Background/Purpose:

Atacicept is a fusion protein that inhibits B-cell stimulating factors BLyS and APRIL. We previously reported the clinical effects of atacicept in lupus patients with active disease (the APRIL-SLE study). Here we report the exploratory analysis between mean drug concentration and clinical outcome in those subjects.

Methods:

Patients with active SLE (≥1 BILAG A and/or B) were treated with corticosteroid taper for 12 weeks. Subjects reaching BILAG C or D at weeks 10 and 12 were randomized 1:1:1 to receive placebo (PLC), atacicept 75 mg (A75) or 150 mg (A150) twice weekly for 4 weeks then weekly for 48 weeks. All patients received standard of care. As previously reported, A150 reduced the frequency of BILAG A and B flares but was discontinued prematurely due to two infection-related deaths. This post-hoc analysis was performed among subjects in all groups randomized at least 52 weeks prior to discontinuation of A150 and who had an opportunity to complete the protocol (n=81, 84, and 81 for PLC, A75, and A150, respectively). For this analysis subjects in the two treatment arms were divided into four quartiles based on mean atacicept concentration, the 1^st being the group with the lowest concentration.

Results:

Subjects with the highest atacicept concentrations (3rd and 4th quartiles) experienced fewer flares during treatment compared to subjects with lower concentrations (1st and 2nd quartiles) and subjects in the PLC group (60, 63, 61, 49, and 29% in the PLC, 1st, 2nd, 3rd, and 4th quartiles, respectively). Similarly, the proportions of subjects using high-dose corticosteroids was lowest among subjects with higher concentrations of atacicept (32, 24, 17, 22 and 15% in the PLC, 1st, 2nd, 3rd and 4th quartiles). Time to first new flares was also longer for atacicept than the PLC. Despite their higher atacicept concentrations subjects in the 4th quartile experienced similar proportions of treatment-emergent serious or severe infectious adverse events vs PLC (4.9 vs 3.7%). Subjects with baseline free BLyS and APRIL concentrations both ≥median experienced fewer flares in the groups with higher atacicept concentrations (2nd, 3rd and 4th quartiles). Results are summarized in the Table 1. The two subjects in the A150 group who died due to infection had mean and max trough levels that were near or below the 25th percentile concentration.

Conclusion:

Subjects in the APRIL-SLE study who achieved the highest concentrations of atacicept showed a reduced risk of SLE flares and increased time to flare. Atacicept was also associated with a reduction in corticosteroid use. Subjects with free BLyS and APRIL levels above median at baseline had an increased flare risk in the PLC group; among these subjects, there was an even greater treatment effect seen in the atacicept groups. These post-hoc results warrant further studies to assess the safety and efficacy of atacicept in SLE patients.

Table 1. Treatment response by quartiles of atacicept mean concentration (trough level): Potential Completer population
	Placebo	Atacicept 1st Quartile	Atacicept 2nd Quartile	Atacicept 3rd Quartile	Atacicept 4th Quartile
	n=81	n=41	n=41	n=41	n=41
Presence of flare* during treatment, n (%), [95% CI]	49 (60.5) [0.49, 0.71]	26 (63.4) [0.47, 0.78]	25 (61.0) [0.45, 0.76]	20 (48.8) [0.33, 0.65]	12 (29.3)# [0.16, 0.46]
Time to new flare (BILAG A or B only) by Kaplan-Meier curve, 25th percentile estimate (day)	97	141	196	167	>365+
Subjects who experienced a serious or severe infection during treatment period, n (%)	3 (3.7)	3 (7.3)	7 (17.1)	0	2 (4.9)
Subjects who had high-dose corticosteroids (≥20 mg/day) post-randomization during treatment period, n (%)	26 (32.1)	10 (24.4)	7 (17.1)	9 (22.0)	6 (14.6)
Baseline ≥median BLyS and ≥median APRIL‡	n=30	n=5	n=13	n=16	n=12
Presence of flare* during treatment, n (%), [95% CI]	23 (76.7) [0.58, 0.90]	4 (80.0) [0.28, 0.99]	6 (46.2) [0.19, 0.75]	7 (43.8) [0.20, 0.70]	1 (8.3)† [0.002, 0.38]
*Flare defined as having an adjudicated BILAG A or B score in any of the 8 organ systems during treatment, or imputed for subjects who had premature treatment discontinuation. +25% percentile estimate is not reached during treatment period.   ‡Categories determined by median of free BLyS (1.9 ng/mL) at baseline and median of free APRIL (2236.7 pg/mL). Two-sided Fisher’s exact test nominal p-value compared to placebo:  � #p=0.002,  †p<0.0001

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exploratory-analysis-of-pharmacokinetic-effects-of-atacicept-in-patients-with-moderate-to-severe-systemic-lupus-erythematosus/