Sparsentan for IgA Nephropathy

Patients with proteinuria greater than 0.75 -1 g/day, despite optimal supportive therapy for at least 90 days, are felt to be at a high risk of disease progression. Although the data is quite limited in these patients, the 2021 KDIGO guidelines suggest that immunosuppressive therapy with glucocorticoids should be considered. The largest randomized controlled trial (RCT) was the TESTING trial, a double-blinded, multicenter RCT that compared oral methylprednisolone (starting at 0.6-0.8 mg/kg/d) to placebo in patients with biopsy-proven IgAN on optimal supportive therapy. These participants had proteinuria of > 1 g/d and an estimated GFR (eGFR) between 20-120 ml/min; its primary composite outcomes were a 40% reduction in eGFR, death due to kidney failure, or reaching ESKD. It found that those treated with methylprednisolone were significantly less likely to achieve the primary renal outcome; however, the trial was discontinued early (after recruiting 262 participants with a median follow-up of 2.1 years) due to excessive adverse effects, especially infections, in the steroid arm.

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The TESTING II trial was therefore completed with a lower dose of methylprednisolone (starting at 0.4 mg/kg/d) with a taper over 6-9 months; patients in the reduced dose cohort needed to have an eGFR of 30-120 ml/min and proteinuria of > 1 g/d despite optimal supportive therapy to be eligible. 503 total patients were randomized with a mean follow-up of 4.2 years. Although patients in the methylprednisolone arm were significantly less likely to reach the primary renal outcomes than those in the placebo arm, those who received steroid therapy were more likely to have serious adverse events, especially those in the higher-dose steroid group.

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Given the lack of conclusive data regarding glucocorticoid therapy in IgAN and the absence of any available therapy for IgA nephropathy at the time of their publication, the 2021 KDIGO guidelines first recommend considering enrollment in a clinical trial for patients at a high risk of disease progression despite optimal supportive therapy. 

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The PROTECT Trial

Sparsentan (brand name Filspari™) in IGAN

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Given its utility in proteinuria reduction in patients with diabetic nephropathy, researchers have postulated that Endothelin Receptor Antagonists (ERAs) may have similar effects in other glomerular diseases.

 

The PROTECT trial was a 114-week, multicenter RCT that compared Sparsentan, a dual endothelin type A and angiotensin receptor antagonist, to Irbesartan in patients with biopsy-proven IgAN at high risk of disease progression despite optimal RAAS blockade.  Patients could participate if their eGFR was > 30 ml/min and proteinuria > 1 g/d. Notable exclusion criteria included IgAN secondary to another etiology, patients with cellular glomerular crescents in > 25% of glomeruli on biopsy, receipt of systemic immunosuppression for > 2 weeks in the three months before screening, and patients with other CKD etiologies in addition to IgAN.

 

Its primary endpoint was the change in urine protein/creatinine ratio at week 36 compared to baseline; important secondary endpoints include the chronic eGFR slope over 1-year (weeks 6-58) and 2-year (weeks 6-110) periods as well as the total eGFR slope during the double-blind period.  Although using sodium-glucose co-transporter 2 (SGLT2) inhibitors was prohibited during the double-blind phase, an open-label extension (OLE) subsequently evaluated the additive effects of Dapagliflozin to Sparsentan.

 

404 patients across 18 countries were ultimately randomized and given study medications. Patients were predominantly male (69.8%) and identified as White-non Hispanic, with approximately 28.5% of patients having Asian ethnicity. The mean eGFR was 57 24 ml/min with a median 24-hour urine protein quantification of 1.8 g/day. The largest proportion of patients by CKD Stage was CKD 3b (GFR < 45 ml/min and 30 ml/min), with approximately ~35% of participants. Sub-group analysis for patients in Asian geographic regions (Hong Kong, Taiwan, and South Korea) was notable for a higher percentage of female patients, a lower proportion of patients with hypertension (HTN), and a lower blood pressure than patients from non-Asian geographic regions. 

 

The immunopathogenesis of IgAN is felt to be a multi-hit hypothesis and likely involves environmental and genetic factors that have not been fully elucidated. A key central finding, however, is the presence of galactose-deficient IgA1 immune complexes, an IgG antibody directed against the O-glycans hinge regions. These immune complexes contribute to glomerular inflammation, mesangial proliferation, interstitial fibrosis, and tubular atrophy with subsequent activation of the renin-angiotensin-aldosterone system and complement. These immune complexes also upregulate growth factors, including Angiotensin II and Endothelin 1 (ET-1). Through a cross-talk mechanism, Angiotensin II upregulates Endothelin 1 production, and Endothelin 1 production, in turn, increases the conversion of Angiotensin I to Angiotensin II. 

 

Due to the lack of approved therapeutic options for patients at high risk of disease progression, there has been significant interest in developing therapies based on the immunopathogenesis of IgAN. Podocytes synthesize Endothelin-1 and express both Endothelin A (ETA) and Endothelin B (ETB).  Exposure to ET-1 in vitro has been shown to disrupt the actin podocyte cytoskeleton resulting in proteinuria. Sparsentan likely achieves the primary endpoint in PROTECT by protecting against these mechanisms of kidney injury and the well-known effect of proteinuria reduction through angiotensin receptor blockade.