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

Abstract

Objective. To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist-naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.Methods. In this phase II study, patients with active RA (n ‫؍‬ 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4-week loading period (twice-weekly dosing), or openlabel adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C-reactive protein level (ACR20-CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety.Results. The proportion of patients meeting the primary end point (ACR20-CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20-CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50-CRP response rates were significantly higher in all activetreatment groups compared with placebo, but ACR70-CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment-free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept.Conclusion. The primary end point (ACR20-CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.

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

“…The trial population was limited to patients for whom therapy with TNF antagonists had previously failed, a patient group traditionally considered to have disease that is refractory to treatment. The effects of atacicept in TNF antagonist-naive patients with RA with an inadequate response to methotrexate have been studied in a separate trial (AUGUST II), in which a statistically significant treatment effect was seen in some secondary end points, but not the primary end point (ACR20-CRP response rate) (43,44). Effects in other patient subpopulations, such as those who are treatment naive, are currently unknown.…”

Pathogenetic insights from the treatment of rheumatoid arthritis

“…In contrast to complete B cell depletion a more subtle approach concerns inhibition of B cell modulatory cytokines. Atacicept, a fusion protein targeting two molecules required for B cell maturation and survival, BAFF und APRIL was studied in RA but failed to show significant anti-inflammatory activity despite lowering rheumatoid factor and circulating B cells levels [56]. One Syk inhibitor (fostamatinib) advanced to phase 3 trials in RA, however efficacy was discouraging [57].…”

The Roles of the TNF-Family Member B-Cell Activation Factor Belonging to the TNF-Family (BAFF) in Autoimmunity

“…Treatment-related decreases in immunoglobulin (particularly IgM) and RF levels were evident and a clear decrease in anticitrullinated protein antibodies was observed in the cohort that received seven doses of 420 mg [131]. However, further studies with atacicept did not demonstrate significant efficacy in RA patients with inadequate response to methotrexate (MTX) [132] or tumor necrosis factor antagonists [133].…”