CGRP Inhibitors and Their Mechanisms

Mechanism-Based Classification

• The American College of Physicians and the VA/DoD recommend fremanezumab, galcanezumab, and eptinezumab, which are humanized monoclonal antibodies that directly bind to the CGRP peptide itself, preventing it from activating its receptor and effectively reducing the amount of free, bioavailable CGRP, for prevention of episodic or chronic migraine based on their ability to reduce mean monthly migraine days through CGRP neutralization 1
• Erenumab, a monoclonal antibody that binds to the CGRP receptor, received a "strong for" recommendation but works by blocking receptor activation, not by reducing the peptide, and may increase risk for development or worsening of hypertension 1, 2

Clinical Implications

• The American College of Physicians gives atogepant a "weak for" recommendation and rimegepant a "neither for nor against" recommendation for episodic migraine prevention, as they are oral CGRP receptor antagonists that competitively block the CGRP receptor without affecting CGRP levels 3, 4
• All CGRP-targeting therapies show similar efficacy in reducing monthly migraine days by approximately 0.8-2.3 days compared to placebo, and the choice between agents should be guided by route of administration preference, cost considerations, and specific safety concerns like hypertension risk with erenumab 1, 3, 5

CGRP Inhibitors for Migraine Prevention and Treatment

Clinical Efficacy and Administration

• The American College of Physicians recommends CGRP-mAbs, which may reduce migraine frequency by 0.80 fewer days per month compared to topiramate (low-certainty evidence) 6
• The American College of Physicians recommends CGRP-mAbs, which may reduce migraine frequency by 0.76 fewer days per month compared to valproate (low-certainty evidence) 6
• Patients with migraine generally prefer oral treatments over injectables (moderate-certainty evidence) 6
• The annual costs for CGRP-mAbs and gepants range from $7,071 to $22,790, substantially higher than traditional preventive medications 6

CGRP Receptor Antagonists

• Atogepant is an oral CGRP receptor antagonist taken daily for episodic migraine prevention 6
• Rimegepant, Ubrogepant, and Zavegepant are oral CGRP receptor antagonists for acute episodic migraine treatment 7, 8

CGRP Inhibitors for Migraine Treatment

Introduction to CGRP Inhibitors

• The American College of Physicians recommends prescribing less costly medications when appropriate, with CGRP monoclonal antibodies (fremanezumab, galcanezumab, or eptinezumab) considered for third-line preventive therapy in adults with chronic or episodic migraine who have failed other treatments 9

Treatment Algorithm

• For acute episodic migraine, consider CGRP antagonist-gepants (rimegepant, ubrogepant, or zavegepant) for acute treatment if combination therapy with a triptan plus NSAID or acetaminophen has failed or is not tolerated 9
• The American College of Physicians suggests that patients with chronic migraine may benefit from topiramate as a first-line preventive option due to its lower cost 10

Migraine Prevention

• For episodic migraine prevention, atogepant (daily oral dosing) is effective, with a 60 mg dose showing the greatest reduction in monthly migraine days (mean difference -1.48 days) 10
• Topiramate is the preferred first-line preventive option for chronic migraine due to its lower cost 10

Special Populations

• In patients with obesity, consider topiramate preferentially due to its weight loss effects 10, 11
• For chronic migraine with medication overuse headache, rule out and manage MOH first through medication withdrawal, then initiate preventive therapy 10

Safety and Efficacy

• CGRP monoclonal antibodies may reduce migraine frequency by 0.76-0.80 fewer days per month compared to valproate or topiramate (low-certainty evidence) 10
• The American College of Physicians recommends discussing adverse effects of all pharmacologic treatments during pregnancy and lactation with patients of childbearing potential 9

Cost Considerations

• Oral gepants cost $4,959-$5,994 annually, while CGRP mAbs cost $7,071-$22,790 annually 10
• Insurance often requires failure of 2-3 traditional preventives before approving CGRP therapies 10

CGRP Inhibitors for Migraine Treatment

Current FDA-Approved Indications

• The American College of Physicians recommends CGRP-targeting therapies, such as gepants (rimegepant, ubrogepant, zavegepant) and lasmiditan, for acute episodic migraine headache attacks, with a strength of evidence based on FDA approval 12
• The American Academy of Neurology supports the use of monoclonal antibodies (fremanezumab, galcanezumab, eptinezumab, erenumab) and oral gepants (atogepant, rimegepant) for prevention of episodic or chronic migraine, as approved by the FDA 12

Migraine Management with Rimegepant and Galcanezumab

Treatment Strategy

• The American College of Physicians recommends using galcanezumab 120 mg subcutaneously monthly for migraine prevention, with rimegepant 75 mg orally as needed for acute breakthrough migraine attacks, based on a strong recommendation from the VA/DoD for prevention of episodic or chronic migraine 13, 14
• Galcanezumab has a strong recommendation from the VA/DoD for prevention of episodic or chronic migraine based on demonstrated reductions in mean monthly migraine days, with rimegepant used for acute treatment without dose adjustment when combined with galcanezumab 13, 14

Migraine Pathophysiology and Treatment

Neuropeptide Targets

• The American College of Physicians recommends CGRP monoclonal antibodies for prevention of episodic or chronic migraine, with CGRP receptor antagonists being FDA-approved for acute episodic migraine treatment 15
• CGRP is the most clinically significant neuropeptide in migraine pathophysiology, with robust evidence demonstrating its release during migraine attacks, its ability to trigger migraine when administered to patients, and the clinical success of CGRP-targeting therapies in both acute and preventive migraine treatment 16, 15
• CGRP levels are elevated in blood samples during migraine attacks, and effective triptan treatment normalizes these levels, establishing a correlation between CGRP levels and migraine severity 16
• CGRP-targeting therapies represent the only unambiguous pain drug development success story in recent decades, with a significant impact on migraine treatment 16