Chee Kay Cheung, MBCHB, MRCP, PhD: There have been a number of agents recently approved for IgA [immunoglobulin A] nephropathy, and these include SGLT2 inhibitors, dapagliflozin in particular, targeted-release budesonide, and sparsentan. I’ll go through each of these one by one. SGLT2 inhibitors work by blocking sodium and glucose reabsorption by the proximal tubule and increase sodium delivery to the macular densa, enhancing tubuloglomerular feedback and reducing afferent arterial supply to the glomerulus. Therefore, they reduce glomerular hyperfiltration and reduce proteinuria, and also reduce other inflammatory effects as well. These seem to be very effective treatments in diabetic kidney disease and in all forms of nondiabetic kidney disease as well, and they’re very safe and well-tolerated treatments. There were analyses of patients with IgA nephropathy from the DAPA-CKD trial and also from EMPA-KIDNEY trial, which showed that these treatments could effectively reduce the number of patients with a significant decline in kidney function, reduce the numbers of patients also requiring dialysis, or reduce the deaths due to kidney or cardiovascular causes. But with SGLT2 inhibitors, I think we just need to bear in mind that these were studies performed in patients with chronic kidney disease. Baseline kidney function of patients with IgA nephropathy entering into these trials were in the 40s. There was no run-in period of optimized supportive care, as we discussed before. Also this demographic of patients entering into these trials does differ quite a lot compared to the phase 3 trials that are going on in IgA nephropathy at the moment. Whether these treatments are going to be as effective for patients earlier on in their disease course, I think, is still to be determined. Another treatment is targeted-release budesonide. Targeted-release budesonide is a specific form of budesonide that’s packaged in a pH-sensitive capsule, which is designed to release this active drug at the terminal ileum, which is where the Peyer’s patches are most concentrated. These Peyer’s patches are specially specialized collections of mucosal immune cells, where it’s widely believed that the majority of the pathogenic form of IgA, called galactose-deficient IgA1, is produced. The drug is then metabolized by the liver and then therefore avoids most of its systemic absorption and [adverse] effects. So it’s believed that targeting Peyer’s patches in this way with budesonide has a specific effect on reducing galactose-deficient IgA production by mucosal immune cells, by targeting B cells and T cells that reside in this area. And the recently published Nefigard trial demonstrated that 9 months of treatment with targeted-release budesonide had a significant effect in reducing proteinuria and stabilizing kidney function, which were most pronounced in the first year of the study. And the effects of this was sustained out to 2 years of follow-up. But sparsentan is a dual endothelin angiotensin receptor antagonist, or DEARA [for] short. So [with] this, the interference system has been studied extensively in diabetic kidney disease, and now it’s being studied IgA nephropathy as well. We see increased activity in patients with IgA nephropathy of the endothelin system in their kidney biopsies. We also have seen it through in vitro experiments and cell culture experiments, that the endothelium signaling has associations with proinflammatory changes in IgA nephropathy in terms of mesangial cell activation and proliferation. By using sparsentan to block both the endothelin system and the renin-angiotensin system, sparsentan has a dual protective effect that can work synergistically. And we’ve seen interim results from the phase 3 PROTECT study in IgA nephropathy, which were recently published, [which] showed that treatment of patients with sparsentan led to a significant fall in protein leak, in proteinuria, by about 48% by 9 months, which was 3 times higher than the active control, irbesartan. We should hopefully see some data on EGFR coming out soon to see if this has a stabilizing effect on kidney function. Based on these results, sparsentan was the second treatment to receive approval from the FDA for treatment [of] IgA nephropathy.

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