Tolerability of calcitonin gene-related peptide monoclonal antibodies and other monoclonal antibodies in adults with concurrent migraine and other medical conditions

Abstract

Background/Hypothesis:

Calcitonin gene-related peptide monoclonal antibodies (CGRP mabs) are relatively new preventive treatments in adult migraine. Co-morbid medical conditions such as autoimmune or other neurologic/oncologic disorders are not uncommon in migraine patients and some exhibit notable co-morbidity such as asthma. These clinical conditions may necessitate concomitant treatment with another monoclonal antibody with a different mechanism of action other than the CGRP pathway in some individuals with migraine.

Methods:

We report a retrospective case series in 23 patients identified from our headache clinic treated concurrently with a CGRP monoclonal antibody and other monoclonal antibody for another medical condition. These other medical conditions were neurologic, oncologic, or autoimmune conditions. These patients were evaluated for tolerability, safety, and stability of disease processes including their migraine response.

Results/Conclusion:

We did not find evidence of new adverse or serious adverse side effects with coadministration of CGRP and non-CGRP monoclonal antibodies during our study time period of 13 months, for the duration of overlap between treatments (between 3 and 12 months).

Introduction

Current research elucidates that calcitonin-gene related peptide (CGRP) plays a pivotal role in migraine genesis. ¹ Recent development of the CGRP monoclonal antibodies is an important addition to the treatment paradigm for managing migraine preventive therapy in adults. ² There are four current CGRP monoclonal antibodies used in migraine prevention for the past several years including erenumab, fremenazumab, galcanezumab, and eptinezumab. They have demonstrated efficacy, tolerability, and safety when used in episodic and chronic migraine. More specific mechanism of action includes CGRP receptor binding in erenumab and binding to the CGRP ligand in the other CGRP monoclonal antibodies. ³

There has been utilization of monoclonal antibodies across all medical specialties including autoimmune disorders, asthma, neurology, and oncology. These have included asthma, eczema, rheumatoid arthritis, psoriasis, and gastrointestinal disease processes such as Crohn’s disease. Many of these conditions occur co-morbidly with migraine. The monoclonal antibodies have specific targeted mechanisms of action such as CGRP in migraine and others such as interleukin 23 and 12, tumor necrosis factor, or anti-myelin oligodendrocyte glycoprotein in other monoclonal antibodies. ^4,5

Further investigation is needed in using multiple monoclonal antibodies chronically in the same patient for different clinical conditions due to continued frequent use of these therapies. Evaluating tolerability in these patients is useful information with ever increasing use of the monoclonal antibodies for multiple disease processes. It can be assumed that monoclonal antibodies are appropriate for combination therapy due to their targeted mechanisms of action and lack of pharmacokinetic interactions; however, there is little data in the literature reporting these findings. ^6,7

Methods

We utilized a retrospective case series headache clinic chart review from our medical records (EPIC), identifying adult migraine patients from 18 to 70 years of age from our headache clinic. These patients presented between February 1, 2020 and March 31, 2021. Sample size was based on available data. Patients identified were undergoing treatment with a CGRP monoclonal antibody with concurrent diagnosis of cancer or autoimmune disease and also receiving treatment with a monoclonal antibody for their other disease process. The diagnosis of migraine was made using the International Classification of Headache Disorders-ICHD-3. ⁸ Approval for this study was obtained from our Institutional Review Board.

Demographic information obtained included age, sex, diagnosis of episodic versus chronic migraine, migraine frequency, monoclonal antibodies being used, and other disease condition treated. Tolerability of the combined therapy was obtained from the medical record visits.

