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

Abstract

Objective. To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.Methods. The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level. Results.No statistically significant differences were observed in the efficacy end points at week 26 (P ‫؍‬ 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.Conclusion. This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II, randomized, placebo-controlled trial

“…Overall, dose loading had no effect on the clinical outcomes or pharmacodynamics. A separate phase II dose-finding study of atacicept in patients with RA and an inadequate response to TNF antagonists (the AUGUST I study) also showed no significant beneficial effect on clinical measures of disease, including the primary end point, the ACR20-CRP (20,21). However, potent dose-dependent biologic activity was observed in that study (20,21).…”

“…The reason for these differential responses is not clear. One possible explanation is selective mobilization of plasma cells into the circulation during treatment (i.e., weeks [16][17][18][19][20][21][22][23][24][25][26]. Another possibility is that this could result from rapid transition of mature B cells into plasma cells.…”

“…The AUGUST I study, which ran in parallel to AUGUST II, was a dose-finding study of atacicept in patients with RA and an inadequate response to tumor necrosis factor (TNF) antagonists. The results of AUGUST I are reported elsewhere (20,21).…”

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…In other words, atacicept at the dosage employed in this clinical trial reduced the level of several biomarkers that are known to drive the progression of RA without showing clinical efficacy at the lowest ACR criteria for an effective clinical response to an experimental therapy. In the other clinical investigation [185], atacicept also was found to reduce total immunoglobulin and RF levels, but failed to alter anti-citrullinated protein antibody levels. The reduction in the levels of IgG-and IgA-RF in response to atacicept was more significant than the response of total IgG and IgA levels to the drug.…”

B cells biology in systemic lupus erythematosus—from bench to bedside

“…Phase Ib placebo-controlled trial displayed biological activity of Atacicept in abating Ig levels and reducing total B cell numbers, in a dose-dependent manner [190]. Two phase II RCT of Atacicept in treating refractory rheumatoid arthritis displayed a rapid and profound decline of Ig and rheumatoid factor levels as well as circulating mature B cells and plasma cells in Atacicept group, although the primary endpoint of ACR20 was not met [191,192]. The biologic effects justify clinical trials in SLE.…”