Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety

Rationale & Objective: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist (DEARA) examined in the ongoing phase 2 DUET trial for focal segmental glomerulosclerosis (FSGS). In the DUET 8-week double-blind period, sparsentan resulted in greater proteinuria reduction versus irbesartan. We report the long-term efficacy and safety of sparsentan during the open-label extension over more than 4 years. Study Design: Patients were examined from their first sparsentan dose (double-blind period or open-label extension) through 4.6 years. Setting & Participants: Patients with FSGS, excluding secondary FSGS. Intervention: Sparsentan (200, 400, and 800 mg/d). Outcomes: Urinary protein-creatinine ratio, FSGS partial remission endpoint (urinary protein-creatinine ratio ≤1.5 g/g and >40% reduction from baseline), estimated glomerular filtration rate, and blood pressure approximately every 12 weeks. Treatment-emergent adverse events by year and cases/100 patient-years. Results: 109 patients were enrolled; 108 received ≥1 sparsentan dose; 103 entered the open-label extension (68 sparsentan, 35 irbesartan during the double-blind period). Sparsentan was ongoing in 45/108 patients (41.7%); median time to treatment discontinuation was 3.9 years (95% CI, 2.6-5.2). Mean percent proteinuria reduction from baseline was sustained through follow-up. Achieving partial remission within 9 months of first sparsentan dose (52.8% of patients) versus not achieving (47.2%) was associated with significantly slower rate of estimated glomerular filtration rate decline over the entire treatment period (−2.70 vs −6.56; P = 0.03) and in the first 2 years (−1.69 vs −6.46; P = 0.03). The most common treatment-emergent adverse events (>9 cases/100 patient-years) were headache, peripheral edema, upper respiratory infection, hyperkalemia, and hypotension. Peripheral edema and hypotension declined from year 1 (13.9% and 15.7% of patients, respectively) to ≤4% in years ≥2. There were no cases of heart failure and no patient deaths. Limitations: The open-label extension does not include a comparison group. Conclusions: Long-term sparsentan treatment showed sustained proteinuria reduction and a consistent safety profile. Plain-Language Summary: There is substantial unmet clinical need for safe and effective treatments for focal segmental glomerulosclerosis (FSGS), a kidney lesion with varied causes. Sparsentan is being studied for treatment of FSGS and targets 2 important pathways (endothelin-1 and angiotensin II) that lead to the loss of kidney function. In the 8-week randomized, double-blind DUET study in patients with FSGS, sparsentan reduced the amount of protein in the urine better than irbesartan (a blood pressure medicine often used to treat FSGS). We examined long-term treatment with sparsentan over >4 years in the DUET open-label extension. We found sustained proteinuria reduction in patients who continued treatment with sparsentan and a consistent safety profile with no new or unexpected adverse effects.