Cost-Effectiveness Analysis of Ubrogepant, Rimegepant, and Zavegepant for Acute Migraine Treatment vs Usual Care

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 with 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 perspective, 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.7 In patients with contraindications, intolerance, or inadequate response to triptans, small-molecule calcitonin gene–related peptide receptor antagonists, also referred to as gepants, have emerged as alternative treatments.9

The gepants ubrogepant (Ubrelvy), Rimegepant (Nurtec ODT), and zavegepant (Zavzpret) were approved by the FDA between 2019 and 2023 for the treatment of acute migraine.10-12 They offer a favorable adverse event profile and multiple dosage forms.13 However, their cost-effectiveness remains uncertain. Previous analyses, including a 2020 Institute of Clinical and Economic Review report, have limitations, such as outdated cost assumptions and the exclusion of newer agents such as zavegepant.14 Studies from China and the UK have primarily focused on rimegepant in specific populations,15,16 limiting their applicability to the US health care system. Although the UK’s National Institute for Health and Care Excellence considers rimegepant cost-effective for patients with inadequate response to 2 or more triptans,17 findings from non-US health care systems may not translate to the US payer perspective. This study aims to fill these gaps by assessing the cost-effectiveness of ubrogepant, rimegepant, and zavegepant for acute treatment of migraine from the US payer perspective, comparing the 3 gepants with each other and with usual care.

METHODS

Model

A Markov model was developed to compare the cost-effectiveness of ubrogepant, rimegepant, and zavegepant with each other and with usual care (Figure 1). Effectiveness measures were derived from 5 clinical trials of these gepants,18-22 with the placebo arms serving as proxies for usual care because gepants are not first-line treatments. However, this approach, employed by Atlas et al14 and Johnston et al,16 may not always reflect real-world scenarios.

Our model was constructed from the US payer’s perspective, following the methodology of Atlas et al, which developed a Markov model with 4 health states that was informed by a network meta-analysis of key clinical trials, previous economic models, systematic literature reviews, and input from diverse stakeholders, including patients, advocacy groups, clinicians, payers, researchers, and manufacturers.14 The Atlas et al model represents the only comprehensive cost-effectiveness analysis of gepants from a US payer perspective available in the literature, and it served as the basis for our model.

Our model included 5 health states: (1) mild migraine while on treatment, (2) moderate migraine while on treatment, (3) severe migraine while on treatment, (4) no migraine while on treatment, and (5) off treatment. All patients began in either moderate or severe migraine states. Transitions to the off-treatment state occurred due to adverse events or lack of efficacy, with no return to other states. Migraine presence was not assessed in the off-treatment state, as the focus was on evaluating the effectiveness of gepants during treatment.

The model used a 48-hour cycle length, reflecting clinical trial data, with transitions assessed at 2-, 8-, and 24-hour intervals. A 5-year time horizon was chosen to evaluate long-term cost-effectiveness. Costs and quality-adjusted life-years (QALYs) were discounted annually at a 3% rate. All analyses were conducted in RStudio 4.3.3 (Posit Software, PBC).

Probabilities

Probabilities for each state at baseline (0 hours) and at 2, 8, 24, and 48 hours were obtained and extrapolated 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 comprehensive 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 lower and upper values of this range were used for our sensitivity analysis. The utility values reported by Desai et al24 closely align with those from Xu et al,27 reinforcing their validity for use in our model. The consistency of findings across these sources supports the reliability of the utility estimates and suggests they reflect real-world patient experiences. For the off-treatment utility value, we assumed a value between the moderate and severe states. This is because all patients at baseline reported either moderate or severe pain, and it is assumed that this would be the same after patients went off treatment. A disutility value of –0.5 was assumed for emergency department (ED) visits and hospitalizations, similar to Atlas et al.14 The utilities were discounted at 3% annually.

Costs

The costs for ubrogepant, rimegepant, and zavegepant were sourced from the average wholesale price (AWP) per unit, as listed in the Red Book.26 To account for manufacturers’ rebates and discounts, the AWP was adjusted with a 30% discount. Atlas et al14 assumed a mix of butalbital, caffeine, and acetaminophen (11.3%); ibuprofen (38.2%); naproxen (32.1%); and opioids (28.3%) to estimate costs for usual care. Similarly, we obtained usual-care costs by considering the following mixture: acetaminophen (11.3%), ibuprofen (38.2%), naproxen (32.1%), and sumatriptan (28.3%). These were also sourced from the Red Book.26 Atlas et al14 did not consider triptans because gepants are recommended for patients who are refractory to triptans. However, the clinical trials18-22 did not specifically recruit such patients, and exact details about the percentage of patients refractory to triptans have not been elaborated on in all the trials. As such, we also included sumatriptan while considering usual-care costs. In addition, according to the AAFP guidelines, opioids should not be used as a first-line option and should only be considered as a last resort.8 As such, opioids were not considered in our mix of usual-care costs, as opposed to Atlas et al.14

We calculated costs assuming 4.3 migraine attacks per month. Thus, the annual costs were calculated for 52 migraine attacks. Additional costs for outpatient, inpatient, ED, and other visits were sourced from Shao et al.25

Shao et al25 reported costs associated with chronic migraine, episodic migraine, and tension-type headaches. Chronic migraines are characterized by 15 or more days of headache per month, and episodic migraines are characterized by fewer than 15 days of headache per month.25 We considered the costs for episodic migraine, aligning with the fewer than 15 migraine days evaluated in our model. We considered these costs to be the same for all the gepants due to the similar clinical profile and indications. An inflation rate of 3.5% was used to calculate 2024 costs. The annual costs were adjusted to per-cycle costs in the model and were discounted at 3% annually. Cost inputs are provided in Table 1.

