Targeting the B-Cell Activating Factor and a Proliferation-Inducing Ligand Pathway in IgAN: From Disease Pathogenesis to Clinical Trial Evidence

Abstract

Immunoglobulin A nephropathy (IgAN) is an immune-mediated glomerular disease driven by dysregulated mucosal B-cell immunity, leading to the overproduction of galactose-deficient IgA1 (Gd-IgA1) and the formation of immune complexes with anti–Gd-IgA1 IgG and IgA immunoglobulins. These immune complexes deposit in the renal mesangium, triggering mesangial activation, proliferation, and downstream inflammatory injury. Central to this process are members of the tumor necrosis factor (TNF) superfamily, a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF). These ligands are crucial for B-cell maturation, IgA class-switch recombination, and the survival of long-lived plasma cells through their receptors: BAFF receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA). Preclinical models in IgAN show that BAFF and APRIL are important regulators of mucosal IgA responses, and their accumulation promotes autoantibody formation and downstream immune-complex mediated glomerular injury. Serum and urinary levels of BAFF and APRIL are elevated in patients with IgAN. Furthermore, APRIL and TACI are overexpressed in mucosal tissue, and their activity correlates with Gd-IgA1 levels, proteinuria, and renal histologic severity in patients with IgAN.

These mechanistic insights provided the rationale for trials testing the safety and efficacy of BAFF and APRIL-targeted therapies. Selective APRIL inhibitors (sibeprenlimab, zigakibart) and dual BAFF-APRIL inhibitors (atacicept, povetacicept, and telitacicept) reduce Gd-IgA1, hematuria, proteinuria and prevent estimated glomerular filtration rate (eGFR) decline. Collectively, these findings position the BAFF and APRIL axis as a central therapeutic node in IgAN, and support biomarker-guided, mechanism-based treatment strategies aimed at long-term disease modification. This review summarizes translational and clinical data on the BAFF and APRIL axis in IgAN, including evidence from recently published clinical trials.

Our understanding of IgAN has evolved substantially over recent years. Seminal studies from diverse geographic regions, including North America and the United Kingdom, have shown that IgAN can follow an aggressive course and represents a significant cause of end-stage kidney disease. These data have reframed IgAN as a more severe disorder than previously appreciated, including among patients presenting with only moderate levels of proteinuria.^1,2 This notion, together with the broad acceptance of both proteinuria and eGFR slope as surrogate end points in IgAN clinical trials,³ has accelerated innovation in drug development for this disease. As a result, recent clinical guidelines acknowledge and support a rapid shift toward more proactive and aggressive therapeutic strategies.

Since 2020, and as of the time this review was written, the US Food and Drug Administration (FDA) has granted either accelerated or full approval to 5 therapies for IgAN, an unprecedented milestone in the history of this condition.4, 5, 6, 7, 8, 9 The recent accelerated approval of sibeprenlimab; a monoclonal APRIL, further underscores the emerging role of B-cell modulating therapies in IgAN management.⁵ Although B-cell directed strategies have previously been explored in the past using rituximab, an anti-CD20 B-cell inhibitor,¹⁰ the current therapeutic paradigm has shifted toward selective modulation of key cytokines involved in B-cell maturation and class switching, particularly BAFF and APRIL, members of the TNF superfamily central to the pathogenesis of IgAN. Herein, we summarize the scientific rationale and available clinical evidence supporting the targeting of BAFF and APRIL as key drivers of disease pathogenesis in IgAN.

IgAN: Clinical Presentation and Prognosis

IgAN is widely recognized as the most common primary glomerulonephritis worldwide and a leading cause of kidney failure in young adults. Its prevalence varies substantially by geographic region, with the highest burden observed in Asia, where IgAN accounts for up to 40% of native kidney biopsies.¹¹ In contrast, registries from African populations report a markedly lower incidence, with new diagnoses comprising as little as 3% of biopsies.12, 13, 14 Historically, the classic clinical archetype of IgAN has been episodic macroscopic hematuria occurring shortly after a mucosal infection of the upper respiratory or gastrointestinal tract. In practice, however, the clinical presentation of IgAN is highly heterogeneous. Macroscopic hematuria, for example, although relatively common in younger patients, is infrequent in individuals > 40 years, raising questions about its reliability as a reproducible indicator of disease activity or progression.15, 16, 17

Data from large registries now indicate that the course of IgAN is far from benign, challenging earlier perceptions of the disease. The UK National Registry of Rare Kidney Diseases, which enrolled patients with biopsy-proven IgAN and proteinuria > 0.5 g/d or eGFR < 60 ml/min per 1.73 m², was used to analyze outcomes in patients with IgAN. In this cohort, 50% of patients reached kidney failure or death at a median of 11.4 years from diagnosis, with a mean age of 48 years at the time of the event. Time-averaged proteinuria was strongly associated with worse kidney survival; however, up to 20% of patients with time-averaged proteinuria < 0.44 g/g still progressed to kidney failure within 10 years.¹ In patients with IgAN and minimal proteinuria (< 0.5 g/d), a reduced eGFR (< 60 ml/min per 1.73 m²) at the time of biopsy is independently associated with a poorer renal prognosis.¹⁸ In addition, similar outcomes were reported on a US-based, multiethnic cohort of 655 adults with IgAN,² collectively highlighting that IgAN progression is more frequent and clinically impactful than previously assumed.

