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Reduction of pain and functional disability over time in patients treated with zavegepant: a post-hoc analysis of the BHV3500-301 phase 3 randomized controlled trial

The Journal of Headache and Pain volume 26, Article number: 1 (2025) Cite this article

Abstract

Background

Migraine is a disabling disorder that impacts 40 million people in the US. Zavegepant is the first calcitonin gene-related peptide (CGRP) receptor antagonist nasal-spray approved for the acute treatment of migraine with or without aura in adults. This study aimed to evaluate the proportion of patients in various pain and functional disability states over 48-h, for patients treated with zavegepant 10 mg nasal-spray versus placebo.

Methods

This post-hoc analysis included adult patients with > 1-year history of migraine from BHV3500-301 (NCT04571060): a phase 3 double-blind, randomized, placebo-controlled, single-attack study. Over 48-h, pain severity and functional disability were captured at various timepoints (pre- and post-dosing). The proportion of patients at each pain severity or functional disability state and the time spent in each category was calculated. These were analyzed for patients with complete timepoint data available and using missing not at random (MNAR) imputation for missing timepoints. Predictors of functional disability were assessed using a mixed-effects logistic regression model.

Results

There were 1,269 patients included in the MNAR imputation analysis, and between 630–641 in the complete-case analysis. As early as 15-min post-dose, a larger proportion of zavegepant patients achieved no/mild pain compared to placebo, despite balanced migraine severity pre-dose. Furthermore, zavegepant patients spent significantly more time (over 2.5-h) in pain freedom compared to placebo. Similarly, a higher proportion of patients with normal function was observed with zavegepant vs placebo, as early as 30-min post-dose. Over 48-h, patients treated with zavegepant spent an average of ~ 3-h longer with normal functioning compared to placebo. Results were similar when analyzing both analytic groups. In a regression model, treatment with zavegepant, lower pain severity, fewer baseline monthly migraine days, and absence of photophobia, phonophobia, and nausea were associated with better functioning (p < 0.05) over 48-h.

Conclusion

This post-hoc analysis demonstrates the benefit of zavegepant nasal spray over placebo on two patient-centric endpoints: time spent with pain freedom and normal functioning over 48-h post-dose. These data support the use of zavegepant for providing rapid and sustained freedom from migraine pain and freedom from migraine related disability, particularly for those who would benefit from the nasal CGRP formulation.

Peer Review reports

Background

Migraine is a common, disabling neurologic disorder characterized by recurrent attacks of head pain that are typically unilateral, throbbing, and associated with a range of symptoms including photophobia, phonophobia, nausea, and vomiting [1]. Migraine affects an estimated 40 million people in the United States (US), and is the most disabling of all health conditions in those younger than 50 years of age [2,3,4]. Many individuals with migraine experience diminished quality of life, reductions in workplace productivity, and limited participation in and enjoyment of social and leisure activities [5,6,7].

In the current treatment paradigm for acute treatment of migraine, oral triptans are recommended as first-line therapy [8]. Some patients do not achieve adequate symptom relief, are contraindicated to receive treatment, or experience intolerable side effects with triptans [9,10,11,12]. Real-world evidence shows that new triptan users have relatively low persistence and retention rates due to adverse events (AEs), lack of efficacy, lack of tolerability, symptom recurrence, or cardiovascular (CV) contraindications [13,14,15,16]. Patients with migraine with a poor response to acute treatment have an increased risk of developing more disabling and resource-intensive conditions, such as chronic migraine and medication-overuse headache (MOH), a distinct syndrome that occurs when drugs intended to relieve migraine headache pain are used too frequently and gradually become the cause of persistent, treatment-refractory headache pain [17]. For patients with acute migraine who are unsuitable for triptans, the American Headache Society and the International Headache Society recommends initiating acute treatment with one of the gepants (rimegepant, zavegepant or ubrogepant) or ditans (lasmiditan) [8, 18].

Calcitonin gene-related peptide (CGRP) receptor antagonists are a new class of therapies that address an unmet need for patients. In addition, they are not known to cause MOH in patients [19]. CGRP receptor antagonists selectively bind with high affinity to the human CGRP receptor, inhibiting CGRP-induced enhancement of pain signaling, blocking CGRP-induced vasodilation without active vasoconstriction, and halting CGRP-induced neurogenic inflammation [20, 21]. Currently available CGRP receptor antagonists for the acute treatment of migraine include rimegepant and ubrogepant (which are administered orally), and zavegepant, which is the only CGRP receptor antagonist available as a nasal spray.

