Integrated safety profile of atacicept: an analysis of pooled data from the atacicept clinical trial programme.

Caroline Gordon,David Jayne,Peter Chang,Patricia Fleuranceau-Morel,Roberto Bassi,Amy Kao,David Wofsy

doi:10.1093/rap/rkz021

Abstract

ObjectiveTo characterize the overall safety profile of atacicept, we conducted an integrated analysis of pooled safety data from all 17 clinical studies to date.MethodsThree data sets were used to investigate safety endpoints: a double-blind placebo-controlled set (n = 1568), an SLE set (n = 761) and a full analysis set (n = 1845; including all 17 studies).ResultsOf 1568 patients in the double-blind placebo-controlled-set, 30.8% received placebo, and 8.2, 24.5 and 36.5% received atacicept 25, 75 and 150 mg, respectively. Treatment-emergent adverse event (TEAE) rates (adjusted by treatment-exposure) were generally higher with atacicept vs placebo, but no consistent association was found between atacicept dose and specific TEAEs or mortality. Serious infection and serious TEAE rates were similar for atacicept and placebo. The TEAE-related discontinuation rates were higher with atacicept vs placebo (16.1 vs 10.9/100 patient-years). In the full analysis set, 11 deaths occurred during treatment. Across indications, exposure-adjusted mortality rates/100 patient-years (95% CI) were 3.60 (0.90, 14.38), 0.34 (0.05, 2.43) and 1.18 (0.49, 2.82) with atacicept 25, 75 and 150 mg, respectively, and 0.44 (0.06, 3.12) with placebo. In SLE patients, exposure-adjusted mortality rates were 1.45 (0.54, 3.87) with atacicept 150 mg and 0.78 (0.29, 2.07) across all atacicept-treated patients. No deaths occurred with atacicept 75 mg or placebo. In the SLE and double-blind placebo-controlled sets, pharmacodynamic effects of atacicept were not associated with increased infection rates.ConclusionThe results of this integrated safety analysis support further development and evaluation of atacicept in selected patients for whom potential benefits might outweigh risks.

Highlights

Atacicept is a fully human, soluble fusion protein consisting of a transmembrane activator and calcium modulating cyclophilin ligand (CAML) interactor extracellular ligand-binding domain and a modified Fc-IgG1 domain [1], which has been shown to bind and neutralize the cytokines B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) in vitro [2]
Treatment-emergent adverse event (TEAE) rates were generally higher with atacicept vs placebo, but no consistent association was found between atacicept dose and specific TEAEs or mortality
Serious infection and serious TEAE rates were similar for atacicept and placebo

Summary

Introduction

Atacicept is a fully human, soluble fusion protein consisting of a transmembrane activator and calcium modulating cyclophilin ligand (CAML) interactor extracellular ligand-binding domain and a modified Fc-IgG1 domain [1], which has been shown to bind and neutralize the cytokines B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) in vitro [2]. Vigolo et al [12] recently demonstrated that atacicept binding is not negatively affected by the loop region of the BLyS 60-mer (a naturally occurring cleaved human BLyS), which was shown temporarily to prevent binding of the anti-BLyS antibody, belimumab. Consistent with these data, atacicept reduces serum Ig levels in a dosedependent manner in humans [13,14,15]

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Conclusion