Scenario Analysis

Scenario analyses were conducted to examine the impact of alternative assumptions on the incremental cost-effectiveness ratios (ICERs). The different scenarios considered are provided in eAppendix Tables 1, 2, and 3 (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 should 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

In the base-case analysis, the annual costs were as follows: $74,806.08 for ubrogepant, $79,491.09 for rimegepant, $92,188.39 for zavegepant, and $53,768.27 for usual care. The QALYs for ubrogepant, rimegepant, zavegepant, and usual care were 2.91, 2.96, 2.95, and 2.81, respectively. All 3 gepants were not cost-effective compared with usual care under willingness-to-pay (WTP) thresholds of $50,000 per QALY, $100,000 per QALY, and $150,000 per QALY, with ICERs of $210,378.10 per QALY for ubrogepant, $171,485.47 per QALY for rimegepant, and $274,429.43 per QALY for zavegepant. Table 2 shows the results for the base-case analysis. The cost-effectiveness plane for all 3 gepants is provided in Figure 2.

The cost-effectiveness acceptability curves for all 3 gepants are given in eAppendix Figure 1. Rimegepant had the highest probability of being cost-effective at all 3 WTP thresholds, followed by ubrogepant and zavegepant.

Compared with each other, rimegepant was more cost-effective than ubrogepant, with an ICER of $93,700.20 per QALY. Rimegepant was both more effective and less costly than zavegepant, thus dominating it. When compared with ubrogepant, zavegepant was not cost-effective, with an ICER of $434,557.75 per QALY. The costs, QALYs, incremental values, and ICERs are detailed in Table 2. eAppendix Table 4 shows the comparisons of the 3 gepants with each other.

Scenario Analyses

Ubrogepant was not cost-effective across all the scenarios, except when the number of migraines per month was 2. The model was the least sensitive to changes in ED costs, outpatient costs, inpatient costs, other costs, the number of hospitalizations, and the disutility of ED visits and hospitalizations because these inputs were the same for ubrogepant and usual care. Ubrogepant was not cost-effective when the usual-care mix did not consider the cost of triptans. Differences with ICER values were seen with changes in utility values, inflation rate, discount rate, off-treatment probability, and other variables; however, these changes did not impact cost-effectiveness.

Similar results were seen with rimegepant, although it was cost-effective in more scenarios than ubrogepant. In addition to the scenario with 2 migraines per month, rimegepant was cost-effective when we considered lower utility values and lower costs. Lower utility values for moderate pain and severe pain improved its cost-effectiveness.

Zavegepant showed similar results to ubrogepant, with the drug being cost-effective only in the case of 2 migraines per month. The tornado diagrams for all 3 gepants are given in eAppendix Figure 2.

DISCUSSION

This analysis found that none of the 3 gepants were cost-effective compared with usual care at a WTP threshold of $150,000 per QALY. Rimegepant had the lowest ICER ($171,485.47 per QALY), followed by ubrogepant ($210,378.10 per QALY) and zavegepant ($274,429.43 per QALY).

Our ICER values differ from those reported by Atlas et al, which estimated $39,800 and $40,000 per QALY for ubrogepant and rimegepant, respectively.14 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.18-22 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,14 which relied on placeholder costs, we used actual 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.14 Although their analysis included discontinuation and alternative treatment costs, the specific costs and methodologies were not clearly outlined. This lack of transparency makes it difficult 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.28 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 al28 and Atlas et al14 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,29 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.14 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 2 key reasons: (1) adjusting one transition probability would necessitate altering others, introducing multiple assumptions that may not reflect real-world data, and (2) Atlas et al found that such modifications had minimal impact on ICERs,14 indicating limited influence on cost-effectiveness outcomes.

Limitations

This study had some limitations. First, the clinical trial populations were predominantly White, middle-aged, and female, which may limit the generalizability of the results to more diverse demographic groups. Second, we assumed certain utility and disutility values, including those for off treatment, ED visits, and hospitalizations, which may not have fully reflected the real-world scenario.

CONCLUSIONS

The 3 FDA-approved gepants for the treatment of acute migraine are not cost-effective compared with usual care and should primarily be reserved for patients who are refractory to triptans. Among these gepants, rimegepant offers the best cost-effectiveness. These 3 agents may, however, be cost-effective for patients experiencing approximately 2 migraines per month. Future research should focus on evaluating the cost-effectiveness of gepants specifically in patients who are triptan refractory.

Data Availability Statement

The R code used for the cost-effectiveness analysis is available in the eAppendix. Any other data may be made available upon request.

Author Affiliations: Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy (PG, LVZ), Athens, GA.

Source of Funding: None.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (PG, LVZ); acquisition of data (PG); analysis and interpretation of data (PG, LVZ); drafting of the manuscript (PG); critical revision of the manuscript for important intellectual content (LVZ); statistical analysis (PG, LVZ); and supervision (LVZ).

Address Correspondence to: Lorenzo Villa Zapata, PhD, University of Georgia College of Pharmacy, 250 W Green St, Athens, GA 30602. Email: lorenzo.villazapata@uga.edu.

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