While the oral route of administration is generally preferred, certain patients can benefit from non-oral therapies [22, 23]. For patients who experience severe nausea or vomiting, who do not respond well to traditional oral treatments, or who have trouble swallowing orally administered medications, intranasal therapies can offer important benefits [24, 25]. Furthermore, intranasal delivery of therapy allows for fast-onset due to bypassing the small bowel gastrointestinal tract absorption, which is often delayed during the acute phase of a migraine attack [26, 27]. However, currently available triptan intranasal migraine treatments (e.g., zolmitriptan, sumatriptan) can be associated with the same safety concerns as their oral counterparts (e.g., CV contraindications and risk of MOH with frequent use), and therefore are not appropriate for all patients. Other therapies for migraine with nasal formulations, such as dihydroergotamine, also has similar CV concerns, the risk of MOH and other AEs, including nausea, paresthesia and nasal congestion associated with them [23, 28,29,30,31]. Zavegepant is the first CGRP receptor antagonist nasal spray approved by the food and drug administration (FDA) for the acute treatment of migraine [32].

The efficacy and safety of zavegepant 10 mg nasal spray was demonstrated in two double-blind, randomized, placebo-controlled, single-dose trials (BHV3500-201, NCT03872453 and BHV3500-301, NCT04571060) [33]. In these trials, zavegepant demonstrated statistical superiority over placebo on the primary endpoints of freedom from pain and freedom from most bothersome symptom (MBS) at 2-h. This effect was observed in adults with or without a history of insufficient response to triptans and in current triptan users [34, 35]. In addition, some patients treated with zavegepant had rapid onset of pain relief as early as 15-min with a return to normal function at 30-min. After a single dose, zavegepant demonstrated superiority to placebo in the freedom from functional disability at 2-h post-dose [33].

During migraine attacks, approximately 90% of patients experience moderate-to-severe pain [5]. Pain is often the most dominant symptom of migraine and is of high importance to patients when evaluating the effectiveness of a therapy. As such, pain freedom at 2-h post-dose is recommended as the primary efficacy outcome in clinical trials of acute migraine therapies [36]. Pain severity is closely linked to health-related quality of life (HRQoL), and rapid and sustained reduction in pain severity is the primary goal of acute migraine treatment. For a more comprehensive understanding of the effect of zavegepant on migraine pain severity, an examination of the proportion of patients in various pain severity states over the 48-h post-dose period is warranted.

Migraine is an incredibly disabling disease; in fact, during a migraine, 75% patients experience mild to moderate functional disability, and one-third require bed rest [5]. Disability due to migraine can be correlated with pain severity, but pain is not the only driver of this outcome and may be influenced by other patient characteristics such as migraine frequency, the presence of related symptoms (e.g., nausea, photophobia, and phonophobia), and any unwanted effects of treatment. Functional disability is an additional patient-centric outcome recommended as an endpoint in clinical trials [36]. Functional disability is also correlated with HRQoL and the impact of a migraine attack on activities of daily living. The objective of this study was to analyze of the time patients spent in various pain severity and functional disability states over the entire 48-h trial period in patients treated with a single-dose of zavegepant 10 mg nasal spray or placebo in the phase 3 BHV3500-301 study. In addition, this study aimed to investigate the impact of patient and migraine characteristics as predictors of functional disability over the 48-h study period. To supplement the primary publication for BHV35000-301, this study aimed to provide a more detailed analysis of pain and functional disability over the duration of the treated migraine attack (out to 48-h).

Methods

Study design and participants

Eligible patients for this post-hoc analysis were patients from BHV3500-301 (NCT04571060): a phase 3 double-blind, randomized, placebo-controlled, single-attack study [33]. In this study, adults with a history of two to eight moderate or severe migraine attacks per month were randomly assigned to receive 10 mg of zavegepant nasal spray or placebo to treat a single migraine attack of moderate or severe pain intensity. Details of study design are summarized in Fig. 1.

Additional details on study design can be found in the primary publication reporting the efficacy and safety of zavegepant in BHV3500-301 [33]. Inclusion and exclusion criteria applied in the BHV3500-301 study are listed in Table 1.

