Cost-Effectiveness of CGRP Antagonists for Acute Migraine Treatment
Table of Contents
ABSTRACT
Objective: Migraine is a debilitating chronic disorder requiring multifaceted treatment approaches, including acute, preventive, and nonpharmacological interventions. Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, also referred to as gepants, provide third-line treatment options for patients refractory to first- and second-line therapies. This study evaluates the cost-effectiveness of 3 CGRP antagonists-ubrogepant (Ubrelvy), rimegepant (Nurtec ODT), and zavegepant (Zavzpret)-compared wiht usual care.
Study Design: Cost-effectiveness analysis of gepants vs usual care.
Methods: We used a Markov model to assess the cost-effectiveness from the US payer’s viewpoint, incorporating 5 health states: mild, moderate, and severe pain while on treatment; no pain while on treatment; and off treatment. The analysis was conducted over a 5-year time horizon with a 48-hour cycle length, discounting costs and quality-adjusted life-years (QALYs) annually at 3%. Scenario analyses were used to determine the robustness of the results.
Results: None of the gepants were cost-effective at willingness-to-pay thresholds of $50,000, $100,000, or $150,000 per QALY. Among the 3 gepants, rimegepant was the most cost-effective option; it had an incremental cost-effectiveness ratio of $93,700.20 per QALY compared with ubrogepant and was both less costly and more effective than zavegepant.
Conclusions: Ubrogepant, rimegepant, and zavegepant are not cost-effective options for acute migraine treatment but may be appropriate for patients experiencing 2 or fewer migraines per month. If a gepant is to be prescribed, rimegepant is the most cost-effective option of the 3.
Am J Manag Care.2025;31(11):In Press
Takeaway points
Gepants (ie, small-molecule calcitonin gene-related peptide receptor antagonists) may be potential options for treating acute migraine in patients refractory to triptans. We assessed the cost-effectiveness of 3 gepants in comparison to usual care for the treatment of acute migraine from the US payer perspective.
* All 3 gepants had incremental cost-effectiveness ratios of more than $150,000 per quality-adjusted life-year.
* All 3 were not cost-effective compared with usual care for the treatment of acute migraine.
* In cases where a gepant is to be prescribed, rimegepant (Nurtec ODT) is the most cost-effective option of the 3.
Migraine is a chronic and disabling neurological disorder characterized by episodic moderate to severe headaches, often accompanied by nausea, photophobia, and phonophobia.1 These headaches are typically unilateral, throbbing, and last between 4 and 72 hours.2 Migraines are a leading cause of disability worldwide.3-5 Risk factors include genetic predisposition,female sex,stress,hormonal imbalances,sleep and dietary disturbances,lower socioeconomic status,obesity,dyslipidemia,diabetes,and hypertension.1,6
First-line treatments for acute migraine, as recommended by the American Headache Society and the American Academy of Family Physicians (AAFP), include acetaminophen, nonsteroidal anti-inflammatory drugs, and triptans.7,8 Dihydroergotamine is also effective for acute management.
methods
model Structure
A Markov model was developed to simulate the clinical and economic outcomes of ubrogepant,rimegepant,and zavegepant for the acute treatment of migraine in adults. The model adopted a monthly cycle length and simulated patients transitioning between four health states: no migraine, mild migraine, moderate migraine, and severe migraine. Patients could transition between these states based on treatment efficacy and disease progression. The model also incorporated a fifth state representing discontinuation of treatment (“off treatment”).
Transition Probabilities
Transition probabilities were informed by data from clinical trials for ubrogepant, rimegepant, and zavegepant. Ubrogepant probabilities were derived from 2 trials (Dodick et al18 and Lipton et al19), both assessing ubrogepant 50 mg. Rimegepant probabilities were sourced from 2 trials (Lipton et al20 and Croop et al21), both assessing rimegepant 75 mg. Zavegepant probabilities were obtained from 1 trial (Lipton et al22), assessing zavegepant 10 mg. Probabilities for the 8-hour time point, unavailable in some trials, were calculated assuming a linear loss of effect over time. Probabilities for usual care were derived from the placebo arms of the clinical trials. The discontinuation probability (“off treatment”) was sourced from Ailani et al,23 which reported discontinuation rates for ubrogepant. Due to the lack of long-term studies for rimegepant and zavegepant, the same discontinuation rates were applied given their similar efficacy and adverse event profiles as agents within the same drug class. Transition probability inputs are provided in Table 1.18-26 The mean number of migraine attacks in a month ranged from 4.0 to 4.6 in the clinical trials, so the model assumed 4.3 migraines per month,for a total of 52 migraines (48-hour cycles) annually.
