A Phase 3 trial comparing the experimental drug sparsentan to the standard treatment irbesartan in patients with focal segmental glomerulosclerosis (FSGS) showed mixed results. The findings highlight both potential benefits and design issues that may influence future kidney disease research.
Trial design reflected the science of its time
The DUPLEX trial, conducted across multiple international centers, included 371 patients with confirmed FSGS through biopsy or genetic testing. Participants required proteinuria levels above 1.5 grams per day and a glomerular filtration rate (GFR) of at least 30 mL/min. The study excluded individuals whose FSGS resulted from another disease or medication, as well as those recently treated with rituximab or cyclophosphamide.
Both groups had similar baseline characteristics, with median urine protein-to-creatinine ratios (UPCR) around 3.0 to 3.1 grams. The primary goal measured the slope of estimated GFR (eGFR) at week 108, while an interim assessment at week 36 focused on FSGS partial remission. Another secondary measure tracked GFR changes through week 112.
Nephrologist Howard Trachtman, who participated in the trial, explained the exclusion of secondary FSGS cases. When the study was planned in 2018, researchers believed these cases were less severe and could be managed by addressing the root cause. That view has since changed, as secondary FSGS frequently resists treatment even after the underlying condition is addressed.
Proteinuria reduction showed early promise
Interim results at week 36 indicated sparsentan’s potential. The partial remission target—a 40% reduction in proteinuria to below 1.5 grams—was achieved by 42% of patients on sparsentan versus 26% on irbesartan. The standard was based on data from earlier FSGS trials and the NEPTUNE study, an observational project tracking glomerular diseases.
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The primary endpoint of eGFR slope at week 108 did not meet statistical significance. Trachtman later identified a flaw in the design: eGFR slope fluctuates more in glomerular diseases like FSGS than in diabetic nephropathy, making it a less dependable measure. The trial’s planners may have overestimated its reliability.
For patients with proteinuria below 1.5 grams, he remained optimistic about the drug. Its safety record includes nearly 1,000 patients monitored for three to five years in both the IgA nephropathy program and the earlier DUET Phase 2 study. This history could make it an option for those outside the original trial criteria.
Trial limits and patient implications
The DUPLEX study’s exclusions and endpoint choices mirror how understanding of FSGS has shifted. Initially, secondary FSGS was considered a separate, less critical issue. Now, doctors know these cases often fail to improve even when the underlying problem is treated. While sparsentan reduced proteinuria, the missed primary endpoint raises doubts about its long-term effects on kidney function.
Patients who don’t meet the trial’s strict criteria—such as those with lower proteinuria or secondary FSGS—may still find the safety data reassuring. However, without stronger evidence of kidney protection, doctors might avoid prescribing it beyond the original study parameters. Future research will need to address these gaps, possibly by adjusting endpoints or broadening eligibility to better match real-world FSGS complexity.
A deeper look at why the primary endpoint was not met will appear in a later analysis.