Table 1 Summary of inclusion and exclusion criteria for BHV3500-301
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Patients recorded information on their migraine attack using a handheld eDiary device. Upon experiencing a moderate or severe migraine, the device instructed the patient to complete the eDiary assessments before taking the study drug and then at 12 timepoints post-dose over the next 48-h. The following measures were recorded by the patient: headache pain intensity using a 4-point numeric rating scale (none, mild, moderate, severe); presence or absence of associated symptoms (nausea, photophobia, phonophobia); current MBS before taking study drug; and the functional disability level using a 4-point numeric rating scale (normal, mildly impaired, severely impaired, requires bedrest). Post-dose headache pain intensity, presence of symptoms, and functional disability levels were recorded at 15-, 30-, 45-, 60-, and 90-min and 2-, 3-, 4-, 6-, 8-, 24-, and 48-h.

Analysis population

This post-hoc analysis examined individual patient data from the phase 3 zavegepant trial (BHV3500-301) [33]. In this trial, 1,978 participants were recruited and screened, of which 1,405 were randomly assigned to receive zavegepant (n = 703) or placebo (n= 702) in 90 study centres across the USA [33]. Eligible patients for this analysis included the 1,269 patients in the efficacy analysis set of BHV3500-301 with post-dose efficacy data. In order to analyze pain severity and functional disability over 48-h, the following outcomes were evaluated: the proportion of patients in each pain severity category at each timepoint; the time patients spent in each pain severity category over 48-h; the proportion of patients in each functional disability state at each timepoint; the time spent in each functional disability state over 48-h, and finally, the predictors of functional disability.

Statistical analysis

Analysis datasets

As some patients were missing data at specific timepoints when completing the eDiaries over the 48-h (with most missing data being from the later timepoints), the proportion of patients in each pain severity and functional disability state was calculated using two different analytic approaches to evaluate the impact of this missing data. The first approach examined complete cases (herein referred to as complete case analysis) and included only the subset of patients with complete data on pain severity or functional disability at all timepoints over the 48-h. The second approach (herein referred to as MNAR imputation analysis) imputed missing data under the missing not at random (MNAR) assumption using the following variables: patient identification, treatment, timepoint, number of prior triptan failures, baseline pain severity, duration of migraine, number of historical moderate or severe migraine attacks per month, use of rescue medications, other pain medications, and concomitant preventive medications. This imputation was chosen as there was a systematic pattern to the missingness with more missingness observed at later timepoints but the contributing factor is unclear. The imputation was performed using the MI procedure from SAS version 9.4M7 [37]. Outcomes of pain and functional disability proportions were generated individually for each of five imputation sets and then averaged using Fully Conditional Specification for the multiple imputation. Baseline characteristics were compared between the complete-case and MNAR imputation analytic datasets.

Time spent in pain and disability states

The proportion of patients who reported each pain severity state (none, mild, moderate, severe) at each timepoint was calculated to summarize the trends in pain severity. To calculate time spent in each pain severity state over the 48-h period, pain time was divided into discrete time windows based on the amount of time between each recorded timepoint in the study (e.g., 45 min – 30 min = 15 min). Pain time was distributed depending on how many pain states were transitioned between the previous time point and the current timepoint. If a patient stayed in the same pain state for an entire time window (e.g., mild → mild), that duration was added to the corresponding pain state category. If a patient transitioned from one pain state to another over a time window (e.g., moderate → mild), it was assumed the transition occurred in the middle of the time window, and the time window was split equally between both pain categories.

The same strategy was implemented for patients who transitioned two (e.g., severe → moderate → mild) and three (e.g., severe→ moderate→ mild→ none) pain states between recorded timepoints. For each trial arm, the mean (standard deviation [SD]) number of hours spent in each pain state was calculated. Independent two-sample t-tests were used to determine if there was a significant difference between trial arms for time spent in each of the four pain states. Cohen’s D effect sizes were also calculated. Pain states were also converted into a binary outcome (none/mild and moderate/severe), and the mean time spent in each binary pain state was summarized and compared across trial arms. The amount of time spent in each pain state over the 48-h period was also calculated for the four pain states and the binary pain states (none/mild and moderate/severe pain).

