Post Hoc Biomarker Analyses from a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Repository Corticotropin Injection (Acthar® Gel) for Persistently Active Systemic Lupus Erythematosus

Abstract

Introduction: We conducted post hoc analyses of biomarker results from a multicenter, randomized, double-blind, placebo-controlled study of repository corticotropin injection (RCI; Acthar® Gel) in patients with persistently active systemic lupus erythematosus (SLE) despite treatment with moderate-dose glucocorticoids.

Methods: Adults with active SLE and moderate to severe rash and/or arthritis were enrolled in the primary study. Patients had active SLE despite treatment with stable glucocorticoids, antimalarials, and nonsteroidal anti-inflammatory drugs and/or immunosuppressants. Patients were randomly assigned to 80 U of RCI or placebo subcutaneously every other day for 4 weeks and then twice weekly through week 24. Blood samples were analyzed for serum cytokines and complement proteins using enzyme-linked immunosorbent or Luminex assays and for circulating leukocytes using flow cytometry. Biomarker levels were reported as percentages of the baseline and were further evaluated in subgroups stratified by baseline SLE Disease Activity Index-2000 (SLEDAI-2K) scores (< 10 vs. ≥ 10), baseline anti-double-stranded DNA levels (< 15 IU/mL vs. ≥ 15 IU/mL), and BILAG-based Combined Lupus Assessment (BICLA) responses at week 20 and 24.

Results: RCI treatment resulted in reduced levels of B cell-activating factor and interleukin-6 cytokines in all subgroups compared with placebo. RCI treatment also resulted in lower levels of CD19+ B cells and CD19+IgD-CD27-CD95+ atypical activated memory B cells than did placebo in the higher baseline disease activity subgroups and in BICLA non-responders. Furthermore, RCI treatment led to greater increases in complement component (C)3 and C4 levels than did placebo in the higher baseline disease activity subgroups and in BICLA responders.

Conclusions: RCI may reduce inflammation through B cell immunomodulation in patients with persistently active SLE, particularly in those with higher disease activity.

Trial registration: ClinicalTrials.gov identifier NCT02953821.

Keywords: Acthar gel; Autoimmune disease; Biomarker; Cytokine; Glucocorticoid; Immune cell; Repository corticotropin injection; Systemic lupus erythematosus.

© 2021. The Author(s).

Figures

Fig. 1

Mean (SEM) percentage of baseline BAFF levels reported by baseline SLEDAI-2 K score (A), baseline anti-dsDNA levels (B), and BICLA response (C), mITT populationa. aPatients who received ≥ 1 dose of study drug and contributed any postbaseline efficacy data. The dotted line represents baseline. *p < 0.05 (nominal), **p < 0.01 (nominal) for the LS mean difference using ANCOVA models with the change from baseline as the dependent variable, treatments as the factor, and baseline values of corresponding endpoints as the covariate, with stratification for location (US and outside the US) and baseline prednisone or equivalent glucocorticoid dose (≤ 20 mg/day and > 20 mg/day). ANCOVA analysis of covariance; anti-dsDNA, anti-double-stranded DNA, BAFF B cell-activating factor, BICLA British Isles Lupus Assessment Group-based Combined Lupus Assessment, LS least squares, mITT modified intention to treat, RCI repository corticotropin injection, SEM standard error of the mean, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000

Fig. 2

Mean (SEM) percentage of baseline IL-6 levels reported by baseline SLEDAI-2K score (A), baseline anti-dsDNA levels (B), and BICLA response (C), mITT populationa. aPatients who received ≥ 1 dose of study drug and contributed any postbaseline efficacy data. The dotted line represents baseline. anti-dsDNA anti-double-stranded DNA, BICLA British Isles Lupus Assessment Group-based Combined Lupus Assessment, IL-6 interleukin 6, mITT modified intention to treat, RCI repository corticotropin injection, SEM standard error of the mean, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000

Fig. 3

Mean (SEM) percentage of baseline CD19+ B cells reported by baseline SLEDAI-2K score (A), baseline anti-dsDNA levels (B), and BICLA response (C), mITT populationa. aParticipants who received ≥ 1 dose of study drug and contributed any postbaseline efficacy data. The dotted line represents baseline. *p < 0.05 (nominal) for the LS mean difference using ANCOVA models with the change from baseline as the dependent variable, treatments as the factor, and baseline values of corresponding endpoints as the covariate, with stratification for location (US and outside the US) and baseline prednisone or equivalent glucocorticoid dose (≤ 20 mg/day and > 20 mg/day). ANCOVA analysis of covariance; anti-dsDNA, anti-double-stranded DNA, BICLA British Isles Lupus Assessment Group-based Combined Lupus Assessment, CD cluster of differentiation, LS least squares, mITT modified intention to treat, RCI repository corticotropin injection, SEM standard error of the mean, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000

Fig. 4

Mean (SEM) percentage of baseline CD19+IgD−CD27−CD95+ B cells reported by baseline SLEDAI-2K scores (A), baseline anti-dsDNA levels (B), and BICLA response (C), mITT populationa. aParticipants who received ≥ 1 dose of study drug and contributed any postbaseline efficacy data. The dotted line represents baseline. anti-dsDNA anti-double-stranded DNA, BICLA British Isles Lupus Assessment Group-based Combined Lupus Assessment, CD cluster of differentiation, IgD immunoglobulin D, mITT modified intention to treat, RCI repository corticotropin injection, SEM standard error of the mean, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000

Fig. 5

Mean (SEM) percentage of baseline complement C3 levels reported by baseline SLEDAI-2K scores (A), baseline Anti-dsDNA levels (B), and BICLA response (C), mITT populationa. aParticipants who received ≥ 1 dose of study drug and contributed any postbaseline efficacy data. The dotted line represents baseline. *p < 0.05 (nominal), **p < 0.01 (nominal) for the LS mean difference using ANCOVA models with the change from baseline as the dependent variable, treatments as the factor, and baseline values of corresponding endpoints as the covariate, with stratification for location (US and outside the US) and baseline prednisone or equivalent glucocorticoid dose (≤ 20 mg/day and > 20 mg/day). ANCOVA analysis of covariance, anti-dsDNA anti-double-stranded DNA, BICLA British Isles Lupus Assessment Group-based Combined Lupus Assessment, C component, LS least squares, mITT modified intention to treat, RCI repository corticotropin injection, SEM standard error of the mean, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000

Fig. 6

Mean (SEM) percentage of baseline complement C4 levels reported by baseline SLEDAI-2K scores (A), baseline Anti-dsDNA levels (B), and BICLA response (C), mITT populationa. aParticipants who received ≥ 1 dose of study drug and contributed any postbaseline efficacy data. The dotted line represents baseline. *p < 0.05 (nominal), **p < 0.01 (nominal) for the LS mean difference using ANCOVA models with the change from baseline as the dependent variable, treatments as the factor, and baseline values of corresponding endpoints as the covariate, with stratification for location (US and outside the US) and baseline prednisone or equivalent glucocorticoid dose (≤ 20 mg/day and > 20 mg/day). ANCOVA analysis of covariance, anti-dsDNA anti-double-stranded DNA, BICLA British Isles Lupus Assessment Group-based Combined Lupus Assessment, C component, LS least squares, mITT modified intention to treat, RCI repository corticotropin injection, SEM standard error of the mean, SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index-2000