Objectives To evaluate efficacy and safety of atacicept in preventing flares of SLE disease activity.
Methods A randomized, double-blind, placebo (PBO)-controlled, multicenter, 52-wk treatment (Tx) with 24-wk follow-up study was conducted. At screening, patients (pts) with active SLE (defined by ≥1 A and/or ≥1 B BILAG score), as well as ANA titer ≥160 and/or anti-dsDNA ≥30 IU/mL, were treated with a corticosteroid taper for 10 wks. Pts reaching BILAG C or D in all organ systems, maintained for 2 further wks, were randomized at baseline 1:1:1 to receive PBO or atacicept 75 or 150 mg SC twice weekly for 4 wks, then weekly for 48 wks. Primary efficacy endpoint was proportion of pts experiencing a flare (defined as a new BILAG A or B score, or early discontinuation imputed as flare) during the 52-wk Tx period.
Results 461 pts (93.3% female; mean age 39.0 yrs) were randomized and formed the ITT population (PBO, n=157; atacicept 75 mg, n=159; atacicept 150 mg, n=145). The 150 mg arm was terminated early due to 2 fatal pulmonary infections; this group had approximately 80% as many days of study drug exposure as the PBO and 75 mg groups. No statistically significant difference was observed in flares between atacicept 75 mg and PBO (57.9% vs 54.1%; OR 1.15, p=0.54). Ad hoc analysis of the 150 mg arm (only discontinuations prior to Tx arm termination were imputed as flares) showed a statistically significant difference compared with PBO (36.6% vs 54.1%; OR 0.48, p=0.002). 150 mg treatment was associated with a significantly delayed time to first new flare (BILAG A or B only) compared with PBO (HR 0.62, p=0.02). Ad hoc analysis was undertaken of all pts scheduled to complete Tx before the closure date of the 150 mg arm, so that all Tx arms had approximately equal days of exposure. In this analysis (75 mg, n=84; 150 mg, n=81; PBO, n=81), the 150 mg dose was superior to PBO in decreasing and delaying new flares (43.2% vs 60.5%, OR 0.49, p=0.03; HR 0.40; p<0.001). Most frequently reported AEs (≥5% of Tx group) were infection and infestations. These were similarly distributed in the PBO and Tx arms. SAE rates were similar in the PBO, 75 mg, and 150 mg groups (13.6%, 14.6%, and 13.9%, respectively) but serious infections were higher in the 150 mg group (4.5%, 3.8%, and 6.9%, respectively). The 2 fatalities in the 150 mg arm were due to pneumococcal and leptospirosis pneumonia, respectively. No other deaths occurred during the study.
Conclusions Although the primary endpoint was not met (75mg group vs PBO), ad hoc analyses suggested that Tx with the 150 mg dose of atacicept was associated with a reduced risk of SLE flares. Total serious AEs were similar between groups, but 2 fatal pulmonary infections led to early termination of the 150 mg group. Additional studies of atacicept in SLE would clarify further the relative risks and benefits.
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Acknowledgements †An affiliate of Merck KGaA, Darmstadt, Germany
Disclosure of Interest D. Isenberg Consultant for: Merck Serono. S.A., C. Gordon Consultant for: Merck Serono. S.A., D. Licu Employee of: Merck Serono. S.A., S. Copt Employee of: Merck Serono. S.A., C. Pena Rossi Employee of: Merck Serono. S.A., D. Wofsy Consultant for: Merck Serono. S.A.