The key role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine has led to the development of multiple therapies targeting the CGRP pathway.^1,2 Several agents have been approved based on favorable efficacy and safety data from clinical trials.¹ However, the extensive physiological roles of CGRP suggest that blocking this key peptide may have potential safety implications, particularly with long-term use.³ So, what do the latest data indicate regarding the safety of CGRP pathway targeting therapies, and are there any differences between the safety profiles of the different types of agents?

Therapies targeting the CGRP pathway for migraine therapy

Currently available therapies targeting the CGRP pathway for migraine treatment can be divided into orally administered small molecules, or gepants, and monoclonal antibodies (mAbs).^2,4 The latter category includes mAbs targeted to CGRP ligand or to the CGRP receptor.^2,4 Although these agents all target the CGRP pathway, they may have different mechanisms of action that could result in distinctive side effect profiles.⁴ 

Physiological roles of CGRP may be affected by therapies targeting the CGRP pathway 

Therapies targeting the CGRP pathway are unlikely to be able to cross the blood–brain barrier, so neurological effects would be expected to occur outside this protected region.^2,3 This includes the anterior pituitary, which contains CGRP receptors. The role of these CGRP receptors, however, remains to be elucidated.^2,3 Therefore, there is potential for therapies targeting the CGRP pathway to affect homeostatic functions regulated by pituitary hormones.³ In the gastrointestinal (GI) tract, CGRP receptors are present in the enteric nervous system, where CGRP plays a role in motility; antagonism of this function could result in diarrhea or constipation.^2,3 Inhibiting the CGRP role in the mucosal integrity of the GI tract may contribute to inflammatory bowel disease.^2,3 In the cardiovascular system, the vasodilatory properties of CGRP have multiple functions, including protection against hypertension, pulmonary arterial hypertension, and coronary ischaemia.^2,3 In the kidneys, CGRP may regulate blood pressure, thereby protecting against hypertensive-related renal disease.² CGRP is also a mediator of wound healing, regulating numerous processes including keratinocyte maturation and migration; additional effects in the skin include promotion of inflammatory reactions, which may affect conditions such as psoriasis and atopic dermatitis.^2,3 As CGRP promotes osteoblast differentiation and inhibits osteoclast genesis, CGRP antagonism has the potential for osteoporosis.²

Short-term safety data from clinical trials of therapies targeting the CGRP pathway

Early studies of some gepants for the treatment of migraine were discontinued following reports of unacceptable levels of liver toxicity.^2,3 However, liver toxicity has not been reported with subsequent gepants, or with mAb therapies targeting the CGRP pathway.³ Indeed, both these types of agents have very favorable safety profiles in addition to demonstrated efficacy in migraine prevention.⁵ The most common adverse events reported with mAbs or gepants targeting the CGRP pathway include: injection site pain or reactions, nasopharyngitis, sinusitis, upper respiratory tract infection, back, neck and extremity pain, urinary tract infection, fatigue, dizziness, nausea, and vomiting.^2,5,6 An additional GI side effect, constipation, has also been reported in some clinical trials of agents targeting the CGRP pathway. Reported rates of constipation in phase III trials varied between agents, with values ranging from 1.6–7.7%, although it should be noted that many studies did not report constipation at all or reported rates similar to those seen in placebo-treated patients.⁷ However, cardiovascular adverse events have not been reported in short-term trials of each type of agent.^5,6

Long-term and post-marketing safety data for therapies targeting the CGRP pathway

Although the safety profiles of all agents were favorable in short-term studies, some adverse effects of CGRP blockade might only become apparent with long-term use. Most available long term clinical trial data are for mAbs targeting the CGRP pathway, with reported safety results consistent with the short-term studies.^8–10 Some cardiovascular adverse events, including hypertension, were detected with long-term use, but most cases were of mild or moderate severity.^8,10 Hypertension was also reported in post-marketing data for one mAb targeting the CGRP receptor, with analysis indicating this adverse event occurred in some patients with either pre-existing hypertension, or in those who had established risk factors.¹¹ Outcomes from a recent study investigating the impact of CGRP pathway mAbs on blood pressure in the real-world setting (N=196) reported that this treatment was associated with an increase in mean systolic and diastolic blood pressure at all time points compared with baseline.¹¹ The majority of patients in the study remained within normal blood pressure limits, however, four patients with normal blood pressure at baseline required antihypertensive treatment.¹¹ Therefore, it is important for healthcare providers to be aware of the possibility that patients with migraine receiving treatment with CGRP receptor mAbs may be at increased risk of developing hypertension.¹¹

