Understanding Gepants

Unlike traditional migraine medications, gepants work as small-molecule CGRP receptor antagonists, providing both acute treatment and preventive options (dependent upon the gepant) for migraine patients.

The development of gepants has provided clinicians and patients with new therapeutic options that work differently from traditional treatments like triptans or ergot derivatives.

The Science Behind CGRP and Migraine

CGRP release during migraine attacks causes several processes including downstream vasodilation, mast cell degranulation, plasma protein extravasation, and ultimately pain transmission. This understanding has led to the development of targeted therapies that can block CGRP effects at the receptor level.

Currently Available Gepants

Several gepants have been developed and approved for clinical use, each with distinct pharmacological profiles and indications. The currently available gepants include medications for both acute treatment and prevention of migraine attacks.

Ubrogepant (Ubrelvy®): The First Oral Gepant

Ubrogepant (Ubrelvy®, MK-1602) was the first gepant approved by the FDA in 2019 for acute treatment of migraine in adults. It is a selective, potent, and competitive human oral CGRP receptor antagonist that has undergone extensive clinical testing.

The pharmacokinetic profile of ubrogepant includes a bioavailability of 1.5 hours to maximum concentration, 87% protein binding, metabolism by CYP3A4, and an elimination half-life of 5-7 hours. Excretion occurs through both hepatic and renal pathways, making dose adjustments necessary for patients with significant hepatic impairment.

Rimegepant (Nurtec ODT®): Dual-Purpose Migraine Treatment

Rimegepant (Nurtec ODT®, BMS-927 is approved for both acute treatment and preventive treatment of migraine, making it the first gepant with dual indications.

For preventive treatment, rimegepant demonstrated significant efficacy in reducing monthly migraine days (MMDs) when taken every other day. In preventive studies, rimegepant was more effective than placebo at reducing the number of MMDs, with beneficial effects maintained over longer treatment periods up to 52 weeks.

Rimegepant is a useful option for the management of migraine in adults, offering both acute relief and preventive benefits with a favorable safety profile and no evidence of hepatotoxicity or cardiovascular toxicity in clinical trials.

Zavegepant (Zavzpret®): The Gepant Nasal Spray

Zavegepant (Zavzpret®) is the most recent addition to the gepant family and was approved by the FDA in 2023 for acute treatment of migraine with or without aura in adults. What sets zavegepant apart is its intranasal delivery system, which offers several advantages over oral medications.

Zavegepant 10 mg is administered as a nasal spray and reaches peak plasma concentration at approximately 30 minutes with a bioavailability of around 5%. Clinical studies have demonstrated that zavegepant is effective and well tolerated for treatment of acute migraine attacks.

Atogepant (Qulipta®): Prevention-Focused Treatment

Atogepant (Qulipta®) was the first gepant developed exclusively for preventive treatment of migraine. It was tested in different doses and timeframes, with a phase 2/3 trial evaluating the time course of effect for migraine prevention. The medication is an important advance in oral preventive migraine therapy.

Study participants had an average age of 42 years and were predominantly female (88%). All participants had a history of chronic migraine for 1 year or more. The study evaluated two doses (30 mg twice daily and 60 mg once daily) in a 1:1 ratio, with results showing mean differences from placebo of -2.4 MMDs in the 30 mg twice daily atogepant group and -1.8 MMDs in the 60 mg once daily atogepant group.

Clinical Advantages of Gepants

Gepants offer several distinct clinical advantages over traditional migraine treatments, making them valuable additions to the therapeutic toolbox. These benefits extend beyond efficacy to include safety, tolerability, and suitability for diverse patient populations.

Patient Selection and Clinical Considerations

Proper patient selection is crucial for optimizing gepant therapy outcomes. These medications offer particular advantages for specific patient populations and clinical scenarios that make them preferred choices over traditional migraine treatments.

Gepants may also be a suitable option for patients planning to conceive given their relatively short half-lives compared to monoclonal antibodies, which have half-lives of 3-4 weeks. This contrasts favorably with the longer-acting CGRP monoclonal antibodies and provides more flexibility for family planning decisions.

Mechanism of Action: How Gepants Work

Understanding the precise mechanism of action of gepants helps explain their clinical efficacy and safety profile. These small-molecule antagonists work by competitive binding to the CLR/RAMP1 receptor complex, effectively blocking CGRP's ability to trigger the cascade of events that lead to migraine pain.

When CGRP binds to its receptor, it activates the Gαs subunit, which subsequently activates adenylyl cyclase. This activation results in adenosine triphosphate (ATP) being catalytically converted to the secondary messenger cyclic adenosine monophosphate (cAMP). The increase in cAMP has several intracellular effects, with the most important being activation of protein kinase A (PKA).

The competitive nature of gepant binding means that these medications can effectively prevent CGRP from activating receptors during migraine attacks. This targeted approach explains why gepants can provide relief without the broader systemic effects seen with some traditional migraine medications.

Clinical Efficacy Data and Real-World Performance

The clinical development program for gepants has been extensive, with multiple phase 2 and phase 3 trials demonstrating consistent efficacy across different patient populations and migraine subtypes. The real-world performance of these medications has generally matched the controlled trial data.

Post-hoc analyses of clinical trial data have provided additional insights into gepant efficacy. For example, rimegepant studies showed that the medication was effective in patients with a history of insufficient response to multiple triptans, suggesting that gepants may fill an important treatment gap for difficult-to-treat patients.

The consistency of efficacy data across different gepants and study populations suggests that CGRP receptor antagonism is a robust therapeutic approach for migraine treatment and prevention.

Safety Profile and Adverse Events

The safety profile of gepants has been one of their most substantial advantages, with clinical trials consistently showing good tolerability and minimal serious adverse events. The most common adverse events reported across gepant studies have been mild to moderate and have not led to significant discontinuation rates.

Importantly, no serious adverse events have been reported across the major gepant clinical trial programs. There have been no cardiovascular issues, no evidence of hepatotoxicity with second-generation gepants, and no safety signals that would limit their use in most patient populations.

Clinical Practice Integration

Successful integration of gepants into clinical practice requires understanding their optimal use patterns, patient selection criteria, and positioning relative to other migraine treatments. These medications are both standalone options and components of comprehensive migraine management strategies.

The choice between different gepants should be individualized based on patient preferences, clinical characteristics, and treatment goals. For patients requiring both acute and preventive treatment, rimegepant's dual indication may offer convenience and treatment continuity advantages.

"Gepants are a new type of migraine medication that work differently from older treatments. They block a specific pathway that causes migraine attacks and have fewer side effects than many traditional options. For people who haven't had success with other migraine medications, gepants offer new hope and more personalized treatment choices." - Cerebral Torque