Advancing Care in Pediatric FSGS: Insights from the DUPLEX Clinical Trial

In this issue we:

• Discuss the epidemiology, prognosis, and historical standard of care for children and adolescents with FSGS
• Describe the evolving treatment landscape, including the recent approval of the first pharmacological treatment for FSGS
• Summarize efficacy and safety data from the pediatric subgroup of patients in the Phase 3 DUPLEX clinical trial

Focal segmental glomerulosclerosis (FSGS) is a rare, progressive kidney condition defined by a histological pattern of glomerular and podocyte injury that results in a variable degree of proteinuria.^1-5 It represents a heterogeneous group of conditions with diverse etiologies that are unified by a shared feature of podocyte injury.^6,8

Although considered rare, FSGS is one of the most common causes of kidney failure and is the underlying cause of nephrotic syndrome in approximately 20% of children.^6,7 In the US, FSGS accounts for an estimated 10% to 15% of pediatric end-stage kidney disease (ESKD), compared with 3% in adults.⁴ Children with FSGS tend to present with a higher baseline estimated glomerular filtration rate (eGFR) and less interstitial fibrosis than adults; however, kidney function in children declines at a rate comparable to that of adults.⁴ Typically, children are more likely than adults to present with nephrotic syndrome, which is characterized by heavy proteinuria, hypoalbuminemia, and edema.^4,9

Proteinuria is a central marker of disease activity in FSGS and a key factor underlying progressive loss of kidney function, with elevated levels associated with an increased risk of progression to kidney failure.¹⁰ Findings from PARASOL further suggest that reduction in proteinuria is an outcome closely associated with long-term kidney prognosis.¹¹

In this pediatric subgroup, numerically greater reductions in proteinuria were observed as early as Week 6 and sustained through Week 108 with sparsentan, with a greater mean reduction at Week 108 versus irbesartan.¹

A higher number of pediatric patients achieved complete remission of proteinuria (urine protein-creatinine ratio [UPCR] <0.3 g/g) with sparsentan versus irbesartan, with similar findings observed across lower proteinuria thresholds (UPCR <0.5 g/g, <0.7 g/g, and 40% reduction from baseline).¹

Fewer pediatric patients receiving sparsentan progressed to kidney failure (sustained eGFR <15 mL/min/1.73 m² or renal replacement therapy) or reached the composite kidney endpoint (confirmed ≥40% eGFR reduction, kidney failure, or death) than with irbesartan.¹

Of the pediatric patients in this analysis, 94% (15/16) in the sparsentan arm and 95% (18/19) in the irbesartan arm received the target doses.¹ Adverse events observed were similar between treatment groups and consistent with those seen in the overall DUPLEX population.¹ The most common treatment-emergent adverse events (TEAEs) in pediatric patients included COVID-19, dizziness, diarrhea, pyrexia, increased blood creatinine, and anemia.¹ Hyperkalemia and hypotension occurred in four patients each, and none of these events were considered serious.¹

FSGS is a rare, progressive condition that affects both children and adults and has historically been managed with supportive care and immunosuppression.^1,4 In the pediatric subgroup of the DUPLEX trial, treatment with sparsentan led to numerically greater and sustained reductions in proteinuria compared with irbesartan, consistent with findings in the overall study population.¹ The adverse events observed with sparsentan were similar to those observed with irbesartan.¹

The recent FDA-approval of the first medication indicated for children 8 years and older living with FSGS marks a new era for these patients and their families, offering a non-immunosuppressive therapy shown to reduce proteinuria, an outcome associated with long-term kidney prognosis.^1,9,10,12