A clinically meaningful observation from the UK National Registry of Rare Kidney Diseases study is that Kaplan–Meier analyses stratified by decade of age at diagnosis show a high lifetime risk of kidney failure across all age groups, with a substantial portion of patients progressing within 10–15 years. When risk is modeled jointly using baseline eGFR and age at diagnosis, nearly all patients are projected to reach kidney failure within their expected lifetime unless the rate of eGFR decline is limited to ≤ 1 ml/min per 1.73 m² per year from diagnosis. Notably, even modestly faster rates of kidney function loss carry substantial long-term consequences—a sustained annual eGFR decline of 3 ml/min per 1.73 m² would result in kidney failure in nearly all patients diagnosed before the of 40 years, whereas an annual decline as low as 1 ml/min per 1.73 m² would still lead to kidney failure in approximately 40% of patients diagnosed before th age of 50 years. These findings highlight the substantial burden of disease progression in IgAN and the need to identify patient subgroups who may benefit from earlier or more aggressive disease-modifying interventions.

The B-cell Axis in IgAN: A Pathogenic Primer

The pathogenesis of IgAN is commonly conceptualized using the widely accepted multihit model often referred to as the “four-hit hypothesis.” In this framework, increased circulating levels of Gd-IgA1 promote the generation of predominantly IgG autoantibodies that recognize exposed O-glycan epitopes in Gd-IgA1. The subsequent formation of circulating immune complexes lead to their deposition within the glomerular mesangium, triggering downstream kidney injury through mesangial cell activation, release of proinflammatory and profibrotic cytokines, and activation of the alternative and lectin complement system pathways that eventually lead to progressive glomerular and tubulointerstitial injury.19, 20, 21, 22, 23 A large body of work now implicates the mucosal immune system and gut–kidney axis as central in the disease process.24, 25, 26

In IgAN, dysregulated B-cell activation and aberrant plasma cell maturation within mucosal-associated lymphoid tissueprimarily the gut-associated and nasopharynx-associated compartments—drive the production of Gd-IgA1.^27,28 Although the relative contribution of each mucosal compartment to systemic Gd-IgA1 production remains uncertain,²⁸ the presence of aberrantly glycosylated IgA identified in tonsillar tissue, the relative increase in circulating gut-homing lymphocytes, and the elevated Gd-IgA1 levels in stool supernatants of patients with IgAN, are among the multiple lines of evidence that implicate mucosal-associated lymphoid tissue, including gut-associated lymphoid tissue and nasopharynx-associated lymphoid tissue, as key sites of pathogenic IgA generation.29, 30, 31

Class-switch recombination (CSR) to IgA-producing B cells occurs in mucosal lymphoid tissues through both T-cell–dependent and T-cell–independent pathways. BAFF and APRIL intersect with multiple critical steps in IgAN pathogenesis and play a particularly important role in T-cell–independent B-cell activation. Gut microbial ligands engage with toll-like receptors on dendritic cells and epithelial cells, promoting BAFF and APRIL signaling that supports T-cell–independent B-cell activation and plasma cell survival.³² In IgAN, elevated circulating BAFF and APRIL levels have been linked to specific microbiota-derived metabolites and expansion of gut-homing B-cells in circulation.³¹ This biology provides a mechanistic framework that links environmental triggers, including gastrointestinal infections, dietary antigens, and microbiome perturbations and the dysregulated mucosal IgA immune responses central to IgAN pathogenesis.

Studies of tonsillar and intestinal tissue show expansion of IgA-secreting plasma cells with mucosal transcriptional signatures, a skewed B-cell repertoire, and evidence of T-cell–independent IgA responses. These T-cell–independent responses, typically triggered by polysaccharide antigens, depend heavily on BAFF and APRIL produced by dendritic cells, macrophages, and epithelial cells.³³ Through these pathways, BAFF and APRIL promote class-switch recombination to IgA and support the survival of both short-lived plasma blasts and long-lived plasma cells.