Similar to the pain severity analysis, functional disability was evaluated for each disability level (normal, mildly impaired, severely impaired, requires bedrest) and as a binary outcome (normal/mildly impaired and severely impaired/requires bed rest). The proportions and amount of time spent in each functional disability state over time were calculated using the same method outlined above for pain severity.

Stratification by baseline severity analysis

Analyses were repeated for the following subsets of patients characterized by severity at baseline: those with severe pain, those with moderate pain, those with severe functional disability and those requiring bedrest. These stratified analyses were conducted for both zavegepant and placebo groups, to characterize their transition through pain states from baseline until 3-h. This time period was selected as patients were allowed to use rescue medications after 2-h if they had not achieved adequate symptom relief. The objective of this analysis was to examine these subgroups of patients in greater detail and to follow their progression through different pain or functional states over time directly after receiving the study drug.

Regression analysis

The predictors of functional disability were examined using a regression model. This was carried out to investigate the impact of patient and migraine characteristics on functional disability. A mixed effects longitudinal logistic regression model to determine predictors of “return to normal function” was fit using a random intercept. The response variable was binary functional disability (normal/mild functional impairment versus severe impairment/requires bedrest). The model included both fixed predictors (age, sex, treatment arm, number of historical moderate or severe attacks per month, historical MBS), and time-varying predictors (pain severity, freedom from photophobia, phonophobia, and nausea, timepoint, and time-treatment interaction.) The odds ratios (ORs) from the regression analysis and analysis of deviance (Type III Wald chi-square tests) were used to identify significant variables. Age and number of attacks were standardized for numerical stability.

Results

Overall

Within this post-hoc study, 1,269 patients were included in the MNAR imputation analysis. For the complete case analysis, 630 patients were included when examining pain severity and 641 patients were included when examining functional disability; this difference in sample sizes was due to one patient who had complete data for pain and incomplete data for functional disability and 12 patients with complete functional disability information and incomplete pain data. Data were relatively complete for the first 2-h post-dose, with only 3% of patients missing data. However, the proportion increased as time progressed, with 40% of patients missing data by 48-h. In the MNAR imputation analysis, a larger proportion of missing data was imputed with higher migraine severity. The proportion of patients with missing data was similar between the zavegepant and placebo arms, and age and sex distributions were similar for both analytic groups (Table 2). Other baseline characteristics were also similar between analytic groups, aside from rescue medication, as outlined in Table 2. Further information on baseline characteristics of the patients included in this trial is available in the primary publication [33].

Table 2 Baseline characteristics stratified by patients with imputed data and complete data
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Time spent in pain states

The proportion of patients in each pain severity category at each timepoint is shown in Fig. 2. A higher proportion of zavegepant patients contributed person-time to the no pain and mild pain health states compared with those treated with placebo; this difference was observed as early as 15-min post-dose and continued through 48-h (Fig. 2). Similar results were found for the complete case analysis and MNAR imputation analysis, however, the MNAR approach estimated more moderate and severe patients at later timepoints than the complete case analysis.

Fig. 1
figure 1

BVH3500-301 study design schematic

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Fig. 2
figure 2

Proportion of patients in each pain severity category by timepoint. Abbreviations: MNAR, missing not at random

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When examining the time spent in each pain severity category over 48-h, there was more time spent with no pain in the zavegepant group compared with the placebo group (Table 3), which was statistically significant. This was true for both the complete case analysis and MNAR imputation analysis. In the complete case analysis, patients spent a mean (SD) of 35.9 (13.7) hours with no pain in the zavegepant group versus 33.1 (15.0) hours in the placebo group (P = 0.016). Similarly, in the MNAR imputation analysis, patients spent a mean of 26.9 (17.8) hours with no pain in the zavegepant group versus 23.2 (18.0) hours in the placebo group (P< 0.001). Cohen’s D estimates for complete cases that were statistically significant ranged from −0.17 to 0.20, while the values for the significant MNAR comparisons ranged from −0.21 to 0.21, these estimates correspond to a small magnitude of effect [38]. When pain was assessed as a binary outcome (none/mild versus moderate/severe), the amount of time spent in the none/mild pain state still favored zavegepant. In the complete case analysis, the zavegepant group spent more time in none/mild pain state than placebo (43.7 [8.4] versus 42.6 [9.3] hours, respectively; P = 0.135), but the difference was not statistically significant. However, a statistically significant difference was reported in the MNAR imputation analysis; patients in the zavegepant group spent a mean (SD) of 36.8 (13.9) hours in the none/mild pain state, while patients in the placebo group spent 34.0 (15.4) hours in the none/mild pain state (P = 0.001).

