Abstract
Sparsentan, a first-in-class, orally active, dual-acting, selective antagonist of the angiotensin II type 1 receptor and the endothelin type A receptor, is in development for the treatment of focal segmental glomerulosclerosis (FSGS). In the ongoing DUET trial in patients with FSGS, sparsentan 200, 400, and 800 mg/d resulted in greater reduction in proteinuria versus irbesartan 300 mg/d over an 8-week double-blind period. Sparsentan continues to be evaluated in an open-label extension (OLE) of the DUET trial. Treatment with sparsentan alone in the OLE resulted in further decline in proteinuria over a total of 84 weeks. The current interim 84-week analysis examined whether newly initiated immunosuppressive therapy (IST) in some patients during the OLE contributed to the observed long-term benefits of sparsentan. DUET patients were aged 8-75 years in the US or 18-75 years in the EU and had biopsy-proven FSGS, baseline (BL) urinary protein-to-creatinine ratio (UP/C) ≥1 g/g, and estimated glomerular filtration rate (eGFR) >30 mL/min. In the OLE, patients randomized to double-blind treatment with sparsentan continued sparsentan (SPAR:SPAR) and those randomized to irbesartan were switched to sparsentan (IRB:SPAR). UP/C, FSGS partial remission endpoint (FPRE; UP/C ≤1.5 g/g and >40% UP/C decrease from BL), eGFR, and blood pressure (BP) were measured every 12 weeks to Week 84 and were compared with BL (Week 0 for SPAR:SPAR; Week 8 for IRB:SPAR). Treatment-emergent adverse events (TEAEs) were examined from first dose of sparsentan through Week 84. Data from all patients and from the remaining population after exclusion of data obtained from patients after initiation of new IST in the OLE were analyzed separately. At Week 84, a total of 22% (22/102) of patients in the OLE safety population had initiated a new IST, including cyclosporine, fluorouracil, prednisone, dexamethasone, hydrocortisone, methylprednisolone, mycophenolate mofetil, rituximab, tacrolimus, and triamcinolone. In the SPAR:SPAR group (n=67), sparsentan resulted in rapid, sustained reduction in UP/C from BL (Table). Sixteen (24%) SPAR:SPAR patients received newly initiated IST during the OLE, which had no effect on UP/C decline. In the IRB:SPAR group (n=35), switching to sparsentan resulted in significant reduction in UP/C (Week 16), which was sustained in the OLE, suggesting additional effect of sparsentan following irbesartan cessation (Table). Similar to the SPAR:SPAR group, the IRB:SPAR group showed no effect of newly initiated IST (n=6; 17%) on UP/C decline. The proportion of patients reaching FPRE was similar over the 84 weeks, regardless of use of newly initiated IST, in both the SPAR:SPAR and IRB:SPAR groups. Newly initiated IST had no effect on the course of eGFR or BP in the SPAR:SPAR or IRB:SPAR groups. Sparsentan was well tolerated through Week 84 with similar or slightly lower frequency of TEAEs in SPAR:SPAR and IRB:SPAR patients not initiating new IST versus total patients. Sparsentan in FSGS resulted in sustained and progressive antiproteinuric effects, early BP reduction, and stable eGFR over 84 weeks. Newly initiated IST had no meaningful impact on the effects of sparsentan over 84 weeks of sparsentan treatment in patients with FSGS.
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