BAFF and APRIL in Mucosal and Systemic Immunity

BAFF and APRIL are produced by myeloid cells, dendritic cells, neutrophils, and epithelial cells in the gut and respiratory tract in response to cellular stress signals.34, 35, 36 These members of the TNF superfamily bind primarily to 2 receptors—B-cell-maturation-antigen (BCMA), and TACI. BCMA is primarily expressed on plasma cells, whereas TACI is expressed on mature B-cells and activated plasma cells (Figure 1). A third receptor, BAFF-R, specific for BAFF, is expressed mainly on transitional B-cells.³⁷ This distinction in receptor usage underlies the divergent roles of the 2 ligands—BAFF signaling through BAFF-R is required for the survival and maturation of transitional and naïve peripheral B-cells, whereas APRIL acts mainly through TACI and BCMA to support long-lived plasma cell survival and antibody production, with comparatively little effect on early B-cell maturation.

Figure 1.

B-cell maturation pathways and dynamic expression of BAFF-APRIL axis receptors, highlighting the transition from BAFF-R dependence in immature/naïve B cells to increasing TACI and BCMA expression during germinal center differentiation and long-lived plasma cell formation. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BAFF-R, B-cell activating factor receptor; BCMA, B-cell-maturation-antigen; BM, Bone Marrow; HSC, Hematopoietic Stem Cell; TACI, transmembrane-activator-and-calcium-modulator-and-cyclophilin-ligand-interactor.Created in https://BioRender.com.

In human and murine systems, BAFF and APRIL promote CSR to IgA and the survival of IgA-secreting plasma cells. Dendritic cells and epithelial cells can induce IgA switching through BAFF and APRIL in a CD-40 independent manner,³⁸ underlining a central role for these ligands in T-cell–independent mucosal responses. APRIL engagement of TACI and BCMA activates nuclear factor κB (NF-κB) and other downstream pathways that upregulate activation-induced cytidine deaminase and the CSR machinery (Figure 2).¹⁵ BCMA, in particular, is essential for the maintenance of long-lived plasma cells in bone marrow and mucosal niches.³⁹

Figure 2.

BAFF and APRIL-driven mucosal B-cell activation, plasma cell differentiation, and therapeutic targets leading to renal immune complex–mediated injury. (1) In the mucosal environment, exposure to microbial antigens at the intestinal epithelium activates local immune responses. (2) Activated dendritic cells and epithelial cells promote the secretion of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), which support mucosal B-cell responses. (3) BAFF and APRIL engage their respective receptors on B-lineage cells, including BAFF receptor (BAFF-R) on naive B cells and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) on activated B cells. (4) This signaling promotes B-cell activation and IgA class-switch recombination (CSR), leading to differentiation into antibody-secreting plasma cells supported through B-cell maturation antigen (BCMA) signaling. Plasma cells subsequently secrete IgA and IgG antibodies, which enter the systemic circulation. (5) Circulating antibodies form immune complexes that persist in the bloodstream. (6) These immune complexes deposit in the kidney glomerulus, triggering mesangial inflammation and glomerular injury, contributing to renal immune complex–mediated disease. Therapeutic interventions targeting upstream and downstream pathways include APRIL/BAFF inhibitors (e.g., sibeprenlimab, zigakibart, belimumab, blisibimod, telitacicept, atacicept, povetacicept), plasma cell–directed therapies (e.g., bortezomib, felzartamab, mezagitamab), local mucosal immune modulation, and complement/inflammation inhibitors, which collectively aim to reduce pathogenic antibody production and renal immune injury. Created in https://BioRender.com.

BAFF and APRIL in Preclinical Models of IgAN

Preclinical models have been crucial in elucidating the BAFF and APRIL axis and in validating this pathway as a therapeutic target in antibody-mediated diseases, particularly IgAN. The role of BAFF in the development of IgAN has been investigated in preclinical mouse models in which overexpression of BAFF induces a nephritic phenotype that closely resembles human IgAN.⁴⁰ Although a similar APRIL overexpression model has not been established, the pathogenic role of APRIL has been explored through blockade studies in mice.⁴¹

BAFF and BAFF-R knockout mice provided early insight into the role of BAFF in B-cell homeostasis. BAFF-deficient mice exhibit a near-complete absence of mature peripheral B-cells and markedly diminished serum Ig levels, whereas transitional B-cells are preserved.⁴² Conversely, BAFF-transgenic mice (BAFF-Tg), which constitutively overexpress BAFF, exhibit abnormal expansion of specific B-cell subsets and loss of B-cell tolerance to self-antigens.⁴³ Moreover, BAFF-Tg mice have been noted to develop an IgA-dominant glomerulonephritis. Characterization of serum IgA in these mice showed abnormal glycosylation by lectin-based assays, with reduced terminal sialic acid content compared with wild-type controls. Notably, these IgA abnormalities appeared to be microbiota dependent, as germ-free BAFF-transgenic mice exhibit IgA levels and phenotypes similar to those observed in wild-type mice.⁴⁰

Despite the relevance of BAFF showed in murine models of IgAN, BAFF inhibition alone has not been shown to significantly reduce nephritogenic IgA production or halt disease progression in these models.⁴⁴ In a recent study using an IgAN-prone mouse model, treatment with an anti-BAFF antibody failed to reduce circulating levels of Gd-IgA1 or IgG-Gd-IgA1 immune complexes. In addition, no improvement in albuminuria or histologic features were observed when compared with control animals. These findings should be interpreted in the context of the model's limitations; the gddY mouse model does not overexpress BAFF, and the negative findings may simply reflect that BAFF is not the primary disease driver in this model.

