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

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.

Keywords: Calcitonin gene-related peptide; Functional disability; Migraine; Pain; Randomized controlled trial; Therapeutics.

Fig. 1

BVH3500-301 study design schematic

Fig. 2

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

Fig. 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

Fig. 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

Fig. 5

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

Fig. 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

Fig. 7

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