Investigation of new adverse drug events reported to the US Food and Drug Administration for one mAb therapy targeting the CGRP receptor also detected a potential signal for cardiac arrhythmia.¹² However, the most striking safety finding from post marketing studies of both types of mAb therapies targeting the CGRP pathway was the higher incidence of constipation when compared with that seen in pre-approval clinical trials.^7,12 

Future perspectives

To date, safety data for therapies targeting the CGRP pathway do not show manifestations, other than GI adverse events, that reflect the multiple roles of the CGRP in human physiology and the potential for off-target toxicities.^2,7 One potential explanation for this is that compensatory mechanisms exist that are replacing some of the CGRP functionality.² Alternatively, it is possible that there are still insufficient data for signals to emerge.^2,5 Although the varied mechanisms of action of these agents could result in differing safety and tolerability profiles,⁴ there is currently no clear evidence that this occurs. Long-term data for all therapies targeting the CGRP pathway in migraine therapy are required to provide a more complete picture of their side effect profiles.^2,5 

References

1. Kumar A, Williamson M, Hess A, DiPette DJ, Potts JD. Alpha-calcitonin gene related peptide: new therapeutic strategies for the treatment and prevention of cardiovascular disease and migraine. Front Physiol 2022;13:826122.
2. Ray JC, Kapoor M, Stark RJ, et al. Calcitonin gene related peptide in migraine: current therapeutics, future implications and potential off-target effects. J Neurol Neurosurg Psychiatry 2021;92:1325.
3. Deen M, Correnti E, Kamm K, et al. Blocking CGRP in migraine patients - a review of pros and cons. J Headache Pain 2017;18:96.
4. Bhakta M, Vuong T, Taura T, Wilson DS, Stratton JR, Mackenzie KD. Migraine therapeutics differentially modulate the CGRP pathway. Cephalalgia 2021;41:499.
5. Rivera-Mancilla E, Villalón CM, MaassenVanDenBrink A. CGRP inhibitors for migraine prophylaxis: a safety review. Expert Opin Drug Saf 2020;19:1237.
6. Mavridis T, Deligianni CI, Karagiorgis G, Daponte A, Breza M, Mitsikostas DD. Monoclonal antibodies targeting CGRP: from clinical studies to real-world evidence-what do we know so far? Pharmaceuticals 2021;14:700.
7. Holzer P, Holzer-Petsche U. Constipation caused by anti-calcitonin gene-related peptide migraine therapeutics explained by antagonism of calcitonin gene-related peptide's motor-stimulating and prosecretory function in the intestine. Front Physiol 2022;12:820006.
8. Goadsby PJ, Silberstein SD, Yeung PP, et al. Long-term safety, tolerability, and efficacy of fremanezumab in migraine: a randomized study. Neurology 2020;95:e2487.
9. Ashina M, Goadsby PJ, Reuter U, et al. Long-term efficacy and safety of erenumab in migraine prevention: results from a 5-year, open-label treatment phase of a randomized clinical trial. Eur J Neurol 2021;28:1716.
10. Dodick DW, Tepper SJ, Ailani J, et al. Risk of hypertension in erenumab-treated patients with migraine: analyses of clinical trial and postmarketing data. Headache 2021;61:1411.
11. de Vries Lentsch S, van der Arend BWH, MaassenVanDenBrink A, Terwindt GM. Blood pressure in patients with migraine treated with monoclonal anti-CGRP (receptor) antibodies. Neurology 2022;99:e1897–904.
12. Macdonald IAW, Gaigher I, Gaigher R. New drugs for flu, migraines. QuarterWatch (Inst Safe Med Pract) 2019.

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