BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

Children's Mercy Hospital Kansas City Missouri

Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania

Department of Nephrology and Research Division Arizona Kidney Disease and Hypertension Center Phoenix Arizona

Department of Nephrology Charles University Prague Czech Republic

Department of Pediatric Nephrology Joseph M Sanzari Children's Hospital Hackensack University Medical Center Hackensack New Jersey

Department of Research and Development Retrophin Inc San Diego California

Division of Nephrology and Dialysis Università Cattolica del Sacro Cuore Fondazione Policlinico A Gemelli Rome Italy

Division of Nephrology and Hypertension Los Angeles Biomedical Research Institute at Harbor University of California Los Angeles Medical Center Torrance California

Division of Nephrology and Hypertension University of North Carolina Kidney Center University of North Carolina at Chapel Hill Chapel Hill North Carolina

Division of Nephrology and Kidney Research Institute University of Washington Seattle Washington

Division of Nephrology Columbia University New York New York

Division of Nephrology Icahn School of Medicine at Mount Sinai New York New York

Division of Nephrology New York University School of Medicine New York New York; and

Division of Nephrology The Children's Hospital of Philadelphia Philadelphia Pennsylvania

Division of Pediatric Nephrology Department of Pediatrics New York University School of Medicine Langone Medical Center New York New York;

Division of Pediatric Nephrology Stanford University Palo Alto California

Division of Pediatric Nephrology University of Michigan Ann Arbor Michigan

Division of Transplant Research Colorado Kidney Care Denver Colorado

General University Hospital Prague Czech Republic

Nephrology Unit Department of Emergency and Organ Transplantation Azienda Ospedaliero Universitaria Policlinico di Bari Bari Italy

Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania

PROMETRIKA LLC Cambridge Massachusetts

Seton Hall Hackensack Meridian School of Medicine Hackensack New Jersey

University of Missouri School of Medicine Kansas City Missouri

J Am Soc Nephrol. 2019 Mar;30(3):518. doi: 10.1681/ASN.2019010051. PubMed

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