Table 3 Mean hours spent in each pain severity state over 48-h period
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The proportion of time spent in the no-pain state was higher in the zavegepant groups compared with the placebo group. This was observed for both the complete case analysis and MNAR imputation analysis (Table 4). The treatment difference (favoring zavegepant over placebo) was larger in the MNAR imputation analysis than in the complete case analysis. When pain severity was assessed as a binary outcome (none/mild versus moderate/severe), the proportion of time spent in the none/mild state still favored zavegepant (data not shown). The zavegepant group spent a higher proportion of time in the none/mild pain state compared with the placebo group (MNAR imputation analysis: 6% difference; complete case analysis: 2% difference).

Table 4 Percent of time spent in each pain state over 48-h
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Stratification by baseline pain severity analysis

When patients were stratified by baseline migraine severity, among the subset of patients with moderate pain at baseline (zavegepant n = 233 and placebo n = 209), there was a higher proportion with mild/no pain as early as 15-min post dose (21.9% versus 12.0%), which was maintained out to 3-h post dose (80.2% versus 70.9%; Fig. 3). This was also observed among the subset of patients with severe pain at baseline (zavegepant n = 94 and placebo n = 94) at 15-min post dose, as a small proportion (6.4%) of zavegepant patients dropped to mild or no pain, compared to 0% of patients in the placebo arm (Fig. 4). More commonly, across both treatment arms, patients achieved pain freedom in a stepwise progression through severe, moderate, mild, and no pain, rather than progressing directly from severe pain to mild or no pain.

Fig. 3
figure 3

Patient journey through pain states from baseline to 3-h, for those with moderate pain at baseline. Footnote: This figure tracks the path patients take through different pain severity states over 3-h. In this figure, at 0-min all patients have moderate pain (purple). The size of the colored band represents the number of people in those groups, with thicker bands representing a larger sample size. For example, at 15-min, most patients remain at a moderate pain state, but some patients begin to transition to mild (blue), severe (red) and no pain (green). As time progresses, a larger proportion of patients transition to other pain states

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Fig. 4
figure 4

Patient journey through pain states from baseline to 3-h, for those with severe pain at baseline. Footnote: This figure tracks the path patients take through different pain severity states over 3-h. In this figure, at 0-min all patients have severe pain (red). The size of the colored band represents the number of people in those groups, with thicker bands representing a larger sample size. For example, at 15-min, most patients from this group remain at severe pain state but some patients begin to transition to moderate (blue), mild (blue) and no pain (green) as early as 15-min. As time progresses, a larger proportion of patients transition to other pain states

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Time spent in disability states

Similar to the analysis examining the proportion and amount of time spent in pain states, zavegepant performed better than placebo when examining functional disability. The proportion of patients in each functional disability level at each timepoint is shown in Fig. 5. A higher proportion of zavegepant patients with normal functioning compared to patients treated with placebo was observed as early as 30-min post-dose.

Fig. 5
figure 5

Proportion of patients in each functional disability state by timepoint. Abbreviations: MNAR, missing not at random

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In both analytic datasets, more time was spent in the normal functional state for zavegepant versus placebo (mean [SD]: 39.5 [11.8] versus 36.7 [14.5], P = 0.007 and 31.9 [16.9] versus 28.2 [18.1], P < 0.001 for the complete case analysis and MNAR imputation analysis respectively; Table 5), this was statistically significant for both analytic data sets. This translates to approximately 3-h more time with normal functioning for zavegepant versus placebo. Cohen’s D estimates for complete cases that were statistically significant ranged from −0.23 to 0.21, while the values for the significant MNAR comparisons ranged from −0.21 to 0.21, these estimates correspond to a small magnitude of effect [38]. When functional disability was assessed as a binary outcome (normal/mild versus severe/bedrest), the amount of time spent in the normal/mild functional state still favored zavegepant. Furthermore, zavegepant-treated patients spent a larger proportion of time with normal functioning (Table 6). This was observed for both complete case analysis (82% versus 76%) and MNAR imputation analysis (66% versus 59%).

