Chee Kay Cheung, MBCHB, MRCP, PhD

Well, I think for a long time we’ve not really had many effective therapies to choose from in IgA [immunoglobulin A] nephropathy [IgAN]. We’ve had ACE [angiotensin-converting enzyme] inhibitors and angiotensin receptor blockers, but not much else. But suddenly we have 2 newly approved therapies for IgA nephropathy specifically, that’s targeted-release budesonide and sparsentan. And suddenly we also have 20 other new therapies that are in clinical development and hopefully will be able to have…some of these that can be used in the near future. I think working out exactly which treatment would be suitable for an individual patient about the specific time in that disease course will be the next challenge. And it could mean that a combination of therapies would be most effective, and I think there will need to be studies to look into that.… There’s more exciting translational work to be done in IgA nephropathy as well. And the good news is that all the phase 2 and phase 3 trials are conducting by repository sample collections as well, so we may be able to get clues from this about which patients are more likely to respond to a particular therapy or not. And we may be able to look at samples in order to develop biomarkers that can assess the degree of responsiveness to treatment or indeed to disease prognosis.

I think you have to bear in mind that while in most patients with IgA nephropathy these things happen quite gradually over a number of years, IgA nephropathy is a progressive disease that will progress to kidney failure in the majority unless we can slow the rate of kidney function loss significantly. I think, fortunately, we have new and exciting therapies that are coming and [we are] continuing to enroll [patients] into ongoing clinical trials that will ensure…we can deliver these therapies to our patients in the future.

Transcripts are AI-generated and edited for clarity and readability.

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Cheung comments on new and future IgAN treatment, and shares clinical pearls with other providers.

Future of IgAN Treatment and Clinical Pearls for Disease Management

We’ve seen from the phase 2 data from ENVISION––which studied sibeprenlimab, an anti-APRIL agent––and also from the interim results from the ORIGIN trial, which studies atacicept, that these agents are looking promising in reducing the galactose deficient IgA1 [immunoglobulin A1], the pathogenic form of IgA, and also reducing IgA levels more generally, but they have less of an effect on reducing IgG levels. So these do seem to have a specific effect on targeting IgA production. And we know that IgG levels are important in terms of infection risk because of the known risk, known association between low IgG levels and increased infection that we’ve seen in other conditions; for example, in patients treated with rituximab in ANCA [antineutrophil cytoplasmic antibody]-associated vasculitis. So [those] data [are] reassuring. The best thing seems to be a class-specific effect of these drugs. We’ve also seen some reassuring vaccination data from the sibeprenlimab trials and ENVISION. There was…a COVID[-19] vaccine substudy, which showed that patients treated with sibeprenlimab were able to mount an adequate COVID[-19] vaccine response, which was comparable to [that of] patients not treated with sibeprenlimab, and also that rates of antibody against COVID[-19] declined at a similar rate [to that of] non-sibeprenlimab treated patients. We can infer some data from studies looking at belimumab, which is an anti-BLyS agent that’s being used for treatment of lupus, again showing that vaccine responses are maintained after belimumab is used for treatment. And these maintained vaccine responses really differ markedly compared [with those of] patients who are treated with rituximab––well, we know that vaccine responses are very poor––so I think that provides some reassurance. But we have to be vigilant…for longer-term effects as well of using these agents. And I think that’s why data from longer-term studies, from open-label extension studies, will be crucial to monitor.

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

Cheung shares his approach to using novel immunotherapies in IgAN to prevent infection.

Data Considerations of Novel Immunotherapies for IgAN

BLyS, …otherwise known as BAFF, and APRIL are 2 really important B-cell survival mediators that are produced in mucosal areas after exposure of dendritic cells and other cells to antigens, and they have a set of overlapping functions and shared sets of receptors on B cells. Both…these cytokines are really important in promoting B-cell survival and B-cell proliferation and plasma cell survival and plasma cells of cells that are responsible for the majority of antibody production, and also in class switch recombination. This is a process by which naïve cells, naïve B cells, switch to IgA-committed [or -] producing B cells. Both…these cytokines, both BLyS and APRIL, have been found in patients with IgA nephropathy [IgAN] to be increased. Overexpression of BLyS or BAFF was itself…shown to cause IgA-like disease in a mouse model, and the rationale for targeting both is to target their functions. And also it could avoid a compensatory increase in the other cytokine if you only target one. So targeting both theoretically could have beneficial outcomes, but we will need to await trial data…to see which is the most effective option to target B cells. Would it be APRIL only? Would it be BLyS and APRIL? Or will it be targeting plasma cells by using an anti-CD38 approach?

I think these agents that we discussed before that target both BLyS or BAFF and APRIL signaling are looking very promising in terms of being able to stop the production of galactose deficient IgA1 at its source and potentially reduce the autoantibodies that are formed against this so that we can target the disease at its initiating steps. I do think in the future that we are likely to need combinations of therapies to be used at different stages of the disease and to be able to work out which particular therapy might be most suitable for an individual patient. Regarding immunomodulatory therapies, clearly I think patients [who] would be most suitable are ones [who] do not suffer from other chronic infective conditions. They would be patients [who] have more preserved levels of kidney function and therefore have less of the irreversible scarring changes that we see in IgA nephropathy. But interestingly, in the phase 3 studies of sibeprenlimab, there will be patients enrolled with lower levels of kidney function compared [with patients in] other trials that are going on at the moment. And it’ll be interesting to see whether effects can be seen in patients with an eGFR [estimated glomerular filtration rate] between 20 [and] 30, for example. Although there are these cautions, I think the phase 2 data from these studies [are] providing reassurance about the safety of this approach regarding infective complications, but we’re not seeing any signal to date.

Cheung reviews the rationale for dual inhibition of BLyS and APRIL in IgAN, as well as the clinical impact of investigational agents on IgAN.

Dual Inhibition of BLyS and APRIL in IgAN

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.

An expert nephrologist provides an overview of the pathophysiology of IgAN before discussing new immunomodulating therapies in clinical trials.

Chee Kay Cheung, MBCHB, MRCP, PhD

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