The role of APRIL in promoting class-switch recombination to IgA and IgA production is primarily supported by mechanistic and mucosal immunology models rather than by data from transgenic IgAN systems alone. APRIL-deficient and TACI-deficient mice have clarified how this ligand-receptor pair shapes IgA responses. APRIL knockout mice display impaired mucosal IgA CSR and reduced IgA levels, particularly in the gut, whereas systemic IgG responses remain relatively preserved.⁴⁵ TACI-deficient mice exhibit reduced IgA production and attenuated responses to T-independent antibody formation. Paradoxically, they can also develop systemic autoimmunity, reflecting TACI’s dual roles in promoting CSR and restraining B-cell activation through inhibitory signals.⁴⁶ These data imply that selective modulation of TACI/APRIL signaling might normalize pathogenic IgA responses without fully disrupting humoral immunity.

In contrast to studies of BAFF blockade, inhibition of APRIL using an anti-APRIL antibody resulted in significant reductions in albuminuria and kidney tissue injury. These effects were accompanied by decreases in circulating IgA levels and glomerular IgA deposition, whereas B-cell populations in the spleen and bone marrow were largely preserved.⁴¹

The importance of BCMA has been further elucidated in BCMA-deficient mouse models. Compared with wild-type mice, survival of long-lived plasma cells is markedly impaired. In contrast, B-cell development, early humoral immune responses, and germinal center reactions remain largely intact.³⁹

Collectively, the preclinical data reinforce several principles with direct relevance to IgAN: (1) BAFF and APRIL are important drivers of B-cell survival and mucosal IgA CSR; (2) dysregulated BAFF and APRIL signaling has been implicated at least in animal models with autoreactivity and excess class-switched Ig, particularly IgA; (3) TACI and BCMA signaling contribute to the persistence of long-lived plasma cells; and (4) inhibition of the BAFF and APRIL axis can attenuate immune-complex mediated injury in IgAN without completely disrupting humoral immunity.

Clinical and Translational Evidence of BAFF and APRIL Dysregulation in IgAN

Translational studies in IgAN have consistently shown that patients with IgAN have elevated serum and urinary levels of BAFF and APRIL compared with healthy controls, with higher concentrations correlating with greater proteinuria, hematuria, and histologic activity.^30,31,47,48 Elevated APRIL levels have even correlated with chances of IgAN recurrence following kidney transplantation.⁴⁹ In situ overexpression of BAFF, has also been identified in tonsillar mononuclear cells in patients with IgAN.^50,51 Furthermore, transcriptomic and genotype profiling of kidney biopsies and peripheral blood has identified upregulation of TNF-superfamily signaling, B-cell activation modules, and plasma-cell signatures in progressive IgAN.^52,53

Genetic studies support this pathogenic framework, showing enrichment of IgAN risk loci in pathways related to mucosal immunity, IgA glycosylation, and TNF superfamily signaling.⁵⁴ Notably, TNFSF13 (encoding APRIL) emerged as a susceptibility gene in a large GWAS of a Southeast Chinese cohort.⁵⁵ Other GWAS have also implicated susceptibility loci within the TNF superfamily, including the TNFSF8/TNFSF15 region and TNFSF13 in IgAN risk. Integrative analyses leveraging colocalization and Mendelian randomization further support a shared genetic basis between these loci, elevated serum IgA levels, and increased risk of IgAN—consistent with a causal contribution of higher IgA levels to disease susceptibility.⁵⁶

Consistent with these observations, BAFF and APRIL biomarker trajectories in interventional studies show trial-level associations between pathway inhibition, reductions in Gd-IgA1, immune complexes, and clinical response. Whether these correlations hold at the individual patient level remains to be established. Furthermore, it is not yet clear whether BAFF and APRIL inhibition selectively reduces Gd-IgA1 or reflects a broader reduction in total IgA production. Despite these uncertainties, the aggregate of this data supports a plausible causal relationship between BAFF and APRIL-driven B-cell biology and nephritogenic IgA production (Table 1).

Table 1.

