Objective. Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.Methods. In this multicenter, phase Ib, randomized, placebo-controlled, dose-escalating trial, 73 patients were enrolled into 6 escalating-dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2-week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.Results. Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment-related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a doserelated decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3-month treatment. Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen.Conclusion. Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

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Background: Atacicept (formerly referred to as TACI-Ig) is a soluble receptor fusion protein comprised of the extracellular domain of TACI and the Fc portion of a human IgG. Atacicept binds to APRIL (A Proliferation-Inducing Ligand) and BLyS (B Lymphocyte Stimulator), which are potent survival factors for normal B cells and are over-expressed in plasma cell malignancies. APRIL and BLyS are produced by MM cellsand other cells within the tumor environment, resulting in the enhanced survival of malignant cells via both autocrine and paracrine loops. The aim of this trial was to determine the tolerability, PK, PD and biological activity of atacicept in patients with MM or WM. Methods: This was an open-label, dose-escalation study to determine the maximum tolerated dose and the optimal biologic dose of atacicept in patients with refractory or relapsed MM or active, progressive WM. Eligible patients were enrolled in sequential cohorts to receive one cycle of five weekly subcutaneous injections of atacicept at 2, 4, 7 or 10 mg/kg. Patients who demonstrated at least stable disease after the first cycle were allowed to continue to the extension phase consisting either of two additional cycles separated by a 4-week wash-out period or 15 weekly injections at a dose of 10 mg/kg. PK was assessed after the 1st and 5th dose. Usual safety parameters were assessed, including measurement of potential anti-atacicept antibodies. The biological activity assessment included M-protein, beta 2-microglobulin, soluble syndecan-1, lymphocyte subpopulation counts (by flow cytometric analysis), polyclonal immunoglobulins, serum and urinary free light chains and CRP. Response was assessed using modified Bladé criteria. Results: A total of 16 patients (12 MM and 4 WM) entered the trial. Fourteen patients completed the study, one patient was withdrawn for progressive disease and one is still being treated. No dose limiting toxicity (DLT) and no SAE related to study drug were observed. Five MM patients and 3 WM patients had stable disease after the first treatment cycle; the rest of the patients progressed. There was no obvious correlation of response with the dose received. Eight patients entered the extension phase: 4 received two additional cycles and 4 received 15 weekly injections of atacicept. Seven of the eight patients have completed the extension: 4 patients with stable disease (3 MM and 1 WM), 2 patients with progressive disease and 1 WM patient with a minimal response (M-component decrease greater than 25%). Most of patients showed a decrease of polyclonal immunoglobulins and B lymphocytes. A marked decrease in the M component and syndecan-1 was observed in several patients, while CRP was not affected. Conclusions: Treatment with atacicept was well tolerated. No dose limiting toxicity was observed. A biological response in accordance with the expected atacicept mode of action was observed in this heavily treated refractory population. Disease stabilization was seen in several patients and one WM patient achieved a minimal response.