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

Abstract

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.

Commentary: Systematic Review of Safety and Efficacy of Atacicept in Treating Immune-Mediated Disorders

“…Importantly, promising significant results of atacicept in SLE patients with high disease activity, serologically active disease, or both described in the same publication, are not mentioned in the review (13). A secondary analysis also showed that patients with high disease activity who received 150 mg atacicept for 24 weeks were more likely to attain low disease activity and remission than those treated with placebo (7).…”

“…The analysis of the ADDRESS II primary endpoint focuses on statistical significance, which is misleading as a trend was observed in the 150 mg group ( 13 ). SLE is a clinically heterogenous disease and so it is important to identify specific cohorts of patients who may respond to a treatment; the beneficial effect of atacicept in a predefined subpopulation of ADDRESS II patients with high disease activity (HDA, SLEDAI-2K ≥10) ( 7 , 13 ) was not discussed in the review article.…”

Emerging B-Cell Therapies in Systemic Lupus Erythematosus

“…Interestingly, post hoc analyses of ADDRESS II demonstrated that low disease activity (LDA) and Lupus Low Disease Activity State (LLDAS) were achieved at week 24 in the patients with high disease activity receiving atacicept 150mg (p<0.01) compared to placebo. 66 In addition, high baseline levels of both serum BlyS and APRIL correlated with a greater treatment response, and increased atacicept exposure correlated with reduced flare rates. 67 The greater reduction in levels of immunoglobulin and plasma and naïve B-cell numbers was associated with greater reductions in flare rate, suggesting there is a dose–response relationship between atacicept concentrations and reduced serum levels of B cells and immunoglobulins.…”

Treatment targets in SLE: remission and low disease activity state

“…In a head-to-head superiority comparison of mycophenolate and azathioprine in patients with active SLE, LLDAS was assessed as a secondary discriminant outcome measure, with more patients in the mycophenolate treatment group attaining and sustaining LLDAS compared with patients treated with azathioprine (79% vs 57% at 12 months, respectively) [ 62 ]. In studies of novel therapies including belimumab, atacicept, baricitinib and anifrolumab, LLDAS was able to discriminate responders to active drug from placebo [ 63–66 ]. Moreover, LLDAS was a more stringent discriminator compared with currently used responder indices such as SRI and BICLA [ 63–65 ].…”