Safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled pilot trial

Abstract

Objective: To explore the safety and tolerability of atacicept in combination with rituximab in patients with active rheumatoid arthritis (RA) receiving rituximab re-treatment.

Methods: In this randomized, double-blind, placebo-controlled pilot trial, 2 infusions (1,000 mg per infusion) of intravenous rituximab, given 2 weeks apart, were followed by once-weekly subcutaneous injections of 150 mg atacicept or placebo for 25 weeks. Primary end points were the nature, incidence, and severity of adverse events (AEs). Secondary end points were the effects on peripheral blood B cells, disease activity biomarkers, and American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) response rates.

Results: Eighteen patients were randomized to receive atacicept and 9 to receive placebo. AEs occurred in 17 atacicept-treated patients (94.4%) and in all 9 placebo-treated patients (100%). There were no infection-related serious adverse events. Hypersensitivity and injection site reactions were more common, and more patients withdrew due to AEs, in the atacicept group. Median reductions in Ig levels from baseline to week 32 were greater with atacicept (median change in IgG -31.2%, IgM -60.9%, and IgA -56.4%) than with placebo (median change in IgG -4.4%, IgM -15.9%, and IgA -8.2%). Peripheral B cell numbers remained low in all patients after rituximab-mediated B cell depletion, limiting comparison of time to recovery between treatment groups. There were no between-group differences in ACR20, ACR50, and ACR70 response rates.

Conclusion: In this exploratory trial, atacicept in combination with rituximab showed no new safety issues. Peripheral B cell counts remained too low to determine whether atacicept delayed B cell re-expansion following rituximab-mediated depletion. Despite clear biologic effects, adding atacicept to rituximab in patients with active RA was not associated with clinical benefit.

Trial registration: ClinicalTrials.gov NCT00664521.

© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1

Disposition of the study patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. AE = adverse event; FU = followup; ITT = intent‐to‐treat.

Figure 2

Change in the levels of total, mature, and memory B cells over time in patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. Values are the percentage change from baseline, expressed as the median with interquartile range. The horizontal broken line indicates baseline.

Figure 3

Change in levels of IgG, IgM, and IgA from baseline to week 32 in patients treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. In A, values are the levels of each immunoglobulin (in gm/liter) over time. The horizontal broken line indicates the lower limit of normal. In B, values are the percentage change from baseline. The horizontal broken line indicates baseline. All results are expressed as the median with interquartile range.

Figure 4

Proportion of patients responding to combination treatment with atacicept versus those treated with placebo over time. Patients were treated with two 1,000‐mg infusions of rituximab given 2 weeks apart, followed by 150 mg atacicept or placebo given once weekly for 25 weeks. Responses were defined according to the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 based on the C‐reative protein (CRP) level.