B-cell and plasma cell–targeted therapies currently in development for IgAN

Agent	Molecule type	Mechanism of action	Most advanced study	Enrollment	Primary end point	Proteinuria reduction (%)	Hematuria reduction	Gd-IgA Reduction	Hypogammaglobulinemia
Sibeprenlimab (VIS649)57	Humanized IgG2κ monoclonal antibody	Selective APRIL inhibition	VISIONARY (Phase 3, interim analysis)	Global	Change in 24-h UPCR at 9 mo	−50.2% vs. placebo	Positive	67.1% at 48 wk	No cases observed
Zigakibart (BION-1301)58,59	Humanized IgG4 monoclonal antibody	APRIL blockade (BCMA and TACI)	BEYOND (Phase 3, ongoing)	Global	Proteinuria and eGFR (ongoing)	Not reported	Positive	70% at 40 wk	Hypogammaglobulinemia did not occur in patients who received zigakibart without concomitant steroids.
Atacicept60	Fc fusion protein (TACI–IgG1)	Dual BAFF and APRIL inhibition	ORIGIN 3 (Phase 3, interim analysis)	Global	% change in 24-hour UPCR at wk 36	−45.7% vs. placebo	Positive	68.3% at 36 wk	No cases observed
Povetacicept61,62	Engineered TACI–Fc fusion protein	Dual BAFF and APRIL inhibition	RAINIER (Phase 3, ongoing)	Global	Proteinuria reduction and eGFR	−64%a	Positive	77% at 48 wk	1 participant in the 80 mg cohort and 4 participants in the 240 mg cohort.
Telitacicept63,64	TACI–Fc fusion protein	Dual BAFF and APRIL inhibition	TELIGAN (Phase 3, data from stage A)	China Only	Change from baseline proteinuria	−55% vs. placebo	Not reported	Not reportedb	Not reported

APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BCMA, B-cell maturation antigen; eGFR, estimated glomerular filtration rate; Gd-IgA, galactose-deficient immunoglobulin A; IgAN, immunoglobulin A nephropathy; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand interactor; UPCR, urine protein-to-creatinine ratio.

^aProteinuria reduction for povetacicept reflects interim results from a phase 1/2 study.

^bData from 24 patients on the phase 2 clinical trial showed Gd-IgA1 reduced by 43.9% and 50.4% at 24 weeks on patients receiving telitacicept 160 mg and 240 mg, respectively.

Clinical Trials Targeting BAFF and APRIL in IgAN

Anti-APRIL Therapies

Sibeprenlimab [VIS649]

Sibeprenlimab is a fully humanized IgG2κ monoclonal antibody that selectively inhibits APRIL by preventing it from binding to its receptors.^65,66 In the phase 2 ENVISION trial [NCT04287985], intravenous (IV) sibeprenlimab administered every 4 weeks for 12 months in adult patients with IgAN reduced proteinuria in a dose dependent manner, stabilized the eGFR, suppressed serum levels of APRIL, and decreased levels of Gd-IgA1, with an acceptable safety profile.⁶⁷

In the phase 3 VISIONARY [NCT05248646] double-blind, randomized, placebo-controlled trial, adults with biopsy-proven primary IgAN and eGFR ≥ 30 ml/min per 1.73 m² with 24-hour urine protein-to-creatinine ratio (UPCR) ≥ 0.75 g/g or urine protein ≥ 1.0 g/d despite 3 months of maximal tolerated conservative therapy were randomized in a 1:1 ratio to receive either subcutaneous sibeprenlimab at a dose of 400 mg or placebo administered every 4 weeks for 100 weeks. The VISIONARY trial is the largest IgAN study to date. Its primary efficacy end point—change in 24-hour UPCR at 9 months from baseline—has been reported in the interim analysis. The secondary end point, annualized eGFR slope estimated over 24 months, will be reported at trial completion. The prespecified interim analysis in the VISIONARY study was performed at 9 months and included the first 320 amongst 510 study patients (152 received sibeprenlimab; 168 received placebo).⁵⁷ In the interim analysis, there was a statistically significant reduction in 24-hour UPCR after 9 months (primary end point) of therapy with sibeprenlimab (–50.2%) whereas there was an increase with placebo (2.1%), corresponding to an adjusted geometric least squares mean 24-hour UPCR that was 51.2% lower with sibeprenlimab than with placebo. APRIL and Gd-IgA1 levels reduced 95.8% and 67.1%, respectively, with sibeprenlimab. Microscopic hematuria had also significantly reduced in the sibeprenlimab group compared with placebo.

