Background/Purpose: Atacicept targets the B-cell-stimulators BLyS and APRIL, and is in development for the treatment of patients (pts) with SLE. Here, we integrated non-clinical and clinical data to determine an appropriate atacicept dose for a Phase 3 (P3) study in auto-antibody positive SLE pts with high disease activity (HDA).

Methods:

Non-clinical data for atacicept were obtained from two murine models: a spontaneous SLE model (given control or mouse TACI-Fc 5 mg/kg intraperitoneally [IP] 3 times per week [wk]) and a 4-hydroxy-3-nitrophenylacetyl-Keyhole Limpet Haemocyanin (NP-KLH) vaccinated model to assess immunomodulation (given control or atacicept 1, 3 or 10 mg/kg IP every third day). Clinical data were obtained from a P1 pharmacokinetic (PK) study in healthy participants (Study 022; single-dose atacicept 25, 75 or 150 mg) and two P2 studies in pts with autoantibody-positive SLE (APRIL-SLE [NCT00624338]; ADDRESS II [NCT01972568]). In both P2 studies, pts were randomized (1:1:1) to once-wkly (QW; initial 4 wks of twice-weekly dosing in APRIL-SLE) subcutaneous atacicept (75 or 150 mg) or placebo (PBO). Primary endpoints: APRIL-SLE, proportion of pts with BILAG A/B flare over 52 wks; ADDRESS II, SRI-4 response at Wk 24. An analysis of SRI-6 response at Wk 24 was performed in ADDRESS II pts with Screening HDA (SLEDAI-2K≥10). A population PK model was developed and population PK model-derived exposure vs probability of clinical response (BILAG A/B flare, SRI-4, SRI-6) evaluated. An exploratory analysis of the impact of atacicept exposure on safety was also performed.

Results:

In the spontaneous SLE model, TACI-Fc 5 mg/kg prevented proteinuria development and glomerular damage. In atacicept-treated NP‑KLH vaccinated mice, anti-KLH IgG decreased markedly (>50% reduction vs control at all doses), with mean atacicept serum trough concentrations (C_min) of ~2.3 µg/mL (1 mg/kg), ~5 µg/mL (3 mg/kg) and ~8.5 µg/mL (10 mg/kg). Atacicept 150 mg QW resulted in greater clinical responses than PBO (APRIL-SLE: BILAG A/B flare, time to flare; ADDRESS II: SRI-4 [modified intention-to-treat] and SRI-6 response [HDA]). In both studies, atacicept exposure-response (E-R) relationships were identified. For maximal flare reduction, atacicept AUCτ (area under the concentration curve over one dosing interval, i.e. 1 wk) ≥1 mg∙hr/mL was identified and was more achievable with 150 than 75 mg (60% vs 15% probability); AUCτ was the exposure metric that contributed to the P3 dose selection. Atacicept exposure for maximal flare reduction corresponded to a C_min of 5 µg/mL which was similar to that observed in the murine models. SRI-4 and SRI-6 (HDA) response rates increased with increasing atacicept AUC within the exposure range observed in ADDRESS II. Atacicept 150 and 75 mg had acceptable safety profiles in SLE pts; there was no apparent E-R relationship for serious infections.

Conclusion: Integrated non-clinical, clinical and E-R data demonstrate an acceptable benefit-risk profile for atacicept in SLE pts with HDA and support the selection of 150 mg QW for P3 studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/atacicept-dose-rationale-for-a-phase-3-study-in-patients-with-high-disease-activity-and-auto-antibody-positive-sle/