Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial

Abstract

Introduction: Atacicept is a soluble, fully human, recombinant fusion protein that inhibits B cell-stimulating factors APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator). The APRIL- LN study aimed to evaluate the efficacy and safety of atacicept in patients with active lupus nephritis (LN), receiving newly initiated corticosteroids (CS) and mycophenolate mofetil (MMF).

Methods: This was a randomized, double-blind, placebo-controlled Phase II/III, 52-week study. At screening (Day -14), patients initiated high-dose CS (the lesser of 0.8 mg/kg/day or 60 mg/day prednisone) and MMF (1 g daily, increased by 1 g/day each week to 3 g daily). From Day 1, atacicept (150 mg, subcutaneously, twice weekly for 4 weeks, then weekly) was initiated with MMF along with a tapered dose of CS.

Results: The trial was terminated after the enrollment of six patients, due to an unexpected decline in serum immunoglobulin G (IgG) and the occurrence of serious infections. Efficacy was thus not evaluated. By Day 1, serum IgG levels had declined substantially in patients then randomized to atacicept (n = 4) compared with placebo (n = 2). Patients receiving atacicept also had more severe proteinuria on Day -14 than those on placebo. Lymphocyte counts were low at screening in all patients. IgG decline continued following initiation (Day 1) of atacicept. Three atacicept-treated patients developed serum IgG below the protocol-defined discontinuation threshold of 3 g/l, two of whom developed serious pneumonia.

Conclusions: Future studies are needed to characterize the safety, efficacy, and pharmacodynamic response of atacicept in LN patients.

Trial registration: ClinicalTrials.gov: NCT00573157.

Figure 1

Immunoglobulin (Ig) levels in all six patients, across the study period. A) IgG, reference range (RR) 5.65 to 17.65 g/l, < 3 g/l represented study discontinuation threshold; B) IgA, RR 0.7 to 4 g/l; C) IgM, RR 0.4 to 2.3 g/l. IgA and IgM were not measured during the screening period (Days-14 to 1). Discontinuation days were not necessarily scheduled follow-up days. LLN, lower limit of normal; ULN, upper limit of normal.