeting the free ligand or the CGRP. Real word data reveal that these two different approaches have almost identical rates of efficacy (Haghdoost et al. 2023). This initially came as a surprise as the different targeting of these therapeutic agents could provide different outcome rates. Blocking CGRP itself acts on both the canonical receptor but also on the amylin receptor, whose signalling would now solely depend on the amylin itself. On the other side, targeting the classical receptor of CGRP theoretically would still allow the interaction of the ligand with the amylin receptor, although recent studies have found that erenumab also interacts with this receptor, but with a lesser selectivity than it has with CGRPr (Garelja et al. 2024). The question of whether this newly described interaction has a meaningful effect on amylin receptor signalling is still a mystery. Moreover, several studies have evaluated the concentrations of CGRP in chronic migraine during the course of mAb therapies (Alpuente et al. 2022; Raffaelli et al. 2023), and it has been showed a link between higher basal interictal concentrations of alpha-CGRP and a tendency to have a better response to the therapies independently of their mechanism of action (Alpuente et al. 2022; Gárate et al. 2023), but there is a lack of explanation specifically linked to the CGRP-levels to why almost half of the patients do not benefit from the medication. Finally, not all patients have elevated levels of CGRP (Gárate et al. 2024), as the large dispersion of data found across studies found proves, and taking all the data together, a plausible explanation would be that some of the migraine attacks, if not the migraine condition itself, could be CGRP-independent in some of the patients, and consequently depend on other molecules.