Plasma SuPAR and therapeutic response to erenumab in migraine: a REFORM study

Abstract

Background: Soluble urokinase-plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation and elevated in plasma of individuals with migraine with aura. As inflammatory cytokines can upregulate calcitonin gene-related peptide (CGRP), suPAR levels might be linked to response to CGRP-targeting therapies. Therefore, we investigated whether plasma suPAR levels are associated with response to the CGRP-receptor antagonist erenumab.

Methods: In this single-center, prospective study, adults with ≥ 4 monthly migraine days received 140 mg erenumab subcutaneously every 4 weeks for 24 weeks. Blood samples were collected at baseline, Week 24 (end of treatment), and Week 48 (24 weeks post-treatment). Responders were defined as achieving a ≥ 50% reduction in monthly migraine days from baseline to weeks 13-24. Associations between baseline suPAR and treatment response were analyzed using logistic and linear regression. Longitudinal changes in suPAR were assessed using linear mixed models.

Results: The study included 623 participants with migraine (mean age 44.1 ± 12.3 years; 90.4% female) and 154 healthy controls. Among participants, 183 (29.4%) had migraine with aura, and 406 (65.2%) had chronic migraine. Baseline plasma suPAR levels were not associated with response to erenumab in the total migraine population (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.64 to 1.07; p = 0.14) or in the aura subgroup (OR 0.73, 95% CI 0.48 to 1.10; p = 0.14). Plasma suPAR levels were significantly higher in non-responders compared to responders at Week 48 (7.5% higher, 95% CI 3.3 to 11.5%; p = 0.005). Non-responders with aura had higher suPAR concentrations than controls at baseline (difference 10.1%; 95% CI 3.0 to 17.8%; p = 0.023) and Week 24 (8.7%; 95% CI 1.6 to 16.2%; p = 0.047). These differences persisted at Week 48 (12.4%; 95% CI 4.6 to 20.7%; p = 0.013). No longitudinal changes in suPAR concentrations were observed.

Conclusions: We did not find an association between baseline plasma suPAR levels and response to erenumab. Plasma suPAR concentrations remained stable, even among participants with aura. These findings suggest that systemic low-grade inflammation, as measured by suPAR, does not influence treatment efficacy.

Trial registration: Pre-registered on ClinicalTrials.gov (NCT04603976 and NCT04674020).

Keywords: Biomarker; Blood; CGRP; Efficacy; Inflammation; Predictors.

Fig. 1

Study flow. legend: Blood samples analyzed for plasma soluble urokinase-type plasminogen activator receptor (suPAR) were collected at baseline (Screening visit during weeks − 5 to -6), Week 24 (± 2), and Week 48 (± 4). Treatment with erenumab was administered every 28th day from day 1 (1st injection) to Week 24. Detailed reasons for exclusion are available in Supplementary Figure S1. Abbreviations: CGRP-mAbs, calcitonin gene-related peptide monoclonal antibodies; MMDs, monthly migraine days; suPAR, soluble urokinase-type plasminogen activator receptor

Fig. 2

Plasma suPAR concentrations (total population). legend: Plasma concentrations of soluble urokinase-type plasminogen activator receptor (suPAR) across the study population. Panel (A) displays suPAR levels for all participants with at least one eligible blood sample (purple). Panel (B) distinguishes between erenumab responders (≥ 50% reduction in monthly migraine days [MMDs], red) and non-responders (< 50% reduction in MMDs, orange). Healthy controls (HCs) are indicated in blue. Box plots represent the median (bold horizontal line) and interquartile range (IQR; top and bottom of the box), with whiskers extending to 1.5 times the IQR. Mean plasma suPAR levels are connected by dots. Statistically significant pairwise differences (p < 0.05) are denoted by dark blue brackets (Supplementary Table S8)

Fig. 3

Plasma suPAR concentrations (migraine with aura subgroup). legend: Plasma concentrations of soluble urokinase-type plasminogen activator receptor (suPAR) across the migraine with aura subpopulation. Panel (A) displays suPAR levels for all participants with at least one eligible blood sample (purple). Panel (B) distinguishes between erenumab responders (≥ 50% reduction in monthly migraine days [MMDs], red) and non-responders (< 50% reduction in MMDs, orange). Healthy controls (HCs) are indicated in blue. Box plots represent the median (bold horizontal line) and interquartile range (IQR; top and bottom of the box), with whiskers extending to 1.5 times the IQR. Mean plasma suPAR levels are connected by dots. Statistically significant pairwise differences (p < 0.05) are denoted by dark blue brackets (Supplementary Table S14)