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 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.

Keywords: angiotensin II; endothelin; focal segmental glomerulosclerosis; proteinuria; sparsentan.

Graphical abstract

Figure 1.

Patient disposition for the double-blind study period. The prespecified plan for allocation of patients to dose cohorts was 20–40–40 for 200–400–800 mg dose cohorts. The EES population included patients who received at least one dose of study drug and had both baseline and week 8 UP/C assessments. Some patients received half of the assigned nominal dose owing to body wt≤50 kg. AE, adverse event; EES, efficacy evaluable set; FAS, full analysis set.

Figure 2.

Compared with irbesartan, there was a greater reduction in UP/C with sparsentan, and a larger proportion of patients achieved FPRE. The figure illustrates the reduction in UP/C from baseline to week 8 for (A) all sparsentan doses for the EES and (B) 400 and 800 mg sparsentan doses for the EES. Reduction in UP/C from baseline to week 8 for (C) all sparsentan doses for the FAS and (D) 400 and 800 mg doses for the FAS. (E) Reduction in 24-hour urinary protein excretion for the EES. (F) Proportion of patients who achieved FPRE for the EES. *Geometric least squares mean percent change from baseline. P values for changes in UP/C from analysis of covariance. FPRE is defined as UP/C≤1.5 g/g and >40% reduction in UP/C. P value for FPRE obtained using the Fisher exact test. For the FAS analysis, patients with a missing UP/C value were imputed as zero. EES, efficacy evaluable set; FAS, full analysis set; FPRE, FSGS partial remission endpoint; FSGS, focal segmental glomerulosclerosis; UP/C, urinary protein-to-creatinine ratio.

Figure 3.

Sparsentan had a greater effect on lowering BP compared with irbesartan, while eGFR remained stable in both groups during the double-blind treatment period among patients in the EES. The figure illustrates the analyses of BP and eGFR on the basis of the efficacy evaluable set. eGFR on the basis of the Modification of Diet in Renal Disease formula for patients aged ≥18 years and Schwartz formula for patients aged <18 years. Data were summarized using descriptive statistics and evaluation of 95% CIs. *P<0.05 compared with baseline. **P<0.05 between treatment groups. BP, blood pressure; DBP, diastolic blood pressure; EES, efficacy evaluable set; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; SD, standard deviation.