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 (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.

• Authors: Howard Trachtman, Peter Nelson, Sharon Adler, Kirk N Campbell, Abanti Chaudhuri, Vimal Kumar Derebail, Giovanni Gambaro, Loreto Gesualdo, Debbie S Gipson, Jonathan Hogan, Kenneth Lieberman, Brad Marder, Kevin Edward Meyers, Esmat Mustafa, Jai Radhakrishnan, Tarak Srivastava, Miganush Stepanians, Vladimír Tesar, Olga Zhdanova, Radko Komers, DUET Study Group
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 29 Issue 11 Pg. 2745-2754 (11 2018) ISSN: 1533-3450 [Electronic] United States
• PMID: 30361325 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society of Nephrology.

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Endothelin A Receptor Antagonists
• Spiro Compounds
• Sulfonamides
• sparsentan
• Creatinine
• Irbesartan

Topics

• Adolescent
• Adult
• Aged
• Angiotensin II Type 1 Receptor Blockers (administration & dosage, adverse effects, therapeutic use)
• Child
• Creatinine (urine)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Endothelin A Receptor Antagonists (administration & dosage, adverse effects, therapeutic use)
• Female
• Glomerulosclerosis, Focal Segmental (drug therapy, urine)
• Humans
• Irbesartan (administration & dosage, adverse effects, therapeutic use)
• Male
• Middle Aged
• Proteinuria (drug therapy, urine)
• Spiro Compounds (administration & dosage, adverse effects, therapeutic use)
• Sulfonamides (administration & dosage, adverse effects, therapeutic use)
• Young Adult