Long-Term Safety of Anti-CGRP Monoclonal Antibodies

Posted on January 04 2026, By: Cerebral Torque

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Long-Term Safety of Anti-CGRP Monoclonal Antibodies

What we know about using erenumab, galcanezumab, fremanezumab, and eptinezumab for 12+ months
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Quick Navigation - CGRP mAb Long-Term Safety
Introduction & Background Key Findings Discontinuation Rates Adverse Events Profile Results by Medication Time Trends Comparison to Oral Preventives Study Limitations Clinical Implications Conclusions

Introduction: Why Long-Term Safety Matters

Anti-CGRP monoclonal antibodies have transformed migraine prevention since erenumab's launch in 2018. These medications - including erenumab, galcanezumab, fremanezumab, and eptinezumab - work by blocking either CGRP itself or its receptor, targeting a key pathway in migraine development.

Given that migraine is a chronic condition affecting over one billion people globally, many patients will use these medications for years. This makes understanding their long-term safety profile particularly important. Unlike traditional oral preventives, these antibodies have longer plasma half-lives of approximately 28 days, resulting in sustained systemic exposure.

About This Research

A recent systematic review and meta-analysis published in The Journal of Headache and Pain synthesized data from 11 studies spanning over 4,300 patients to evaluate the long-term safety of anti-CGRP mAbs. This is the first comprehensive review analyzing all four approved medications with treatment durations of 12 months or longer.

The Four Anti-CGRP Monoclonal Antibodies

Erenumab (Aimovig) - Targets the CGRP receptor; given as monthly subcutaneous injection

Galcanezumab (Emgality) - Targets CGRP ligand; given as monthly subcutaneous injection

Fremanezumab (Ajovy) - Targets CGRP ligand; available as monthly or quarterly subcutaneous injection

Eptinezumab (Vyepti) - Targets CGRP ligand; given as quarterly intravenous infusion

Key Findings: The Bottom Line

The analysis found that these medications show good long-term tolerability, with low rates of discontinuation due to side effects. Here's what the numbers tell us:

23%
Overall Discontinuation
Patients who stopped treatment for any reason (including lack of efficacy, personal choice, and other factors)
3%
AE-Related Discontinuation
Patients who stopped specifically due to adverse events - a reassuringly low number
4,379
Total Participants
Across 11 studies with observation periods ranging from 48 to 256 weeks
<5%
Stable AE Discontinuation
Rate remained below 5% even beyond the first year of treatment

What This Means

The gap between overall discontinuation (23%) and discontinuation due to adverse events (3%) is significant. Most patients who stop treatment do so for reasons other than side effects - primarily lack of efficacy or personal decision. This suggests that when these medications work for a patient, they're generally well-tolerated long-term.

Understanding Discontinuation Rates

Looking at why patients stop treatment provides valuable insights for clinical practice. The research found that discontinuation patterns varied based on several factors.

Reasons for Treatment Discontinuation
Adverse Events 3% (pooled)
Lack of Efficacy Frequently reported
Patient Decision Frequently reported
New Therapy Initiation Occasionally reported
Loss to Follow-up Occasionally reported

One study stood out with an 18% adverse event-related discontinuation rate, but this was in a particularly treatment-resistant population - patients with chronic migraine who had failed at least three prior preventive medications. This real-world cohort likely reflects patients with more complex migraine patterns who may be more sensitive to medication effects.

Administrative Factors

The research notes that reimbursement regulations, while not explicitly reported in studies, may also influence real-world discontinuation rates. Insurance requirements for prior authorization or step therapy could affect treatment patterns in ways not captured by clinical trial data.

Adverse Events: What to Expect

The analysis grouped adverse events by type and found that most occurred at relatively low rates. Importantly, the majority were non-serious and didn't require stopping treatment.

Adverse Event Incidence by Category

Pooled incidence rates from long-term studies, showing which side effects are most commonly reported with anti-CGRP mAb treatment.

