Randomized Phase II JANUS Study of Atacicept in Patients With IgA Nephropathy and Persistent Proteinuria.

Introduction: Patients with IgA nephropathy (IgAN) and persistent proteinuria are at risk of progression to kidney failure. Atacicept is a novel B-cell-targeted immunomodulator, shown to reduce immunoglobulin levels in patients with autoimmune diseases. Methods: JANUS (NCT02808429) was a phase II study that assessed the safety, pharmacodynamic effects, and efficacy of atacicept in patients with IgAN and proteinuria ≥1 g/d or 0.75 mg/mg on 24-hour UPCR despite maximal standard of care therapy. Results: A total of 16 patients were randomized 1:1:1 to placebo (n = 5), atacicept 25 mg (n = 6), or atacicept 75 mg (n = 5) once weekly using subcutaneous injection. Twelve (75%) completed ≥48 weeks of treatment; 8 (50%) completed 72 weeks of treatment and the 24-week safety follow-up period. Fourteen patients reported treatment-emergent adverse events (TEAEs). Most TEAEs were mild or moderate in severity. Three patients (placebo n = 1; atacicept 25 mg n = 2) reported serious TEAEs, none of which were treatment related. Dose-dependent reductions in IgA, IgG, IgM, and galactose-deficient (Gd)-IgA1 with atacicept at week 24 were maintained to week 72. Early reduction in proteinuria was observed at week 24 with atacicept. Renal function progressively declined with placebo but remained stable under exposure to atacicept. Conclusion: Atacicept has an acceptable safety profile in patients with IgAN and is effective at reducing the levels of pathogenic factor Gd-IgA1, with potential improvements in proteinuria and renal function.

Safety and clinical activity of atacicept in the long-term extension of the phase 2b ADDRESS II study in systemic lupus erythematosus.

OBJECTIVES: Atacicept reduced SLE disease activity in the phase 2b ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. METHODS: In the 24-week, randomized, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary endpoint. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. RESULTS: In total, 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4-93.2%), and 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. CONCLUSION: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02070978.

Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study.

OBJECTIVE: Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS: Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician's Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS: Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION: At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.