Table 5 Mean hours spend in each functional state over 48-h
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Table 6 Percent of time spent in each functional state over 48-h
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Stratification by baseline functional disability analysis

The progression of patients experiencing severe functional disability or requiring bedrest at baseline is presented in Fig. 6. No clear effect of zavegepant on this outcome was observed at the earliest timepoints, as similar proportions of those with normal functional disability were observed between study arms. However, descriptively at 2-and 3-h post-dose, there was a lower proportion of patients with severe functional disability/requiring bedrest in those treated with zavegepant compared to placebo.

Fig. 6
figure 6

Patient journey through functional disability states from baseline to 3-h, for those with severe functional disability or bedrest at baseline. Footnote: This figure tracks the path patients take through different functional disability states over 3-h. In this figure, at 0-min all patients have severe functional disability /requires bedrest state (red). The size of the colored band represents the number of people in those groups, with thicker bands representing a larger sample size. For example, at 30-min, most patients remain at a severe functional disability/requires bedrest state but some patients begin to transition to a mildly impaired functional state (blue) or no functional impairment state (green). As time progresses, a larger proportion of patients transition to other pain states

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Regression analysis

When examining predictors of functional disability, treatment with zavegepant was associated with a better return to function over the 48-h period vs placebo (Tables 7 and 8, Fig. 7). OR estimates of normal function/mildly impaired vs severely impaired function/requires bedrest for zavegepant vs placebo ranged from 1.44 to 2.22 between 15-min to 4-h, and statistically significant ORs were achieved at 6-h (OR: 3.11, 95% CI: 1.01, 9.55) and 8-h (OR: 4.03, 95% CI: 1.09, 14.85) (Fig. 7). Higher pain severity was strongly linked to worse odds of normal/mild functional impairment (OR: 0.01, 95% CI: 0.00, 0.01). Other variables in the model, such as freedom from photophobia (OR: 7.52, 95% CI: 4.47, 12.64), freedom from phonophobia (OR: 5.50 95% CI: 3.66, 8.26), and freedom from nausea (OR: 6.34 95% CI:4.65, 8.65) were associated with better odds of normal/mild functional impairment with statistical significance. Finally, a greater mean number of historical moderate or severe monthly migraine attacks (within the 2–8 monthly attack range defined as trial inclusion criteria) was associated with lower odds of normal/mild functional impairment (OR: 0.64 95% CI: 0.47, 0.86).

Table 7 Results of mixed effects logistic regression model examining predictions of normal function/mildly impaired versus (severely impaired function/requires bedrest)
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Table 8 Regression analysis of deviance (Wald III test)
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Fig. 7
figure 7

Forest plot of the time-specific effects of zavegepant examining normal function/ mildly impaired function versus severely impaired function/requires bedrest

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Discussion

Results of this post-hoc analysis showed a higher proportion of patients in the zavegepant group versus the placebo group with no/mild pain compared with moderate/severe pain at each post-dose timepoint from 15-min to 48-h. Starting as early as 15-min post dose there was a higher proportion of zavegepant patients with mild or no pain compared to patients treated with placebo, which translated to approximately 3-h more time in a state of pain freedom over the study period.

Results were consistent across analyses (complete case analysis versus MNAR imputation analysis) and classification of pain severity outcomes (four severity states versus binary states). However, some differences were observed with MNAR imputation analysis yielding larger treatment differences and more significant p values compared to the complete case analysis, most likely due to the larger sample size.

When patients were stratified by pain severity at baseline, more patients with moderate pain achieved pain relief and pain freedom during the first 3-h. This is consistent with literature suggesting that migraines with more severe pain are more difficult to treat [39,40,41]. However, albeit a small number, some patients who reported severe pain at baseline treated with zavegepant reported mild or no pain as early as 15-min, suggesting that the effect can be rapid in those patients who respond well to zavegepant.

When examining functional disability, improvements were observed as early as 30-min post-dose for zavegepant-treated patients, which led to an additional ~ 3-h with normal functional ability over the 48-h period compared to placebo.