Adverse Event Category Pooled Incidence Clinical Notes
Upper Respiratory Tract Infection 20.4%(95% CI: 4.3-59.2%) Most frequently reported AE; also common in placebo groups. American Headache Society notes infections are not considered a major safety concern in clinical practice. Many studies were conducted during COVID-19 pandemic.
Pain-Related Symptoms 3.8%(95% CI: 1.6-9.0%) Includes various pain complaints beyond headache
GI/Abdominal Symptoms 2.5%(95% CI: 0.8-7.8%) Includes nausea, abdominal discomfort
Constipation <3%(in this analysis) Lower than typically reported (10-20% for erenumab); may reflect underreporting in extension studies or selective continuation of tolerant patients
Headache-Related Symptoms <3% Paradoxical headache complaints
Neurological Symptoms <3% Various neurological complaints
Psychiatric Symptoms <3% Mood-related effects
Cardiovascular Symptoms <2% Rarely reported in this analysis
Skin Reactions <2% Injection site reactions more common with subcutaneous formulations
Hypersensitivity <2% Allergic-type reactions

Pharmacovigilance Insights

Post-marketing surveillance data provides additional context beyond clinical trials. These real-world reports indicate that constipation, injection site reactions, and alopecia are most common with erenumab; injection site reactions occur more frequently with galcanezumab and fremanezumab; and eptinezumab is more frequently associated with fatigue and throat-related symptoms. Some signals like alopecia and palpitations appear in pharmacovigilance data but were less prominent in clinical trial reports.

Results by Medication

The meta-analysis included different numbers of studies for each medication, with erenumab having the most long-term data available. Here's how they compare:

AE-Related Discontinuation by Medication
Erenumab 4%
Galcanezumab 6%
Fremanezumab 4%
Eptinezumab 1%

Important Context

These differences were statistically significant (p < 0.001), but interpretation requires caution. Only erenumab results were based on multiple studies; the other medications had limited data from one or two studies each. The lower rate for eptinezumab may reflect its quarterly IV dosing (fewer total doses) or different patient populations in its studies.

Study Distribution by Medication

Overview of included studies showing the relative amount of long-term data available for each anti-CGRP mAb.

Medication Number of Studies Study Types Duration Range
Erenumab 7 studies Open-label extensions, real-world studies 52-256 weeks
Eptinezumab 2 studies Open-label phase 3, extension 48-96 weeks
Galcanezumab 1 study Open-label extension 48 weeks
Fremanezumab 1 study Real-world 96 weeks

Time Trends: Does Safety Change Over Time?

One of the key questions about long-term treatment is whether new problems emerge with extended use. The analysis looked at how adverse event rates changed over time.

<5%
AE Discontinuation After Year 1
Rates remained consistently low beyond the first year of treatment
>70%
Any AE at Baseline
High initial incidence that did not meaningfully increase with longer follow-up
Stable Safety Profile

The data suggests that adverse event-related discontinuation remained stable after the first year, with no clear signs of increasing safety concerns over time. While most patients reported at least one adverse event at some point, the majority were non-serious and didn't require stopping treatment. Some real-world cohorts showed higher early discontinuation that then plateaued, likely reflecting initial patient selection and monitoring.

No New Adverse Event Types

An important finding: no new types of adverse events emerged with longer treatment duration. The side effects seen in longer studies were the same ones already reported in shorter clinical trials. This provides reassurance that extended use doesn't appear to uncover previously unknown safety concerns.

Comparison to Traditional Oral Preventives

To put these numbers in context, it helps to compare them to traditional oral migraine preventives like propranolol, amitriptyline, and topiramate.

Discontinuation Rates Comparison
Traditional Oral Preventives (6 months) 21-81%
Traditional Oral Preventives (12 months) 45-93%
Anti-CGRP mAbs (12+ months) 23% overall, 3% AE-related

The contrast is striking. Traditional oral preventives have historically been associated with limited efficacy, poor tolerability, and high discontinuation rates. Anti-CGRP mAbs maintain much lower discontinuation rates even when patients are treated for significantly longer periods.

Why the Difference?

Several factors may contribute to better tolerability: targeted mechanism of action (affecting only the CGRP pathway rather than multiple neurotransmitter systems), monthly or quarterly dosing (avoiding daily medication burden), and the lack of typical oral medication side effects like sedation, weight gain, or cognitive effects. This has led professional guidelines, including from the American Headache Society, to recommend CGRP-targeting therapies as a first-line option for migraine prevention.

Study Limitations: What We Don't Know

While the findings are encouraging, the research has important limitations that should inform how we interpret the results.

Key Limitations
Limited Data for Some Medications

Data for fremanezumab, galcanezumab, and eptinezumab came from only one or two long-term studies each, restricting the robustness and generalizability of estimates for these medications.

Selection Bias in Extension Studies

Open-label extension trials only enrolled patients who tolerated and benefited from treatment during the initial randomized phase. This selective continuation of responders inherently underestimates discontinuation and may obscure safety signals that would emerge in a broader population.

Heterogeneous Reporting

Studies used different thresholds for reporting adverse events (some captured all events, others only those occurring in >5% of patients or ≥4 events per 100 patient-years). This makes direct comparisons challenging.

