Background Atacicept neutralizes the B cell maturation/survival factors BLyS and APRIL and has been investigated in autoimmune diseases.
Objectives This Phase II, randomized, double-blind, placebo-controlled, multicenter trial assessed safety and efficacy of atacicept in combination with rituximab, in patients with rheumatoid arthritis (RA).
Methods Patients with active RA (DAS28 >3.2) who had received previous rituximab treatment and were candidates for rituximab retreatment were included. Two rituximab infusions (Wks 1 and 3) were given followed by randomization at Wk 7 to atacicept 150 mg or placebo, given subcutaneously once-weekly (2:1 ratio) for 25 weeks. Patients were followed up for 32 weeks off treatment. Primary endpoints were nature, incidence, severity of AEs (particularly infections); proportion of patients developing IgG levels <3 g/L; laboratory safety parameters; immunization status. Secondary endpoints included effect on peripheral blood B cells; biomarkers; composite measures of disease activity.
Results Of 28 patients given rituximab, 18 were randomized to atacicept, 9 to placebo; 1 patient dropped out after the first rituximab infusion due to an AE (cough). Most patients (94.4% atacicept, 100% placebo) experienced ≥1 AE. SAEs were experienced by 1 patient on atacicept (transient ischemic attack [TIA], drug hypersensitivity) and 2 on placebo (TIA, ruptured cerebral aneurysm) during treatment and by 6 (33.3%) atacicept-treated patients during follow up. AEs led to discontinuation in 4 (22.2%) atacicept-treated patients (hypersensitivity reactions, pruritis, diarrhea/gastritis) vs. 1 (11.1%) placebo-treated patient (ruptured cerebral aneurysm). Infection rates were similar in both groups (12 patients [66.7%] on atacicept; 6 patients [66.7%] on placebo). No infection-related SAEs occurred during treatment and rates were similar between groups during follow up. Hypersensitivity-related events were more common in atacicept-treated patients. Three patients (16.6%) on atacicept withdrew from the study due to hypersensitivity-related events compared with 0 (0%) on placebo. Atacicept reduced total IgG by 35.6% (SD ±15%) at Wk 32, with gradual recovery during follow up (-10% at Wk 64); no patient had IgG <3 g/L. Atacicept reduced immunization titers at Wk 32 (median reduction ≤34%); median values returned to baseline by Wk 48. Decreases in rheumatoid factor (RF), including IgG-RF, IgA-RF and IgM-RF, were ∼60–65%. Atacicept treatment was not associated with subsequent delay in B cell recovery during follow-up. At Wk 32, ACR-CRP20, ACR-CRP50 and ACR-CRP70 response rates were 33.3%, 11.1% and 5.6% respectively in the atacicept group vs. 22.2%, 11.1% and 0% in the placebo group. Hematologic, biochemical, vital signs and ECG assessments revealed no safety concerns.
Conclusions In this exploratory trial, addition of atacicept to rituximab was associated with an increased risk of events that could be hypersensitivity-related. There was no increase in the clinical response rate.
Disclosure of Interest R. van Vollenhoven Grant/Research support from: Abbott Laboratories; GlaxoSmithKline; MSD; Merck Serono S.A.; Pfizer Inc.; Roche Pharmaceuticals; UCB Pharma, Consultant for: Abbott Laboratories; GlaxoSmithKline; MSD; Merck Serono S.A.; Pfizer Inc.; Roche Pharmaceuticals; UCB Pharma, S. Wax Employee of: EMD Serono Inc., S. Copt Employee of: Merck Serono S.A., P. Tak Shareholder of: Arthrogen B.V., Consultant for: Genentech; Roche Pharmaceuticals; Merck Serono S.A., Employee of: GlaxoSmithKline