What are the potential long-term side effects of Fremanezumab (Erenumab) for preventive treatment of migraines?

Long-Term Side Effects of Fremanezumab

Fremanezumab demonstrates excellent long-term safety with minimal serious adverse events, primarily limited to injection site reactions, with no evidence of organ toxicity, cardiovascular complications, or significant immunogenicity over extended treatment periods up to 12-15 months. 1, 2

Most Common Long-Term Side Effects

Injection Site Reactions (Most Frequent)

• Injection site reactions are the predominant adverse effect, occurring in 43-45% of patients compared to 38% with placebo 1
• Specific reactions include:
  • Erythema (24% of patients) 2
  • Induration (10%) 2
  • Pain (8%) 2
  • Pruritus (6%) 2
• These reactions are typically mild and do not lead to treatment discontinuation in most cases 1, 2

Upper Respiratory Infections

• Nasopharyngitis was the most common non-injection-related adverse event, occurring in 64% of patients in long-term studies 2
• This rate is not substantially different from expected community rates and may not be directly drug-related 2

Serious Long-Term Safety Concerns

Hypersensitivity Reactions (Rare but Important)

• Anaphylactic reactions and angioedema have been reported in post-marketing surveillance, though the exact frequency cannot be reliably estimated 1
• These represent the most serious potential adverse events requiring immediate discontinuation 1

Hepatic Function

• Abnormalities of hepatic function occurred in only 1% of fremanezumab-treated patients versus <1% with placebo in controlled trials 3
• No pattern of liver toxicity has emerged with long-term use, distinguishing fremanezumab favorably from traditional preventive medications like valproate 4

Cardiovascular Safety

• Unlike erenumab (another CGRP-targeting therapy), fremanezumab has NOT been associated with development or worsening of hypertension in post-marketing studies 5, 6
• Theoretical concerns about vasoconstriction with CGRP blockade have not materialized clinically 6
• CGRP is involved in cardiovascular homeostasis, but targeting the peptide itself (rather than the receptor) appears to preserve other physiological pathways 4

Immunogenicity (Very Low Risk)

Anti-Drug Antibody Development

• Treatment-emergent anti-drug antibodies (ADA) developed in only 0.4% of patients (6 out of 1,701) in 3-month controlled trials 1
• In long-term open-label studies extending to 12 months, ADA were detected in only 1.6% of patients (30 out of 1,888) 1
• Of those who developed antibodies, only 17 patients showed neutralizing activity 1
• The incidence of anti-drug antibodies in Japanese patients over 52 weeks was similarly low at 2.4% 2
• Importantly, antibody development did not demonstrate impact on efficacy or safety, though data are limited 1

Discontinuation Rates (Remarkably Low)

Treatment Persistence

• Discontinuation due to adverse events was only 1% in controlled trials and 4% in long-term studies 1, 2
• Discontinuation due to lack of efficacy was only 2% over 12 months 2
• These exceptionally low discontinuation rates contrast sharply with traditional preventive medications like topiramate, which has 162 fewer discontinuations per 1,000 patients when compared to CGRP monoclonal antibodies 6

Long-Term Efficacy Maintenance (Sustained Benefits)

Duration of Effect

• Fremanezumab maintains efficacy throughout 12 months of treatment without evidence of tolerance or diminishing response 2, 7
• Reductions in monthly migraine days were evident from 1 month after initial administration and sustained through 12 months 2
• In the FOCUS study extending to 6 months, patients achieved mean reductions of 4.7-5.5 monthly migraine days that were maintained 7

Theoretical Long-Term Concerns (Not Yet Observed)

Physiological CGRP Functions

• CGRP is involved in multiple biological activities including cardiovascular function, gastrointestinal motility, and bone metabolism 4
• Long-term blockade of CGRP theoretically could affect these systems, but no clinical evidence of such effects has emerged in studies up to 15 months 1, 4
• Targeting CGRP peptide (rather than its receptor) may preserve alternative signaling pathways, potentially reducing risk of physiological disruption 4

Special Populations and Considerations

Pregnancy and Lactation

• Long-term safety data in pregnancy are not available 5
• Unlike valproate (which is absolutely contraindicated in women of childbearing potential), fremanezumab does not have this restriction, but caution is warranted 6

Pediatric Use

• Recent approval for use in children and adolescents represents unique positioning among migraine treatments 8
• Long-term safety data in this population are still emerging 8

Clinical Implications for Long-Term Use

Treatment Duration

• Efficacy should be assessed after 3-6 months, and treatment can be paused after 6-12 months of success to determine if preventive therapy can be discontinued 6
• This approach minimizes unnecessary drug exposure while maintaining therapeutic benefits 6

Monitoring Requirements

• No specific laboratory monitoring is required for fremanezumab, unlike traditional preventives that may require hepatic or hematologic surveillance 4
• Patients should be counseled about signs of hypersensitivity reactions 1