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A3012 - Eosinophilic Granulomatosis with Polyangiitis Patient Characteristics and Clinical Response to Mepolizumab Compared to Placebo
Author Block: J. Steinfeld1, S. Mallett2, J. Brown2, E. S. Bradford3, S. Yancey3, M. Wechsler4; 1GSK Pharmaceuticals, King of Prussia, PA, United States, 2GSK Pharmaceuticals, London, United Kingdom, 3GlaxoSmithKline, Research Triangle Park, NC, United States, 4National Jewish Health, Denver, CO, United States.
Rationale: Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) is a systemic vasculitis associated with asthma, eosinophilia, sinusitis, pulmonary infiltrates, and neuropathy. Study MEA115921 (NCT02020889) was a double blind, randomized, placebo controlled study to investigate the efficacy and safety of mepolizumab in the treatment of EGPA (Wechsler 2017). The study showed a statistically significant benefit of mepolizumab versus placebo for both co-primary endpoints: duration of accrued remission and the proportion of subjects in remission at both Weeks 36 and 48. Significant benefits were also demonstrated in time to first relapse, relapse rate, and percentage decrease in oral corticosteroid dose (OCS) dosage during weeks 48-52. A larger treatment effect was shown in subjects with a higher baseline blood eosinophil count (BEC) (≥150 cells/uL). Post hoc modelling and subgroup analysis was needed to further characterize the relationship between patient and disease characteristics of interest and treatment benefit.
Methods: A stepwise procedure was used to build a post hoc statistical model to explore the relationship between important baseline characteristics and treatment effect. A separate modelling exercise was carried out for each endpoint of clinical interest. Post-hoc subgroup analysis was also performed to understand the effect of these baseline characteristics.
Results: Increasing baseline BEC, on a continuous scale, was associated with increased treatment effect in some but not all measures of clinical benefit. No other factors were consistently associated with treatment effect across multiple endpoints. Although a larger treatment effect (in terms of accrued duration of remission and percentage decrease in OCS dose) was seen with a lower baseline OCS dose, baseline OCS dose was disproportionately higher among those with a lower baseline BEC. Baseline OCS dose could confound accrued remission. Due to the need to taper chronic OCS slowly, subjects with a higher baseline OCS dose had less time during the treatment period to achieve the remission OCS target of ≤4 mg/day. There was no evidence of an association of treatment effect with OCS on the remission status at Weeks 36 and 48 co-primary endpoint.
Conclusions: These data demonstrate an association between higher baseline BEC and increased benefits of mepolizumab across several measures of efficacy, consistent with previous work (Wechsler 2017). However, results were inconsistent across endpoints and overall it was not possible to define a consistent eosinophil threshold for which treatment benefit was observed.
Funding: GSK [Study 115921/NCT02020889] in collaboration with NIAID [U01 AI097073] and the Division of Intramural Research, NIAID, NIH.