When a subset of patients with severe functional disability or bedrest were examined in greater detail, the benefit of zavegepant appeared to be slightly more delayed than for the overall sample, with benefits becoming apparent around 2-h post dose (versus 30-min overall). This is expected given treating patients with severe disability is more challenging [42], and it is promising that benefits were observed among these patients, even if these were not as immediate as those with mild functional disability at baseline.

When examining the predictors of functional disability, zavegepant treatment, lower pain severity, number of historical moderate or severe attacks per month and freedom from nausea, phonophobia, and photophobia were associated with better function, when modelled using mixed effects logistic regression. These results firstly demonstrate that zavegepant is a meaningful treatment option for return to normal function when compared to placebo. Secondly, these results highlight the impact of migraine baseline characteristics and the presence or absence of other migraine-related symptoms on functional disability. This is in line with other studies which have demonstrated that baseline characteristics can impact treatment response [43, 44].

Prior research has confirmed that for acute treatments, rapid pain relief and rapid return to function are important qualities to patients, along with no symptom recurrence [25, 45]. While 2-h pain freedom, pain relief, and freedom from MBS are important endpoints for regulatory approval, the effectiveness of treatment over the typical duration of migraine (24–48-h) is undeniably important to patients. These findings suggest that zavegepant can start to reduce symptoms quickly and that, on average, treatment with zavegepant reduces the time spent with migraine-related disability and head-pain by 3-h over 48-h.

Migraine-related disability experienced by individuals both during and in between attacks (interictal period) is substantial, and is related to reduced HRQoL and increased prevalence of anxiety and depression [46]. Effective acute treatments can alleviate both attack-related disability and interictal burden by reducing symptoms and restoring normal function more rapidly, and by reducing anxiety and fear patients may have regarding future attacks [47]. Findings of the current analysis are particularly meaningful given the unmet need for effective migraine treatments, which is even more pronounced among those with insufficient response to or contraindication to triptans. Even for patients who do respond well to triptans, but who experience a substantial number of migraine attacks per month, CGRP receptor antagonists, such as zavegepant, have the potential to be a valuable addition to their treatment armament, to prevent overuse of triptans and possible development of MOH. However, future research is needed to fully understand this.

To our knowledge, none of the nasal triptan therapies have examined pain severity or functional disability over 48-h in the same level of detail as the current analysis. Sustained pain relief and freedom at 48-h have been reported in some nasal triptan studies [48, 49]. Cady et al. reported significantly greater pain relief and pain freedom at 48-h among those treated with sumatriptan when compared to placebo. [49] Similarly, Djupesland et al. reported a significantly greater proportion of patients with pain freedom from 120-min to 48-h post-dose in the sumatriptan group compared to the placebo patients. [48]

Freedom from functional disability has been described in the literature examining migraine nasal therapies [48,49,50,51,52,53]. For example, Djupesland et al. reported 63% with no disability at 2-h compared to just 31% of placebo patients. [48] Similarly, Lipton et al. reported a significantly greater mean change reduction in functional disability in the DFN-02 group compared to the placebo group. [50] Significant differences at two hours were also reported for other nasal therapies when compared to placebo [49, 51,52,53]. However, none of the above studies have examined this outcome over 48-h. Post-hoc analyses of other novel acute oral therapies (lasmiditan, rimegepant) have examined functional disability in greater detail [54, 55]. A relationship between pain freedom and disability was noted in a pooled analysis of lasmiditan trials, though the current analyses was able to quantify this further using longitudinal modeling [54]. This confirms that while pain severity is clearly linked to functional disability, it is not the only contributor to migraine-related disability.

There are several strengths to this analysis. Firstly, patients were selected from the BHV3500-301 phase 3 trial which was a rigorously conducted randomized placebo-controlled trial. Additionally, in this current post-hoc analysis sensitivity analyses were conducted to determine the impact of missing timepoints over the study period including using an MNAR imputation analysis. This allowed us to examine the impact of zavegepant on the proportion and amount of time spent in various pain and functional disability states for all patients. Furthermore, characterizing pain severity and functional disability over the 48-h period provides a more nuanced understanding of the benefits of zavegepant versus primary endpoints required in registrational trials. Moreover, no other study has compared zavegepant with placebo with respect to time spent in various pain severity states, functional categories, or percentages of patients in pain severity or functional state categories. Translating the benefit of zavegepant into hours of normal functioning and pain freedom gained vs placebo provides an endpoint that is easily interpretable for patients and can aid in clinical decision making.