COVID-19 Pandemic Impact

Eight of eleven included studies were conducted during the pandemic, which may have increased respiratory infection rates and affected follow-up procedures. Only two studies explicitly distinguished COVID-19 from other respiratory infections.

Risk of Bias

All included studies were judged to have serious overall risk of bias using the ROBINS-I assessment tool. For open-label extensions, the main concerns were selective participant enrollment and unblinded outcome measurement. For real-world studies, confounding due to non-random treatment assignment was the primary issue. These limitations don't invalidate the findings, but they mean results should be interpreted cautiously.

What This Means for Clinical Practice

Despite limitations, this research provides useful guidance for clinicians and patients considering long-term CGRP mAb treatment.

For Healthcare Providers

  • Counsel patients that if they tolerate these medications initially, long-term tolerability is likely to remain good
  • Set realistic expectations - while side effects are generally mild, some patients (especially those with treatment-resistant migraine) may have higher discontinuation rates
  • Monitor consistently even after the first year, but don't expect new types of adverse events to emerge
  • Consider switching between different anti-CGRP mAbs if one isn't tolerated, as adverse event profiles may differ

For Patients

If you've been doing well on an anti-CGRP medication, the evidence suggests you can likely continue long-term without expecting significant new problems to develop. The 3% discontinuation rate due to side effects is reassuring. However, stay in communication with your healthcare provider about any new symptoms, as individual responses can vary.

Future Research Needs

The authors highlight several areas needing more investigation:

  • More long-term studies for galcanezumab, fremanezumab, and eptinezumab
  • Registry-based real-world surveillance extending beyond clinical trial populations
  • Better characterization of patients by demographic factors and reasons for discontinuation
  • Direct comparisons between medications in head-to-head long-term studies
  • Studies specifically designed to detect rare or late-emerging adverse events

Conclusions

This comprehensive meta-analysis provides the most complete picture to date of what happens when patients use anti-CGRP monoclonal antibodies for a year or longer.

Key Takeaways
Overall Tolerability Good
AE-Related Discontinuation Consistently low (3%)
New Safety Signals None detected
Adverse Event Types Mostly mild, non-serious
Safety Over Time Stable profile
Evidence Quality Limited, needs more studies

The bottom line: anti-CGRP mAbs appear to be well-tolerated for long-term use, with most patients who respond initially able to continue treatment without significant safety concerns. While the evidence base still has gaps - particularly for medications other than erenumab - the available data supports their use as a durable preventive option for migraine.

"These findings provide some evidence for the sustained good tolerability of anti-CGRP (receptor) mAbs in clinical practice, while underscoring the need for further clinical studies and continued real-world surveillance to detect rare outcomes and evaluate long-term safety."
Important Medical Disclaimer

This information is for educational purposes only and should not replace professional medical advice, diagnosis, or treatment. Always consult with a qualified healthcare provider before starting, stopping, or changing any medication. Individual responses to treatments may vary.

References

  1. Hoehne CL, Overeem LH, Sanchez-Del-Rio M, et al. Decoding the long-term safety of anti-CGRP (receptor) mAbs: a meta-analysis and systematic review. J Headache Pain. 2025. https://doi.org/10.1186/s10194-025-02256-0
  2. Ashina M, Katsarava Z, Do TP, et al. Migraine: epidemiology and systems of care. Lancet. 2021;397:1485-95.
  3. Ornello R, Caponnetto V, Ahmed F, et al. Evidence-based guidelines for the pharmacological treatment of migraine, summary version. Cephalalgia. 2025;45:03331024251321500.
  4. Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache. 2024;64:333-41.
  5. Hepp Z, Bloudek LM, Varon SF. Systematic Review of Migraine Prophylaxis Adherence and Persistence. J Manag Care Pharm. 2014;20:22-33.
  6. Aleksovska K, Hershey AD, Deen M, et al. Efficacy and safety of monoclonal antibodies targeting CGRP in migraine prevention. GRADE tables elaborated by the ad hoc working group of the International Headache Society. Cephalalgia. 2023;43:03331024231206162.
  7. Straburzyński M, Kopyt D, Marschollek K, et al. Increased infection risk in patients on preventive CGRP-targeting therapies - a meta-analysis and clinical effect assessment. J Headache Pain. 2025;26:88.
  8. Sun W, Li Y, Xia B, et al. Adverse event reporting of four anti-Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: a real-world study based on the FDA adverse event reporting system. Front Pharmacol. 2024;14:1257282.

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