DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

Abstract

Background We evaluated and compared the effects of sparsentan, a dual endothelin type A (ET A) 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 m 2 , 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.

Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells

“…Our studies need to be validated in other models and in human disease, although they may also highlight a potential mechanism for the proven renoprotective activities of EdnrA inhibitors in FSGS. 44 Also, a better understanding of the context in which alteration of mitochondrial function, ROS overproduction, and its effects on ESL degradation enzyme activity in GECs might lead to greater insights into the mechanisms of the pathogenesis of chronic kidney disease.…”

Podocytopathies

“…Instead of immunosuppression, SRNS requires rigorous control of glomerular hyperfiltration with a RASi and by reducing dietary salt. Recently, sparsentan, a dual endothelin type A (ET A ) and angiotensin I type 1 receptor antagonist showed a robust anti-proteinuric effect in a phase II clinical trial compared with monotherapy with the angio tensin receptor blocker irbesartan 204 . In secondary podocytopathies, management is focused on treating the underlying disorder.…”

SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia

“…In this regard, the whole therapeutic approach to IgA nephropathy is being re-evaluated and draft Kidney Disease: Improving Global Outcomes (KDIGO) guidelines emphasize the need to enroll patients in clinical trials. Another issue would be how to integrate SGLT2 inhibitors with forthcoming broad nephroprotective drugs, such as finerenone, as kidney RCTs such asFIDELIO and FIGARO will be reporting later this year and next year [ 22 , 23 ], sparsentan [ 24 , 25 ] or bardoxolone [ 26 ], among others, which are undergoing RCTs in diverse nephropathies. For future trials, the question will be whether the addition of a new treatment to the standard therapy with RAS blockade and SGLT2 inhibitors is beneficial compared with such standard treatments in renal progression.…”