Patient Characteristics
Participants from all 5 clinical trials had a mean age of 40.0 to 41.7 years, with 81% to 91% being female and 73.4% to 84.5% being White.18-22 The inclusion criteria required individuals to be 18 years or older, have a 1-year history of migraine, experience 2 to 8 moderate to severe migraines per month, and be able to distinguish a migraine from other types of headaches. At baseline, across all 5 clinical trials, 60.5% to 61.9% of participants reported a moderate-pain migraine as the qualifying attack, whereas 38.1% to 39.5% of participants reported a severe-pain migraine.
Outcome Measures
The primary outcome measure was the severity of pain at 2,8,24,and 48 hours post dose,recorded by participants in an electronic diary. Pain severity was rated as no pain, mild, moderate, or severe.
Effectiveness
Utilities for no pain, mild pain, moderate pain, and severe pain were obtained from Desai et al,24 as shown in table 1. These utility values were used to calculate QALYs for each health state in the Markov model.
Atlas et al14 sourced health state utility values from Xu et al.27 Although the latter provides utility values for acute migraines,the data were obtained from a single trial (NCT00246337).
Although Desai et al24 is an abstract, it was selected for its systematic review of 29 studies, many of which were conducted in the US, making it one of the most complete sources available. The inclusion of multiple studies utilizing established health utility measurement tools-such as the EuroQol 5-Dimension, Health Utilities Index-Mark 3, and 36-Item Short Form survey-enhances the robustness and generalizability of the reported utility values.The breadth and quality of evidence in this review outweigh the limitations of it being an abstract.
Desai et al24 reported a range of utilities for each pain stage, and the midpoint value of this range was used for the base case and the l
eAppendix available at ajmc.com.
The cost of usual care was assumed to not contain triptans in 1 scenario, where the following mixture was considered: acetaminophen (11.3%), ibuprofen (38.2%), naproxen (32.1%), and dihydroergotamine (28.3%).According to the AAFP guidelines, intranasal dihydroergotamine has strong evidence of efficacy in the acute treatment of migraine and is considered as a second-line option.8 Because opioids shoudl be considered only as a last resort,8 dihydroergotamine was included in this scenario instead of opioids, which had been considered in Atlas et al.14
The health state utility values in Desai et al24 were reported as a range. We considered the lower and upper values of this range in different scenarios. Time horizons of 2 years and 10 years were evaluated in other scenarios. Scenarios in which the inflation rate was 2% and 4%, compared with 3.5% in the base case, were also assessed. In addition,we considered discount rates of 2% and 6%. Scenarios were also considered in which the number of migraines per month was assumed to be 2 and 8. Variations in costs,off-treatment probability,and individual treatment values were also assessed.
Although a wide range of scenarios could be explored, a targeted selection was chosen based on the results from Atlas et al,14 the clinical relevance, and the potential to meaningfully influence cost-effectiveness results.
RESULTS
Base-Case Analysis
Cost-Effectiveness Analysis of Gepants for Migraine: A Detailed examination
Our analysis reveals that gepants – ubrogepant, rimegepant, and zavegepant – demonstrate limited cost-effectiveness compared to usual care for migraine treatment. Specifically, we calculated incremental cost-effectiveness ratios (ICERs) of $274,429.43 per QALY for ubrogepant, $93,700.20 per QALY for rimegepant, and $288,898.88 per QALY for zavegepant. These values exceed commonly accepted willingness-to-pay (WTP) thresholds, indicating that the incremental benefit gained from these therapies does not justify their additional cost.
These ICER values differ from those reported by Atlas et al, who estimated $39,800 and $40,000 per QALY for ubrogepant and rimegepant, respectively. These discrepancies arise from several factors. First, our analysis included sumatriptan in the usual-care cost mix instead of opioids, aligning with the clinical trials used for effectiveness data. Because the trials did not focus solely on patients who were triptan refractory, we included triptans in usual-care costs. A scenario excluding triptans confirmed that none of the gepants were cost-effective under that assumption. Second, our model expanded on prior work by refining pain-state transitions and by excluding postgepant migraine treatment as a separate health state. Third, unlike Atlas et al, which relied on placeholder costs, we used actual average Wholesale Prices (AWPs) for gepants, ensuring a more accurate cost assessment. Fourth, Atlas et al reported similar total costs for gepants and usual care ($10,660 and $10,050 respectively), resulting in an ICER below the WTP threshold. Although their analysis included discontinuation and option treatment costs, the specific costs and methodologies were not clearly outlined. This lack of transparency makes it arduous to fully assess how Atlas et al arrived at such similar total costs for the gepants and usual care. In contrast, our analysis provides a more detailed breakdown of cost inputs, ensuring greater clarity and transparency in the cost-effectiveness estimation.
