Mo039the 24-Week Interim Analysis Results of a Randomized, Double-Blind, Placebo-Controlled Phase Ii Study of Atacicept in Patients With Iga Nephropathy and Persistent Proteinuria

Abstract

Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Despite being described over 50 years ago, there remains no approved therapy for this common global cause of kidney failure. The central pathogenic feature in IgAN is the formation of circulating IgA containing immune complexes which have the propensity to deposit in the kidneys and trigger glomerular inflammation and tubulointerstitial scarring. The primary substrate for immune complex formation is an excess of poorly O-galactosylated polymeric IgA1 (Gd-IgA1) in the circulation. These IgA1 O-glycoforms are thought to trigger the formation of IgA and IgG autoantibodies. Atacicept is a human TACI-Ig fusion protein that inhibits B cell-stimulating factors, BLyS and APRIL, and has been associated with reductions in levels of serum IgA and IgG, as well as reductions in mature B cells and plasma cells. A number of studies have shown elevated levels of BLyS, APRIL and Gd-IgA1 in IgAN patients which have been linked to worse clinical outcomes. IgAN patients with persistent proteinuria >1 g/day are at increased risk of progression to end-stage renal disease. This Phase II study examines the safety and efficacy of atacicept in reducing pathogenic Gd-IgA1 levels and measures of renal activity in IgAN. Method This Phase II study (NCT02808429) enrolled patients with IgAN and proteinuria ≥1 g/day or 0.75 mg/mg on 24-hour urine protein-creatinine ratio (UPCR) despite maximal standard of care therapy (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker). Enrolled patients were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. The primary endpoint was a change in proteinuria by 24-hour UPCR at Week 48; key secondary endpoints included change in eGFR, serum immunoglobulin and Gd-IgA1 levels. Results Data from the 24-week interim analysis are reported here for enrolled patients (placebo=5; atacicept 25mg=6; atacicept 75mg=5). A consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG and IgM) and, in particular, Gd-IgA1 (Figure) were observed through Week 24. In parallel, proteinuria (24-hour UPCR) showed a higher median % reduction from baseline with atacicept at Week 24: -18.67% and -25.34% with atacicept 25 mg and 75 mg, respectively, vs +0.098% with placebo (Figure). eGFR remained stable over time. TEAEs were reported by 81% of the subjects. TEAEs were mild or moderate in severity, with no severe TEAEs reported. No serious related events, events with severe hypogammaglobulinemia or fatal outcome were reported. Conclusion These 24-week interim analysis results provide early proof of concept for the potential treatment of atacicept in patients with IgAN and persistent proteinuria.

Developing High-Affinity Decoy Receptor Optimized for Multiple Myeloma and Diffuse Large B Cell Lymphoma Treatment

“…These other agents were a recombinant soluble TACI-Fc (sTACI-Fc) decoy receptor that binds APRIL and BAFF at 6.4 nM and 160 pM respectively (Wu et al, 2000), as well as an antibody against BAFF ( α BAFF Ab) with a K D of 0.995 nM and no reported binding to APRIL (Shin et al, 2018). The clinical versions of both molecules are currently used for the treatment of various B cell related autoimmune diseases (Bag-Ozbek and Hui-Yuen, 2021; Barratt et al, 2020; Lee and Amengual, 2020). We performed an in vivo head-to-head comparison study evaluating the antitumor efficacy of sBCMA-Fc V3, sTACI-Fc, α BAFF Ab and wild-type sBCMA-Fc in SU-DHL-6 DLBCL tumors.…”

“…As a result, inhibition of TACI signaling (e.g. atacicept) showed modest efficacy in MM but is clinically effective at treating other B-cell related diseases such as IgA Nephropathy (24).…”

An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective

“…Atacicept (NCT02808429 and NCT04716231) and RC-18 (NCT04291781) are recombinant human BLyS receptor-antibody fusion proteins that target both BAFF and APRIL, and phase II clinical trials to evaluate their efficacy and safety in the treatment of IgAN are currently ongoing ( Table 1 ). Notably, the preliminary results of a phase II study (NCT02808429) examining the safety and efficacy of atacicept in reducing Gd-IgA1 and renal activity in patients with IgAN were previously presented by Barratt et al recently ( Barratt et al, 2020 ). The interim analysis revealed that, at week 24, patients with IgAN had a consistent, dose-dependent reduction in IgA, IgG, IgM, and Gd-IgA1, and a higher median % reduction from baseline in UPCR with atacicept than did those who received placebo.…”

An Update on the Current State of Management and Clinical Trials for IgA Nephropathy

“…Atacicept is a fully humanized fusion protein that contains the extracellular portion of TACI and inhibits both BAFF and APRIL signaling. Preliminary results from a Phase II trial suggest a dose-dependent effect on proteinuria levels [ 36 ]. This trial was terminated early due to slow recruitment, and further studies of atacicept in IgAN are planned.…”