One of the limitations of this analysis is that data became less available over time, though similar levels of missing data have been noted in other post-hoc analyses of acute treatment of migraine trials [54]. Over 40% of patients had ≥ 1 missing timepoint by 48-h and the proportion of missing data was larger for patients with higher severity. Secondly, the findings of this post-hoc analysis are based on a single attack and therefore could not take into account possible variance between attacks within individuals and it was also unable to assess the consistency of treatment effects of zavegepant. Furthermore, as this was a single attack study, this may impact the generalizability of this study. Future research should investigate real world, long-term use of oral and intranasal CGRP receptor antagonists to assess their impact on migraine-related disability and HRQoL, both during and between attacks (interictal period).

Conclusions

In this post-hoc analysis, zavegepant nasal spray was associated with rapid and sustained pain reduction and improvements in patient’s functional ability, resulting in more time spent with pain freedom and in a state of normal functioning compared to placebo, over the 48-h post-treatment. This study also demonstrated that, independent of pain, there are other factors linked to patient functioning, including the presence of nausea, phonophobia, photophobia and migraine frequency. Findings support the use of zavegepant as an important tool for patients requiring rapid and sustained relief from migraine pain and disability. Zavegepant is particularly suited for patients who would benefit from a non-oral formulation (e.g., due to nausea and vomiting), and without the challenges of existing nasal triptans (e.g., CV contraindications, tolerability issues, and risk of medication overuse headache).

Data availability

To preserve patients’ privacy, individual patient data from the BHV3500-301 (NCT04571060) dataset are not publicly available.

Abbreviations

AE:

Adverse event

CGRP:

Calcitonin gene-related peptide

CI:

Confidence interval

CV:

Cardiovascular

FDA:

US Food and Drug Administration

FF:

Freedom from

HRQoL:

Health-related quality of life

ICHD:

International Classification of Headache Disorder

MBS:

Most bothersome symptom

MHD:

Monthly migraine days

MNAR:

Missing not at random

MOH:

Migraine overuse headache

SD:

Standard deviation

US:

United states

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Acknowledgements

The study was supported by Pfizer, developer of zavegepant. We thank the participants and investigative staff at study centres.

Funding

This study was funded by Pfizer.

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Authors and Affiliations

  1. Broadstreet Health Economics & Outcomes Research, Vancouver, BC, Canada

    Lauren Powell, Fiona O’Sullivan, Pramoda Jayasinghe & Basia Rogula

  2. Pfizer Inc, NYC, USA

    Feng Dai, Jessica Cirillo & Samantha Sweeney

  3. Pfizer R&D UK Ltd., Tadworth, Surrey, UK

    Lucy Abraham

  4. Department of Neurology, Medstar Georgetown University Hospital, Washington, DC, USA

    Jessica Ailani

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Contributions

The following outlines the author's contributions. Study design: LP; JC, JA, SS, PJ, BR, Data analysis: PJ, BR, FD; Data interpretation: All authors. Manuscript preparation: LP, FOS. Manuscript review and revisions: All authors. Final approval of manuscript: All authors.

Corresponding author

Correspondence to Jessica Cirillo.

Ethics declarations

Ethics approvals and consent to participate

Ethics approval for the BHV3500-301 (NCT04571060) trial was approved was obtained in accordance with the principles of the Guidelines for Good Clinical Practice, the Declaration of Helsinki, and all applicable local regulations. The protocol was approved by a central institutional review board (Advarra IRB, Columbia, MD, USA, number 0000080) and by a local institutional review board (Biomedical Research Alliance of New York Institutional Review Board, Lake Success, NY, USA, number 00010793) for one study centre.

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No applicable.

Competing interests

BR, FOS, LP, and PJ, and are employees of Broadstreet HEOR, which received funds from Pfizer for this work. FD JC, LA and SS are employed by and own stock/stock options in Pfizer. JA has received personal compensation for serving as a consultant for Pfizer.

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Powell, L., O’Sullivan, F., Jayasinghe, P. et al. Reduction of pain and functional disability over time in patients treated with zavegepant: a post-hoc analysis of the BHV3500-301 phase 3 randomized controlled trial. J Headache Pain 26, 1 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s10194-024-01915-y

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The Journal of Headache and Pain

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