Background/Purpose:

Atacicept is a fusion protein that inhibits B cell stimulating factors BLyS and APRIL. We examined the pharmacodynamic (PD) effects of atacicept in patients with SLE. We also investigated whether PD markers have the potential to function as predictors of flare and clinical response to atacicept.

Methods:

APRIL-SLE was a double-blind, placebo-controlled study of subjects with active SLE that had become inactive during a 12-week course of tapered corticosteroids. Subjects were then 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 the percent of subjects experiencing an SLE flare (BILAG A and/or B) during a 52-week treatment period. Patients also were followed during a 24-week follow-up period. PD analyses were conducted on the treatment completer population. Analyses of BLyS and APRIL levels as potential predictive biomarkers were performed on the potential completer population. Efficacy and safety results are reported separately.

Results:

Atacicept induced substantial changes in PD and disease-related markers, including reductions in Ig levels, autoantibody levels, and both naïve and memory B cells, as well as increases in complement levels (Table). Except for memory B cells, which continued to decline, these effects lessened during the follow-up period but did not fully return to baseline over 24 weeks. The atacicept treatment effect (reduction in flares vs placebo) was observed in subjects with BLyS or APRIL levels ≥median, but not subjects with levels < median (except in the atacicept 150 mg arm). The difference was most pronounced in patients with both baseline BLyS and APRIL ≥median, with flare rates of 76, 53 and 23% in the placebo, 75 mg, and 150 mg groups, respectively. Atacicept-treated patients with the greatest absolute decrease in IgG experienced the fewest new flares (37.2% for patients in the bottom tertile [<–4 g/L] vs 61.5% for the upper tertile [≥–1.5 g/L]). This pattern was also observed for changes in IgM (47.5 vs 60.0%) and for naïve B cells (38.2 vs 57.1%). The incidence of infection was comparable regardless of BLyS or APRIL level at baseline, or the degree of decline in IgG or IgM levels.

Conclusion:

Atacicept caused declines in IgG, IgA and IgM, as well as naïve and memory B cells. With the exception of memory B cells, these levels returned towards baseline after therapy. Atacicept also had favorable effects on anti-dsDNA and complement levels. The exploratory post-hoc analysis of potential predictive biomarkers identified a subgroup of patients with higher BLyS and APRIL levels at baseline who were more likely to benefit from treatment. In addition, patients with the largest decrease in Ig levels and/or naïve B cells demonstrated a greater clinical response. Further studies are required to clarify the associations between biomarkers and clinical response to atacicept.

Table. Median percent change from baseline; Treatment Completer population
	Placebo (n=111)		Atacicept 75 mg (n=112)		Atacicept 150 mg (n=62)
	Wk 52	24-wk FU	Wk 52	24-wk FU	Wk 52	24-wk FU
Total IgG	3.23	3.51	–30.40	–7.01	–37.62	–9.24
Total IgA	2.12	1.16	–52.61	–16.22	–57.89	–21.96
Total IgM	–1.44	–3.13	–65.74	–29.27	–68.75	–24.04
Naïve B cells*	–9.00	–5.63	–80.12	–66.67	–81.47	–66.67
Memory B cells*	–2.17	9.30	–12.50	–50.00	–28.21	–40.00
Plasma cells*	0.00	–34.85	–61.58	–55.00	–67.08	0.00
	Wk 52	12-wk FU	Wk 52	12-wk FU	Wk 52	12-wk FU
Anti-dsDNA (subjects +ve at screening)†	13.89	41.42	–31.46	–20.85	–37.86	­–11.78
C3 (subj ‡	4.13	3.56	7.15	3.01	15.38	5.43
C4 (subj §	–0.44	0.00	42.71	18.18	49.50	48.94
*Flow cytometry population: placebo, n=37; atacicept 75 mg, n=38; atacicept 150 mg, n=25; †Anti-dsDNA >=30 IU/ml; placebo, n=71; atacicept 75 mg, n=62; atacicept 150 mg, n=43; ‡C3 <0.9 g/L; placebo, n=33; atacicept 75 mg, n=53; atacicept 150 mg, n=28; §C4 <0.1 g/L; placebo, n=28; atacicept 75 mg, n=32; atacicept 150 mg, n=17; Wk=week; FU=follow-up; IgG=immunoglobulin G; IgA=immunoglobulin A; IgM=immunoglobulin M

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacodynamics-and-predictive-biomarkers-in-patients-treated-with-atacicept-data-from-the-april-sle-trial/