Results

We identified 23 patients who were on both CGRP monoclonal antibodies for episodic or chronic migraine and one other monoclonal antibody for another medical condition (see Table 1). The patients’ ages were between 19 years old and 69 years old. Nineteen patients were female with four being male. Three of the patients were on fremanezumab, eight were on erenumab, eleven were on galcanezumab, and one was on eptinezumab. The other medical conditions than migraine requiring another monoclonal antibody were variable and included: ulcerative colitis (1), asthma (1), aortitis (1), hidradenitis suppurativa (1), rheumatoid arthritis (3), hyperlipidemia (1), stiff person syndrome (1), sarcoidosis (1), psoriatic arthritis (4), anti-myelin oligodendrocyte glycoprotein syndrome (1), Crohn’s disease (4), lymphoplasmacytic lymphoma (1), multiple sclerosis (2), and osteoporosis (1). The other monoclonal antibodies that were used in other medical conditions than migraine included: vedolizumab (1), omalizumab (1), tocilizumab (1), adalimumab (2), evolocumab (1), infliximab (5), rituximab (3), abatacept (2), etanercept (1), golimumab (1), ustekinumab (2), natalizumab (1), denosumab (1), and ocrelizumab (1). At the time of our investigation, the patients involved were on overlapping therapy with a CGRP monoclonal antibody and another monoclonal antibody between 3 months and 12 months. Prior to CGRP monoclonal antibody therapy, the patients, where the data was available, had an average total headache days per month of 22.3, and an average migraine days per month of 16.6. Following CGRP monoclonal antibody therapy, the patients had an average total headache days per month of 16.6, and an average migraine days per month of 9.8. Among all the patients, the only side effects reported were constipation, hair loss, and injection site reactions. There were no serious adverse events reported. In all 23 patients, they remained on the other non-CGRP monoclonal antibodies for the duration of overlap of treatment with CGRP monoclonal antibodies without adjustments in dosage or discontinuation of the non-CGRP antibody.

Table 1.

Patients on Dual Monoclonal Antibodies.

Age	Gender	Migraine diagnosis	CGRP ab name	Other monoclonal ab name	Side effects from CGRP monoclonal antibody	Other diagnosis requiring a monoclonal antibody	Tolerability/new side effects	Stability/dosing changes after initiation of CGRP	Overlap of treatments (if discontinue, list reason)
59	F	Chronic migraine with aura	Fremanezumab	Vedolizumab	None	Ulcerative colitis	None	Stable	3 months
43	F	Chronic migraine without aura	Eptinezumab	Omalizumab	None	Asthma	None	Stable	9 months
41	M	Chronic migraine without aura	Erenumab	Tocilizumab	None	Aortitis	None	Stable	6 months
45	F	Chronic migraine without aura	Galcanezumab	Adalimumab	Hair loss	Hydradinitis suppurativa	None	Stable	6 months (discontinued due to hair loss)
43	M	Chronic migraine without aura	Galcanezumab	Evolocumab	None	Hyperlipidemia	None	Stable	12 months
56	F	Episodic migraine without aura	Galcanezumab	Infliximab	None	Rheumatoid arthritis	None	Stable	12 months
65	M	Episodic migraine without aura	Galcanezumab	Rituximab	None	Stiff person syndrome	None	Stable	4 months
44	F	Chronic migraine without aura	Erenumab	Infliximab	None	Sarcoidosis	None	Stable	3 months
39	F	Chronic migraine with aura	Erenumab	Infliximab	None	Psoriasis with arthropathy	None	Stable	12 months
57	F	Chronic migraine without aura	Erenumab	Abetacept	None	Psoriatic arthritis	None	Stable	12 months
48	F	Chronic migraine without aura	Galcanezumab	Etanercept	None	Rheumatoid arthritis	None	Stable	3 months
19	F	Episodic migraine without aura	Erenumab	Golimumab	Constipation	Rheumatoid arthritis	None	Stable	3 months (discontinued due to constipation)
19	F	Chronic migraine without aura	Fremanezumab	Rituximab	None	Anti-myelin oligodendrocyte glycoprotein syndrome	None	Stable	3 months
22	F	Episodic migraine without aura	Galcanezumab	Infliximab	None	Crohn’s	None	Stable	12 months
23	F	Episodic migraine without aura	Erenumab	Infliximab	None	Crohn’s	None	Stable	12 months
60	F	Chronic migraine without aura	Erenumab	Ustekinumab	None	Crohn’s	None	Stable	3 months
69	F	Chronic migraine with aura	Galcanezumab and most recently Erenumab	Rituximab	None	Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic lymphoma)	None	Stable	6 months (discontinued due to ineffectiveness)
41	F	Chronic migraine without aura	Erenumab	Natalizumab	None	MS	None	Stable	6 months (discontinued due to insurance reasons)
68	M	Chronic migraine without aura	Galcanezumab	Adalimumab	None	Crohn’s	None	Stable	3 months
56	F	Chronic migraine with aura	Galcanezumab	Denosumab	None	Osteoporosis	None	Stable	12 months
55	F	Chronic migraine without aura	Galcanezumab	Abetacept	None	Psoriatic arthritis	None	Stable	12 months
53	F	Episodic migraine without aura	Fremanezumab	Ustekinumab	Injection site reactions	Psoriatic arthritis	None	Stable	6 months
50	F	Chronic migraine without aura	Galcanezumab	Ocrelizumab	None	MS	None	Stable	6 months

