Atacicept in patients with rheumatoid arthritis: Results of a multicenter, phase ib, double‐blind, placebo‐controlled, dose‐escalating, single‐ and repeated‐dose study

Abstract

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.

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

“…Previous studies in RA have indicated that levels of APRIL and BLyS are elevated in synovial fluid relative to serum and have identified both antibody-secreting plasma cells and APRIL-secreting cells within the RA synovium (39,40), suggesting that local inhibition of autoimmune responses may be required for clinical effects. Phase I studies of atacicept in patients with RA have demonstrated that atacicept does enter the synovial compartment and form complexes with BLyS (26,41). However, these observations were made in very small numbers of patients, and whereas one study demonstrated lower levels of atacicept in the synovial fluid than in the circulation (26), the other showed local and systemic levels to be comparable (41).…”

“…Phase I studies of atacicept in patients with RA have demonstrated that atacicept does enter the synovial compartment and form complexes with BLyS (26,41). However, these observations were made in very small numbers of patients, and whereas one study demonstrated lower levels of atacicept in the synovial fluid than in the circulation (26), the other showed local and systemic levels to be comparable (41). Nevertheless, the possibility that atacicept may affect cells in the synovial compartment to a lesser extent than it affects those in the periphery cannot be excluded at this stage.…”

“…Several phase I studies of subcutaneous and intravenous atacicept have been completed, including a safety study in healthy volunteers and dose-escalating studies in patients with SLE, RA, or B cell malignancies (22)(23)(24)(25)(26). In all 5 phase I studies reported to date, atacicept raised no unexpected safety concerns over a range of doses.…”

“…In all 5 phase I studies reported to date, atacicept raised no unexpected safety concerns over a range of doses. Furthermore, atacicept was shown to reduce immunoglobulin and RF levels in patients with RA (26) and to reduce levels of mature B cells and serum immunoglobulin in patients with SLE (22). However, a recent phase II study of mycophenolate mofetil versus the combination of mycophenolate mofetil plus atacicept in patients with lupus nephritis was terminated early because of an unexpected incidence of infectious complications (27).…”

BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus

“…Treatment of autoimmune-prone lupus mice with Atacicept resulted in delays in the development of proteinuria and increased survival (49). Initial human trials with Atacicept have demonstrated remarkable declines in total serum immunoglobulin levels: in patients treated with Atacicept every 2 weeks for 12 weeks, reductions were seen out to the endpoint at day 85, and median IgG values were reduced by 21%, IgA values by 37% and IgM values by 54% compared to baseline values (50). This is about double the reduction seen in Belimumabtreated patients, (IgG 10%, IgA 14%, IgM 29%, after Belimumab treatment iv at days 0, 14, 28 and every 28 days to 52 weeks along with standard of care, and then analysis at week 52).…”