How do Calcitonin Gene-Related Peptide (CGRP) medications work?

From the Guidelines

CGRP medications work by blocking calcitonin gene-related peptide, a protein involved in pain transmission and blood vessel dilation during migraines, and include monoclonal antibodies and small molecule antagonists that prevent CGRP from binding to its receptors, thereby interrupting the cascade of events that lead to migraine pain. These medications, such as erenumab, fremanezumab, and galcanezumab, are given as monthly or quarterly injections, and have been shown to reduce migraine frequency when taken regularly 1. The small molecule antagonists, such as ubrogepant and rimegepant, are taken orally and are used for acute treatment when a migraine begins. CGRP plays a key role in migraine pathophysiology by causing neurogenic inflammation, sensitizing pain pathways, and dilating blood vessels in the brain. By preventing CGRP from binding to its receptors, these medications interrupt the cascade of events that lead to migraine pain, and have been shown to be effective in reducing migraine frequency and severity 1.

Some key points to consider when using CGRP medications include:

• They are generally well-tolerated, with mild side effects such as injection site reactions or nausea and fatigue
• They can be used in combination with other migraine treatments, such as triptans or ergots
• They may be effective in patients who have not responded to other preventive treatments
• They may have a favorable safety profile compared to other migraine treatments, such as opioids or barbiturates

It's worth noting that the evidence for CGRP medications is based on high-quality studies, including randomized controlled trials and meta-analyses, which have demonstrated their efficacy and safety in reducing migraine frequency and severity 1. Overall, CGRP medications represent a significant advance in migraine therapy, and can be a valuable treatment option for patients with migraine.

From the FDA Drug Label

Fremanezumab-vfrm is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor. Erenumab-aooe is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function.

CGRP Meds Mechanism of Action:

• CGRP meds, such as fremanezumab and erenumab, work by binding to CGRP ligand or receptor, thereby blocking its binding to the receptor and antagonizing CGRP receptor function.
• This blockage of CGRP is thought to be the mechanism by which these medications exert their clinical effects, although the exact relationship between pharmacodynamic activity and clinical effects is unknown 2 3.
• The medications are administered via subcutaneous injection and have been shown to have a long half-life, with fremanezumab having a half-life of approximately 31 days and erenumab having a half-life of approximately 28 days.
• Key points about CGRP meds include:
  • Mechanism of action: binding to CGRP ligand or receptor
  • Administration: subcutaneous injection
  • Half-life: approximately 28-31 days
  • Pharmacokinetics: non-linear kinetics due to binding to CGRP receptor 2 3

From the Research

Mechanism of Action

• CGRP meds work by targeting the calcitonin gene-related peptide (CGRP) ligands and CGRP receptors, which play a pivotal role in migraine pathophysiology 4
• There are two types of CGRP function-blocking modalities: monoclonal antibodies and small molecules (gepants) 4

Types of CGRP Meds

• Monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab have received FDA approval for the prevention of migraine 4
• Gepants: ubrogepant and rimegepant have been approved by the FDA for the acute treatment of migraine 4

Efficacy and Safety

• Clinical trials have established the efficacy, safety, and tolerability of CGRP monoclonal antibodies and gepants 4
• Network meta-analysis has shown that certain CGRP monoclonal antibodies (e.g. erenumab, fremanezumab, galcanezumab) are superior to placebo in reducing average migraine days per month 5
• Indirect comparison of topiramate and monoclonal antibodies against CGRP or its receptor has shown that the efficacy of CGRP(R) mAbs to reduce migraine days does not differ from topiramate, but the safety profile is in favor of the CGRP(R) mAbs 6

Switching CGRP Meds

• Switching anti-CGRP monoclonal antibodies in chronic migraine may be a viable option for individuals who experience ineffectiveness or adverse effects with their current treatment 7
• Real-world observations have shown modest improvements in headache outcomes when switching anti-CGRP-mAb, although significant results were only observed in those that switched due to ineffectiveness 7