The safety profile was similar with sibeprenlimab and placebo. Total IgA and IgM levels were reduced by approximately 70% with sibeprenlimab, whereas IgG levels were reduced by 35%. Importantly, 9 patients in the sibeprenlimab group had postbaseline IgG levels ≤ 400 mg/dL. Of these 9 patients, 2 experienced adverse events during the treatment period—moderate COVID-19 in 1 and a mild urinary tract infection in the other—both of which resolved without dose modification. No deaths were reported, and the incidence of serious adverse events that occurred during the treatment period was 3.5% with sibeprenlimab and 4.4% with placebo.⁵⁷

During the treatment period in the VISIONARY Study, 88 of 256 (34%) patients treated with sibeprenlimab developed antidrug antibodies (ADA). Among the 88 patients who tested positive for ADA, 21 patients (23.9%) developed ADA that had neutralizing activity. Sibeprenlimab exposure in patients with IgAN who developed ADA was ∼40% lower than in patients with undetectable ADA over the treatment period. The reduction in 24-hour UPCR from baseline to month 9 was numerically lower in patients who developed ADA (41.6%) compared with those who did not (52.7%). The clinical significance of the differences in proteinuria reduction according to the presence or absence of ADA is not clear. Further data on ADA on safety and efficacy of sibeprenlimab in IgAN are warranted before any concrete conclusions can be made.

On the basis of these favorable results, in November 2025 the FDA granted accelerated approval to sibeprenlimab (Voyxact) for reduction of proteinuria in adults with primary IgAN at risk for disease progression.⁵

Zigakibart [BION-1301]

Zigakibart is a humanized IgG4 monoclonal antibody that binds to and blocks APRIL binding to BCMA and TACI. In an ongoing Phase 1/2 clinical trial that included 40 patients with IgAN [NCT03945318], treatment with zigakibart was well tolerated and resulted in robust and durable reductions in Gd-IgA1 levels and proteinuria, decreased microscopic hematuria, and ensured sustained stabilization of eGFR, which were maintained over 100 weeks of treatment.⁵⁸ A phase 3 trial regarding the use of zigakibart in IgAN is ongoing [The BEYOND study, NCT NCT05852938] that will further evaluate its effect on proteinuria, eGFR, and clinical end points in patients with IgAN.⁵⁹

Dual BAFF and APRIL Inhibitors

Atacicept

Atacicept is a first-in-class, fully humanized fusion protein comprising the extracellular domain of TACI—native receptor for both BAFF and APRIL—fused to the Fc region of IgG1, resulting in a soluble receptor with high affinity for both BAFF and APRIL cytokines.⁶⁸ In the phase 2b ORIGIN randomized, double-blind, placebo-controlled clinical trial with 116 adult patients with IgAN, patients were randomized to subcutaneous atacicept 25, 75, or 150 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary end points were changes in 24-hour UPCR at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary end point was met at week 24 as mean UPCR decreased from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary end point was met given mean UPCR having reduced from baseline by 34% in the combined atacicept group versus a 2% increase noticed in placebo, resulting in a significant 35% reduction with atacicept compared with placebo. Furthermore, atacicept stabilized eGFR at week 36, whereas the placebo group declined, resulting in a significant between-group difference of 11% (approximately 5.7 ml/min per 1.73 m²). Gd-IgA1 was reduced by 60% versus placebo. Safety profiles were comparable between groups, with no major adverse events.⁶⁹

In the open-label extension of the ORIGIN trial, 113 participants received atacicept 150 mg subcutaneously weekly for an additional 60 weeks (96 weeks total). The drug was well tolerated; 3 serious infections occurred, all resolved, with no opportunistic or fatal events. Only 1 participant discontinued due to IgG < 3 g/l. Sustained reductions were observed in Gd-IgA1 (−66 ± 2%), hematuria (−75%), and UPCR (−52 ± 5%), with a mean annualized eGFR slope of −0.6 ± 0.5 ml/min per 1.73 m². Participants initially on placebo who crossed over to atacicept at week 36 achieved comparable reductions in Gd-IgA1, hematuria, and UPCR, with improvement in eGFR trajectory.⁷⁰

The ORIGIN 3 [NCT04716231] is an ongoing, phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving adult patients with kidney biopsy proven IgAN with 24-hour UPCR ≥ 1g/g or 24-hour proteinuria ≥ 1 g/d, eGFR ≥ 30 ml/min per 1.73 m², and stable conservative treatment ≥ 12 weeks. Patients were randomized in a 1:1 ratio to receive subcutaneous atacicept 150 mg once weekly versus placebo. The primary end point was the percentage change from baseline in the 24-hour UPCR at week 36.⁶⁰