Touchette et al also found that ubrogepant and rimegepant were not cost-effective compared with usual care, reporting ICERs of $569,600 and $559,500, respectively. Their model assumed gepants would be priced 20% higher than branded sumatriptan, which aligns with current AWP estimates. Despite being authored by the same research group, Touchette et al and Atlas et al reached differing conclusions, likely due to variations in pricing assumptions and methodologies.However, a lack of detailed reporting limits direct comparison of their findings.
among gepants, rimegepant was the most cost-effective option, with an ICER of $93,700.20 per QALY compared with ubrogepant. Additionally, rimegepant dominated zavegepant, being both less costly and more effective. The oral disintegrating tablet formulation of rimegepant may enhance patient adherence,although further real-world evidence is needed to confirm this.
Our scenario analyses showed that gepants were not cost-effective under most conditions but became cost-effective when assuming only 2 migraine attacks per month. This aligns with the findings of Atlas et al, which showed that ICERs improved significantly as the number of monthly migraines decreased. Unlike Atlas et al, we incorporated actual AWP pricing and a different usual-care mix, which may explain differences in cost-effectiveness thresholds.
Our model’s robustness was supported by the fact that cost-effectiveness conclusions remained unchanged across most scenarios.Transition probabilities were not modified due to two key reasons.
Beyond pain Relief: Understanding New Options for Acute Migraine Treatment
Migraine is a common neurological disorder characterized by moderate to severe headache, often accompanied by nausea, vomiting, and sensitivity to light and sound. It significantly impacts quality of life, with ample personal and economic burdens. While many individuals manage migraine with over-the-counter pain relievers, a significant portion requires more targeted therapies.For decades,triptans were the mainstay of acute migraine treatment,but recent years have seen the emergence of a new class of drugs called gepants,offering fresh hope for those seeking effective relief.
The Migraine Landscape: A Complex Condition
Migraine isn’t simply a headache; it’s a complex neurological process. Current understanding points to a cascade of events involving brain activity, blood vessel changes, and neurotransmitter fluctuations. The exact mechanisms are still being investigated, but it’s clear that migraine involves more than just pain. the impact extends beyond the headache itself, encompassing a range of debilitating symptoms and affecting daily functioning (steiner et al., 2022). Globally, migraine affects a substantial portion of the population, with varying prevalence rates and a significant impact on disability (Amiri et al., 2022).
Traditional Acute Treatments: Triptans and Beyond
For years, triptans – drugs that target serotonin receptors – have been the primary prescription medication for acute migraine attacks. they work by constricting blood vessels in the brain and reducing inflammation. Though, triptans aren’t suitable for everyone. Contraindications include cardiovascular disease, and some individuals experience side effects or find them ineffective (Marmura et al., 2015). other options,like nonsteroidal anti-inflammatory drugs (NSAIDs) and combination analgesics,are frequently enough used,but their efficacy can be limited,especially for moderate to severe attacks (Mayans & Walling,2018).
Enter the Gepants: A New Avenue for Relief
Gepants represent a newer class of medications specifically designed to target a protein called CGRP (calcitonin gene-related peptide). CGRP plays a crucial role in the progress of migraine headaches. During a migraine attack, CGRP levels rise, contributing to inflammation and pain signaling. gepants work by blocking the CGRP receptor, effectively preventing CGRP from triggering the migraine cascade (Li et al., 2023).
Currently, three gepants are approved by the FDA for acute migraine treatment:
* Ubrogepant (Ubrelvy): Approved in 2019, ubrogepant was the first gepant to reach the market (Scott, 2020).
* Rimegepant (Nurtec ODT): Approved in 2020, rimegepant is unique in that it’s also approved for preventative migraine treatment (Scott, 2020).
* Zavegepant (Zavzpret): The newest addition, approved in 2023, zavegepant is administered via a nasal spray, offering a rapid onset of action (Dhillon, 2023).
How Gepants Fit into Clinical Practice
The American headache Society has provided guidance on integrating these new treatments into clinical practice (Ailani et al., 2021). Gepants are generally well-tolerated, with a favorable side effect profile compared to triptans. They offer a valuable alternative for individuals who haven’t responded adequately to triptans, have contraindications to their use, or prefer a different mechanism of action.
