A novel agent targeting APRIL: A new hope for elderly patients of IgA nephropathy

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, characterized by mesangial IgA deposition. Asymptomatic hematuria with varying degrees of proteinuria is the most common clinical presentation, and 20%–40% of patients progress to end-stage kidney disease within 20 years after disease onset.¹ Currently, the “four-hit hypothesis” explains the pathogenesis of IgAN.² This hypothesis suggests that IgAN begins with elevated levels of circulating abnormally glycosylated galactose-deficient IgA1 (gd-IgA1), followed by the formation of immune complexes with anti-gd-IgA1 antibodies that ultimately deposit in the glomerular mesangium, leading to kidney injury. With the progressive studies of the pathogenesis of IgAN, key molecules in the pathogenesis have gradually become potential targets for future treatment strategies, and corresponding new drugs have been constantly emerging, as shown in Table 1. A proliferation inducing ligand (APRIL) is the 13th member of the TNF superfamily (TNFSF13), and as one of the growth factors of B cells, it can participate in the occurrence and development of IgAN by promoting B cell activation and the generation of gd-IgA1.³ The analysis of genome-wide association studies further suggests that TNFSF13 is a genome-wide locus significantly associated with IgAN, identifying the pathogenic signaling pathway and providing important evidence support for targeted drug development.⁴ Blocking APRIL activity is a potential therapeutic approach to reduce circulating levels of gd-IgA1 and its associated immune complexes.

The traditional treatment strategy of IgA nephropathy is mainly based on supportive treatment, combined with immunosuppressive therapy. In recent years, great progress has been made in the pathogenesis of IgA nephropathy, and put forward a new viewpoint on the treatment of IgA nephropathy. The new view is that the treatment needs to manage the two basic drivers of continuous nephron loss in IgAN at the same time. The focus of management in most patients should be to prevent or reduce IgA immune complex formation and immune complex-mediated glomerular injury. In parallel, manage the consequences of existing IgAN-induced nephron loss.

Sibeprenlimab (VIS649) is a humanized IgG2 monoclonal antibody that binds to and neutralizes the activity of APRIL. Blocking APRIL activity presents a potential method of treatment to reduce circulating levels of galactose-deficient IgA1 and associated immune complexes. The Phase II multicenter, double-blind, randomized, placebo-controlled trial of sibeprenlimab aims to evaluate the efficacy and safety of the drug in treating adult patients, who had biopsy-confirmed IgAN.¹⁶ Eligible patients with estimated glomerular filtration rate (eGFR) ≥30 mL per minute per 1.73 m² (as calculated with the use of the 2009 Chronic Kidney Disease Epidemiology Collaboration equation) and 24-h urinary protein-to-creatinine ratio of at least 0.75 g of protein per gram of creatinine (or a urinary protein level of ≥1.0 g per day), receiving optimal supportive care, were randomized in a 1:1:1:1 ratio to receive intravenous infusion of sibeprenlimab at a dose of 2, 4, or 8 mg per kg of body weight or placebo, once a month for 12 months. The primary efficacy end point was the change from baseline in the 24-h urinary protein-to-creatinine ratio (measured on the natural log scale and derived from a 24-h urine collection) at month 12. Secondary efficacy end point mainly included the change from baseline in the eGFR at month 12.

A total of 155 patients were randomly assigned to receive sibeprenlimab at a dose of 2 mg per kg (38 patients), 4 mg per kg (41 patients), or 8 mg per kg (38 patients) or placebo (38 patients), with a median follow-up of 16.0 months. From baseline to month 12, the geometric mean ratio reduction (±SE) in the 24-h urinary protein-to-creatinine ratio 47.2 ± 8.2% in the sibeprenlimab 2-mg group, 58.8 ± 6.1% in the sibeprenlimab 4-mg group, 62.0 ± 5.7% in the sibeprenlimab 8-mg group, and 20.0 ± 12.6% in the placebo group. The least-squares mean (±SE) changes from baseline in eGFR at the end of the 12-month treatment period were − 2.7 ± 1.8, 0.2 ± 1.7, and − 1.5 ± 1.8 mL per minute per 1.73 m² in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups, respectively. The average lymphocyte count showed no significant change at month 12 compared to baseline. Adverse events (AEs) were similar across all groups and were mostly mild to moderate in severity. The most common AEs (incidence of ≥5% in the pooled sibeprenlimab group) were coronavirus disease 2019 (COVID-19), pyrexia, nasopharyngitis, upper respiratory tract infection, headache, hypertension, diarrhea, and muscle spasm. Longer-term data should be required to assess the safety of targeting B cells and plasma cells by this approach, and any potential impact on immunogenicity.

This Phase II clinical trial demonstrates that sibeprenlimab can significantly reduce urine protein in IgAN patients in a dose-dependent manner. Limitations of the trial include the relatively short follow-up period, which precludes the evaluation of the long-term renal function efficacy of sibeprenlimab, and some confounding factors between groups, such as the slightly younger age, higher proportion of females, higher median baseline eGFR, higher levels of proteinuria, higher crescent formation ratio, and longer biopsy time in the placebo group. The efficacy and safety of sibeprenlimab in a larger population of patients with IgA nephropathy are under investigation in an ongoing phase III trial (VISIONARY; NCT05248646).

In the past, the main treatment strategies for IgAN, especially high-risk progressive IgAN, included adequate supportive care and glucocorticoid. However, glucocorticoids have more side-effects, especially in elderly patients, which seriously affect the clinical prognosis of elderly patients. With the advances in the understanding of the pathogenesis of IgAN, the treatment of IgAN is gradually shifting towards towards the level of etiological treatment. Sibeprenlimab, as described above, targets and neutralizes human APRIL at specific antigenic epitopes, inhibiting APRIL-mediated B-cell activation and reducing the production of pathogenic IgA1. This novel agent should avoid the use of glucocorticoid and corresponding severe side-effects, which should usher in a new era in the treatment of IgAN, especially in elderly patients.

Dr. Liu conceptualized the manuscript, did the literature search and wrote the manuscript draft. Dr. Zuo critically revised the manuscript draft.

This work was supported by funding program(Beijing Hospital Clinical Research 121 Project:BJ-2019-197).

The authors have nothing to report.