In a prespecified interim analysis of the ORIGIN 3 trial, 203 patients were included (106 patients in the atacicept group vs. 97 patients in the placebo group). The demographic and clinical characteristics of patients were similar in both groups. At week 36, the percentage reduction from baseline in the 24-hour UPCR was 45.7% in the atacicept group and 6.8% in the placebo group, with a geometric mean between-group difference of 41.8 percentage points. Adverse events were observed in 59.3% of the patients in the atacicept group and in 50.0% in the placebo group; most were mild or moderate in severity. Serum levels of IgG, IgA, and IgM reduced after treatment with atacicept, and the decreased Ig levels stabilized after week 24; hypogammaglobulinemia was not reported in this interim analysis. However, given the relatively short follow-up, the potential risk of hypogammaglobulinemia with longer-term use—as has been observed with other B-cell-targeted therapies—remains to be defined and warrants continued monitoring in future analyses. Treatment with atacicept was also associated with significant reductions in Gd-IgA1 levels and resolution of microscopic hematuria.⁶⁰ Reductions in Gd-IgA1 levels occurred very early in the trial, at 4 weeks, preceding the reduction in proteinuria noted at 12 weeks, which suggests that early immunologic response translates to subsequent clinical benefit in patients on treatment with atacicept for IgAN.

Povetacicept

Povetacicept is a next-generation, engineered dual antagonist of the BAFF and APRIL pathways designed to achieve balanced inhibition of pathogenic B-cell and plasma-cell survival signals while preserving broader humoral immunity. Unlike first-generation TACI-Fc constructs, povetacicept has been molecularly modified to improve ligand-binding kinetics and pharmacokinetic durability, resulting in sustained suppression of BAFF- and APRIL-mediated signaling through TACI and BCMA with more controlled effects on BAFF-R–dependent naïve B-cell compartments.⁷¹ The AIS-D03 RUBY-3 [NCT05732402] trial is a phase 1 and 2 open-label study evaluating povetacicept in adult participants with IgAN or primary membranous nephropathy (pMN), with eGFR ≥ 30 ml/min per 1.73 m². Inclusion criteria for patients with IgAN were kidney biopsy within 10 years and proteinuria ≥ 0.5 g/g. The primary objective was safety; secondary objectives included change from baseline in UPCR, eGFR, Gd-IgA1, clinical remission [defined as 24-hour UPCR < 0.5 g/g, negative hematuria, and eGFR < 25% reduction from baseline], and hematuria resolution for the IgAN cohort. Povetacicept was administered subcutaneously every 4 weeks to 54 participants with IgAN (21 received 80 mg, 33 received 240 mg) and 10 with pMN (all received 80 mg). In an interim analysis, participants with IgAN on 80 mg had a 64% mean 24-hour UPCR decrease (95% confidence interval, –76 to –48) from baseline (1.3 g/g to 0.5 g/g; 65% with UPCR < 0.5 g/g) with stable eGFR at week 48. Early decline in Gd-IgA1 at week 12 (57%), continued at week 48 (77%). Approximately 90% achieved hematuria resolution and 53% achieved clinical remission. Efficacy outcomes were similar with 240 mg Povetacicept.⁶¹ The phase 3 RAINIER [NCT06564142] is evaluating the effect of povetacicept on proteinuria reduction and effect on eGFR in IgAN.⁶²

Telitacicept

Telitacicept is a soluble fusion protein composed of TACI and Fc domain of human IgG that inhibits BAFF and APRIL cytokines and has shown efficacy in real-world and clinical studies from China.⁶³ Nonrandomized real-world studies have confirmed reductions in proteinuria and stabilization of kidney function in IgAN.⁷² Telitacicept has shown reduction in both circulating Gd-IgA1 and IgA-containing immune complexes in IgAN.⁷³ The combination of telitacicept with low-dose mycophenolate mofetil has been proposed as a potential immunomodulatory treatment for IgAN.⁷⁴

A phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-part (stage A and B) study enrolled adult Chinese IgAN patients with 24-hour UPCR ≥ 0.8 g/g or proteinuria ≥ 1.0 g/d despite maximal conservative therapy. In stage A, patients were randomized (1:1) to receive subcutaneous telitacicept 240 mg or placebo weekly for 39 weeks. The primary efficacy end point was change from baseline in 24-hour UPCR at week 39. A total of 318 patients were randomized (159 in each group). At week 39 the geometric mean ratio of UPCR was 55% lower with telitacicept versus placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. The CD19+ B-cell count, and IgG, IgA, and IgM levels decreased with telitacicept and were unchanged with placebo. The most common adverse events with telitacicept were upper respiratory tract infections and injection site reactions. The incidence of serious adverse events was lower with telitacicept versus placebo (2.5% vs. 8.2%). Thus, in Chinese IgAN patients at high risk of progression, treatment with telitacicept for 39 weeks resulted in a rapid, substantial, and statistically significant reduction in proteinuria compared with placebo, with a favorable safety profile.⁶⁴ Stage B, that involves treatment from week 40–104 is ongoing. These studies collectively suggest that telitacicept may be an effective and safe treatment for IgAN, however further data from non-Asian, particularly non-Chinese, patients with IgAN are warranted.

