The Pathophysiology of IgAN and Use of Immunomodulating Therapies

Chee Kay Cheung, MBChB, MRCP, PhD: Our current understanding of the underlying pathophysiology of IgA [immunoglobulin A] nephropathy is framed by the 4 heads hypothesis. Firstly, in all patients with IgA nephropathy [IgAN] there’s an increase in circulating levels of a specific form of IgA called galactose deficient IgA1. This lacks galactose residues from its extended hinge region and ends up in patients’ IgA nephropathy in the circulation. In susceptible individuals there is an autoantibody response to this, and IgG and IgA antibodies are formed toward that galactose deficient IgA1. So the GDIgA1 [galactose deficient IgA1] plus the corresponding autoantibodies form immune complexes and…these then deposit within the kidneys in the glomerular mesangium and trigger a range of proinflammatory effects that lead to mesangial cell activation, inflammatory cytokine release, extracellular matrix release, complement activation, disruption of the glomerular filtration barrier, increased proteinuria, and downstream increased fibrosis and ultimately loss of kidney function. We now have good evidence that the source of this galactose deficient IgA1 and pathogenic IgA in IgA nephropathy is coming from the mucosal immune system. And importantly, one of the most important sources of this is the gut and also the respiratory tracts.

It’s been recognized for some time that central to the pathogenesis of IgA nephropathy are these increased levels of the pathogenic form of IgA galactose deficient IgA1 in the circulation. Earlier studies did look at rituximab as a way to see if we could deplete antibodies in this way as we do in ANCA [antineutrophil cytoplasmic antibody]-associated vasculitis, but [the results of] these studies were negative in terms of effects on protecting kidney function, in reducing proteinuria, or importantly in reducing levels of galactose deficient IgA1 despite adequate depletion of peripheral B cells. So targeting production of galactose deficient IgA1 has been targeted in different ways now and attention has been turned toward the B-cell survival factors––BAFF, otherwise known as BLyS, and APRIL, which have also been studied in other autoimmune conditions including lupus. There’s a lot of excitement now in targeting the cytokines and several treatments that are in development to do so. Two APRIL inhibitors are in development for IgA nephropathy. The first one is super panda map or VIS649, which has been studied in a phase 2 trial called ENVISION, and that was studied in about 150 patients. An interim analysis of the ENVISION trial was presented at last year’s ASM meeting, which showed monthly intravenous treatment with sibeprenlimab led to significant falls in levels of proteinuria, stabilization of kidney function up to 1 year of follow-up, and importantly this corresponded with a large decrease in galactose deficient IgA1 levels to around 60%. We should be able to see full results from the ENVISION trial later this year, and this drug is now being studied in its subcutaneous form in the Visionary Study, which is currently recruiting.

There’s also been another anti-APRIL agent in development called zigakibart, which is a monoclonal antibody that’s being developed. This has been studied in a smaller open-label phase 1/phase 2 trial in IgA nephropathy, again demonstrating very significant reductions in galactose deficient IgA1, reductions in proteinuria, and this drug is now being brought forward to be studied in a phase 3 trial called BEYOND. There’s also development of treatments that target both of these B-cell survival mediators, both BAFF, or BLyS, and APRIL. And the theory for doing that is that both the cytokines have overlapping roles in B-cell survival, B-cell proliferation, and in class switching of naïve B cells to IgA-producing cells. The first of these treatments that targets both BAFF and APRIL is called atacicept, which contains the extracellular portion of the TACI receptor and therefore binds to both of these cytokines and inhibits their functions. There was a small dose-finding study called JANUS which had positive findings in terms of again reducing proteinuria and reducing galactose deficient IgA levels. And this study led to the larger phase 2 study called the ORIGIN trial, [whose] interim results…were presented at this year’s ERA (European Renal Association) congress in Milan. This study had approximately…120 patients. Again, atacicept was very effective in reducing galactose deficient IgA1 levels, reducing proteinuria, and importantly, stabilizing kidney function. And there was a significant difference compared [with] the placebo-treated patients, who experienced a decline in kidney function by 12 months. There [are] also other therapies that target both BAFF and APRIL, and these include telitacicept, which has been studied in a phase 2 trial in China, again showing good results, and that’s been brought forward to a phase 3 trial, and povetacicept as well, which again inhibits both BAFF and APRIL. This is currently being studied in a basket trial that studies IgA nephropathy, membranous nephropathy, and lupus nephritis as well. Another way of targeting an immunomodulatory response is by targeting the complement system. We know the complement is activated in the IgA nephropathy because we can see in biopsies of patients with IgA nephropathy [that] up to around 90% of patients will have evidence of C3 deposition. And also if we look for evidence of deposition of alternative pathway and of lectin pathway components, these are also associated with more severe disease, if you see these components in the biopsy or breakdown products in the…plasma or in urinary breakdown products as well. So there’s a lot of attention that’s been turned toward targeting the complement system in IgA nephropathy by targeting the alternative pathway, the lectin pathway, and also the common terminal pathway as well.

Two drugs that are most advanced in their development would be iptacopan, which is a factor B inhibitor that blocks the alternative pathway, and narsoplimab, which is a MASP-2 inhibitor which blocks the initiating steps of the lectin pathway. Iptacopan was studied in a phase 2 trial, which…demonstrated a dose-dependent reduction in proteinuria as early as 3 months, and full results from that study should be published very soon, and a phase 3 trial of iptacopan called APPLAUSE[-IgAN] has now been fully recruited to and is in follow-up. And there [have] also been studies of the lectin pathway inhibitor narsoplimab in a smaller phase 2 trial, which demonstrated that open-label treatment was effective in reducing proteinuria and stabilizing kidney function compared [with] a retrospective matched cohort. And again, narsoplimab is being studied now in a large global phase 3 trial, which is currently recruiting.

Transcript is AI-generated and edited for clarity and readability.