Background/Purpose:

Atacicept is a fusion protein that inhibits B-cell stimulation factors BLyS and APRIL. Levels of BLyS and APRIL are elevated in patients with SLE. We report on the efficacy and safety of atacicept in preventing new flares of SLE during 52 weeks on treatment and 24 weeks of safety follow-up in the APRIL-SLE trial.

Methods:

Subjects with active SLE (≥1 BILAG A and/or B) were treated with a corticosteroid taper for 10 weeks.  Subjects reaching BILAG C or D were randomized 1:1:1 to receive placebo or atacicept 75 or 150 mg twice weekly for 4 weeks, then weekly for 48 weeks. The primary outcome measure was percent of subjects experiencing a flare, defined as a new BILAG A or B, during the 52-week treatment period.  Subjects were also followed during a 24-week follow-up period.

Results:

461 subjects were randomized (placebo, n=157; atacicept 75 mg, n=159; atacicept 150 mg, n=145). The primary endpoint was not met in the atacicept 75 mg arm (flare rate 57.9% vs 54.1% among controls; OR 1.15, p=0.54). Treatment was discontinued in the 150 mg arm after enrollment of 145 subjects due to two fatal pulmonary infections (pneumococcus and leptospirosis). The flare rate in the 150 mg arm was 36.6% vs 54.1% in the placebo arm (OR 0.48, p=0.002). Time to first new flare was significantly longer in the 150 mg arm vs placebo (HR 0.62, p=0.02). Improvements were seen with atacicept 75 mg and 150 mg in SF-36 physical and mental summary scores exceeding the minimal clinically important difference (MCID=2.5) at Week 52 (atacicept 75 mg=3.14, 2.64; 150 mg=4.26, 3.46; placebo=2.00, 1.33). Adverse events (AEs) due to infection were similarly distributed in the placebo and treatment arms during treatment and during the 24-week follow-up period (Table). Serious AE (SAE) rates, and SAE rates due to infection, were also similar in the placebo, 75 mg, and 150 mg groups (5.8%, 7.0%, and 5.6%, respectively) throughout the treatment and follow-up period. There were no deaths during the follow-up period.

Conclusion:

The primary endpoint was not met in the atacicept 75 mg arm compared with placebo. Two fatal infections in the 150 mg arm caused sufficient concern to terminate this arm prematurely. Ad-hoc analysis of those subjects who had received 150 mg atacicept (either by reaching 52 weeks or by withdrawing during the 52-week treatment period) showed a reduced risk of SLE flares, and increased time to flare. Clinically meaningful improvements in quality of life were observed in both atacicept arms compared to controls.  Total SAEs were similar between groups. Fewer subjects in all groups experienced AEs during the 24-week follow-up period than during the 52-week treatment period. Taken together, these findings show signals suggestive of risk as well as efficacy for atacicept.  Future studies will be needed to further clarify the balance between risk and benefit and to identify subsets of subjects in whom the benefits may outweigh the risks.

Table. Proportion of subjects experiencing at least one adverse event (safety population)
	Placebo (n=154)		Atacicept 75 mg (n=157)		Atacicept 150 mg (n=144)
	Week 52	(24-week follow-up)	Week 52	24-week follow-up	Week 52	24-week follow-up
Adverse events*	117 (76.0)	48 (31.2)	130 (82.8)	59 (37.6)	116 (80.6)	50 (34.7)
Serious adverse events*	21 (13.6)	9 (5.8)	23 (14.6)	11 (7.0)	20 (13.9)	8 (5.6)
Infections*	80 (51.9)	27 (17.5)	93 (59.2)	32 (20.4)	79 (54.9)	28 (19.4)
Serious infections*	7 (4.5)	4 (2.6)	6 (3.8)	7 (4.5)	10 (6.9)	2 (1.4)
*All data are n (%).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-and-safety-of-atacicept-for-prevention-of-flares-in-subjects-with-moderate-to-severe-systemic-lupus-erythematosus-sle/