Inefficacy of Rituximab in IgAN

Rituximab is a chimeric monoclonal antibody directed against CD20, a surface antigen expressed on most mature B-cells. It mediates B-cell depletion through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis, resulting in effective elimination of circulating CD20⁺ B cells. Importantly, plasma cells and hematopoietic stem cells are spared, as they do not express CD20. Although rituximab achieves robust depletion of peripheral blood B-cells, its effects on tissue-resident B-cell populations—particularly within lymphoid tissues and inflamed organs—are more variable and often incomplete, which may limit its impact on antibody-secreting plasma-cell–driven disease processes.

In an open label trial, 34 adult patients IgAN with proteinuria > 1 g/d were randomized to receive rituximab or standard conservative therapy. Treatment with rituximab depleted B-cells and was well tolerated. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group, and there was no change in eGFR in both groups. Serum levels of Gd-IgA1 or antibodies against Gd-IgA1 did not change.¹⁰ Reasons for this lack of efficacy are unclear; however, it may be possible that Gd-IgA1 producing B-cells are CD20-negative, or deeply rooted to mucosal immune tissue that may be resistant to CD20 depletion because of high levels of B-cell survival factors, such as BAFF and APRIL, within its microenvironment.⁷⁵ Rituximab is not used for the management of IgAN.

Conclusion

Experimental evidence positions the BAFF and APRIL axis as an important upstream driver in the pathogenesis of IgAN, providing a strong mechanistic rationale for therapeutic targeting. These cytokines are key mediators of B-cell maturation, plasma cell survival, and mucosal antibody production, and aberrant signaling through either pathway has been implicated in autoimmunity and glomerular injury. Translational human data further support this biology, showing that BAFF and APRIL dysregulation correlates with disease activity, Gd-IgA1levels, and histologic severity. Early- and late-phase clinical trials indicate that selective APRIL inhibition and dual BAFF/APRIL blockade can meaningfully reduce proteinuria and hematuria, lower pathogenic IgA1, and slow eGFR decline, with acceptable medium-term safety profiles.

Despite the rapidly evolving therapeutic landscape in IgAN, important questions remain unanswered. How therapies targeting BAFF and APRIL will integrate into an increasingly crowded treatment algorithm, and whether combination approaches will offer additive benefit, remains to be established through prospective trials and real-world evidence. Whether selective APRIL inhibition confers meaningful mechanistic or clinical advantages over dual BAFF/APRIL blockade has yet to be determined from long-term head-to-head data. Although we cannot draw definitive conclusions given the absence of direct comparative data, one could speculate that selective APRIL blockade may offer a theoretical advantage of less profound immunosuppression compared with dual BAFF/APRIL blockade, given its more targeted mechanism of action. This could translate into reduced infection risk and better preservation of vaccine-induced immunity. In a murine study, selective APRIL inhibition had minimal effects on splenic B-cell populations compared with dual APRIL/BAFF inhibition.⁷⁶ Moreover, vaccine-induced protective responses were more reduced in mice receiving dual APRIL/BAFF inhibition in the same study. It is important to note that these effects have not been studied in humans, and that safety data, infection risk, and Ig suppression available from interim analyses of phase 3 studies appear comparable among the available agents. Notably, available data suggest that selective APRIL blockade and dual BAFF/APRIL blockade have shown comparable efficacy, which may argue against a clear advantage of 1 approach over the other in terms of disease control. However, this remains speculative, and the relative clinical advantages of selective versus dual blockade, including effects on vaccine responsiveness, remain to be defined in future studies and head-to-head comparisons. Whether baseline biomarkers, such as serum BAFF or APRIL levels, could guide the selection between these strategies remains an open and clinically important question. The durability of therapeutic responses, long-term safety—including the implications of sustained Ig suppression—and the consequences of treatment discontinuation represent critical knowledge gaps that ongoing phase 3 trials and their open-label extensions are positioned to address in the coming years.

Disclosure

GVR has received consulting fees, honoraria, and/or research support from pharmaceutical companies engaged in the development of therapies for IgAN and other glomerular diseases, including Otsuka, Vera Therapeutics, Travere Therapeutics, Calliditas Therapeutics, and Natera. These relationships had no influence on the content of this review. AR has received research support from Otsuka. AR serves as a consultant for Vertex Pharmaceuticals, Vera Therapeutics, and Travere Therapeutics. AR serves on the advisory board for Vera Therapeutics, Vertex Pharmaceuticals, Otsuka, Travere Therapeutics, Novartis Pharmaceuticals, and Calliditas Therapeutics. KNC reports serving as a consultant for Novartis, Otsuka, Travere, and Vera. LSR reports serving as consultant for Vera Therapeutics and ANI therapeutics and serves on the advisory board for Calliditas and Travere.