ab: antibody; CGRP: Calcitonin gene-related peptide; F: Female; M: Male; MS: Multiple sclerosis.

Discussion

Many migraine patients have other underlying medical conditions that may necessitate the use of monoclonal antibodies. Our data supports that CGRP monoclonal antibodies can be safe and well-tolerated when used in conjunction with other monoclonal antibodies. The only reported side effects found during our chart review were constipation, hair loss, and injection site reaction. These three side effects have been well described and widely reported with CGRP monoclonal antibodies alone, so it is unlikely that the reported side effects are related to the combination of monoclonal antibodies. Furthermore, no patients had adjustments in dosage or discontinuation of their other non-CGRP monoclonal antibodies for the duration of overlap of treatment.

Limitations of our study are that each side effect was counted quantitatively as opposed to any measure of qualitative severity, a limitation of the data interpretation. Qualitative metrics of the medication side effects in terms of frequency, intensity, and duration could be included in future studies. Also, we did not have access to all of the records from specialists/providers prescribing the other non-CGRP monoclonal antibody medications. It is possible that the patients did not report to our headache team side effects or lack of efficacy with the other monoclonal antibody medications, thinking it to be unrelated or irrelevant to their headache clinic visits. Future prospective studies could ask specific questions about side effects and efficacy of both monoclonal antibody medications. Our study patient number is small, heavily populated with women patients, and only within one institution, which could limit the generalizability of study. Our retrospective chart review design could easily be reproduced across multiple institutions to increase the sample size of the study. We also did not evaluate for race/ethnicity, limiting the generalizability of our study. This could be evaluated in further studies. Finally, headache and migraine day frequency was not collected on every single patient, nor was the duration of CGRP monoclonal antibody treatment consistent among patients, limiting the generalizability of our study in the context of CGRP monoclonal antibody efficacy. Future studies could monitor CGRP monoclonal antibody therapy for the standard 3-month period seen in previous clinical trials. We may have been more likely to choose monoclonal antibodies in patients already tolerating them due to familiarity with administration/patient preference/patient tolerability, creating selection bias. Also, the headache providers may have been biased to ask more about side effects on patients taking two monoclonal antibodies.

Theoretically, given CGRP monoclonal antibodies’ unique targeted mechanism of action targeting either CGRP itself or the CGRP receptor, it can be inferred that CGRP monoclonal antibodies would likely have minimal interaction with other monoclonal antibodies with different mechanisms of action. However, from our literature review, there was limited data reporting these findings. Further, ideally prospective investigation would be needed to establish statistical significance of any clinically significant crossover effects (or lack thereof) of combination monoclonal antibody therapy. The power of our data is obviously limited due to small sample size of 23, and further investigations are needed regarding the safety and tolerability of using multiple monoclonal antibodies for a single patient. Our data, however, is a good starting point for future investigations.

Clinical implications

• Many patients take both CGRP antibodies along with other monoclonal antibodies for other medical conditions. Our limited study found there to be tolerability of coadministration of these different antibodies.

• Future prospective studies could ask specific questions about side effects and efficacy of both monoclonal antibody medications.