Looking Ahead
The development of gepants marks a significant advancement in acute migraine treatment. Ongoing research continues to explore the full potential of CGRP-targeted therapies, including their role in preventative care and the identification of personalized treatment strategies. As our understanding of migraine evolves, so too will the options available to those seeking relief from this debilitating condition (eigenbrodt et al., 2021; Goadsby, 2018; Goadsby et al., 2002).
References
- Atlas S, Touchette D, agboola F, et al. Acute Treatments for migraine: Evidence-Based Recommendations from the American Headache Society.
- Goadsby PJ, Lipton RB, Ferrari MD. Migraine-current understanding and treatment. N Engl J Med. 2002;346(4):257-270.doi:10.1056/NEJMra010917
- Steiner TJ, Terwindt GM, Katsarava Z, et al. migraine-attributed burden,impact and disability,and migraine-impacted quality of life: expert consensus on definitions from a Delphi process. cephalalgia.2022;42(13):1387-1396. doi:10.1177/03331024221110102
- Goadsby PJ. Migraine and other primary headache disorders. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. *Harrison’s principles of
The Rise of Gepants: A New class of Migraine Medication
Migraines are a debilitating neurological condition affecting millions worldwide. Characterized by intense headaches, nausea, and sensitivity to light and sound, migraines can significantly impact quality of life.For decades,treatments focused on older medications like triptans and ergotamines. However,a new class of drugs called gepants is emerging as a promising alternative,offering a different approach to migraine relief.
Understanding Migraine Pathology & the CGRP Connection
To understand how gepants work, it’s crucial to understand the role of calcitonin gene-related peptide (CGRP). CGRP is a molecule involved in the transmission of pain signals in the brain and plays a critical role in the pathophysiology of migraine. during a migraine attack, CGRP levels increase, leading to inflammation and vasodilation in the brain, contributing to the characteristic headache pain.
What are Gepants?
gepants are a relatively new class of medications that work by blocking the CGRP receptor. By preventing CGRP from binding to its receptor,gepants effectively interrupt the migraine pain pathway. unlike triptans, which primarily constrict blood vessels, gepants offer a more targeted approach by directly addressing the underlying biological mechanism of migraine.
Types of Gepants Currently Available
Currently, three gepants are approved by the FDA for acute migraine treatment:
* Rimegepant (Nurtec ODT): Approved in 2020, rimegepant is unique in that it’s approved for both acute treatment and preventative use. It’s available as an orally disintegrating tablet, making it convenient for those experiencing nausea during a migraine attack.https://www.nice.org.uk/guidance/ta919/resources/rimegepant-for-treating-migraine-pdf-82615495535557
* Ubrogepant (Ubrelvy): Approved in 2019, ubrogepant is specifically designed for the acute treatment of migraine with or without aura. (Dodick et al., 2019)
* Zavegepant (Zavzpret): Approved in 2023, zavegepant is administered as a nasal spray, offering a fast-acting option for individuals who have difficulty taking oral medication during an attack. (Lipton et al., 2023)
Clinical Trial Evidence
Clinical trials have demonstrated the efficacy of gepants in relieving migraine pain.
* A study published in the New England Journal of Medicine showed that ubrogepant significantly reduced pain and associated symptoms compared to placebo in patients with acute migraine. (Lipton et al., 2019)
* Research on rimegepant, also in the New England Journal of Medicine, indicated its effectiveness in both acute treatment and prevention of migraine attacks. (Lipton et al., 2019)
* Trials for zavegepant, published in Lancet Neurology, highlighted its rapid onset of action and effectiveness when delivered via nasal spray. (Lipton et al., 2023)
Gepants vs. Triptans: What’s the Difference?
| Feature | Gepants | Triptans |
|---|---|---|
| Mechanism | Blocks CGRP receptor | Serotonin receptor agonist (vasoconstriction) |
| Cardiovascular Risk | Generally lower | Potential for vasoconstriction-related risks |
| Use in Patients with Cardiovascular Disease | May be safer option | Use with caution |
| Management | Oral, Nasal Spray | Oral, Injection, Nasal Spray |
| Prevention | Rimegepant approved for prevention | Not typically used for prevention |
Side Effects and Considerations
Gepants are generally well-tolerated, with common side effects including nausea, dry mouth, and fatigue. They are not without potential drug interactions, so it’s crucial to discuss your complete medication list with your doctor.
The Future of Migraine Treatment
Gepants represent a significant advancement in migraine treatment, offering a targeted and frequently enough well-tolerated option for those who haven’t found relief with traditional therapies. Ongoing research continues to explore the full potential of this drug class, including its use in broader populations and for different types of migraine.
references
- Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med.2019;381(23):2230-2241. doi:10.1
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