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Sparsentan Failed to Preserve Kidney Function Over Time in FSGS

— However, more patients on the drug achieved partial remission of proteinuria vs irbesartan

Last Updated November 7, 2023
MedpageToday

PHILADELPHIA -- Treatment with sparsentan (Filspari) led to no significant differences in estimated glomerular filtration rate (eGFR) slope compared with irbesartan among patients with focal segmental glomerulosclerosis (FSGS), the phase III DUPLEX trial showed.

At the final analysis, the between-group differences in the primary endpoint of eGFR slope were not significant:

  • Total slope: -5.4 vs -5.7 mL/min/1.73 m2 per year with sparsentan and irbesartan, respectively (P=0.75)
  • Chronic slope: -4.8 vs -5.7 mL/min/1.73 m2 per year (P=0.42)

Mean change in eGFR from baseline to week 112 was -10.4 mL/min/1.73 m2 with sparsentan and -12.1 mL/min/1.73 m2 with irbesartan, also not a significant difference, reported Howard Trachtman, MD, of the University of Michigan in Ann Arbor, during the American Society of Nephrology's Kidney Week.

However, in a prespecified interim analysis at 36 weeks, more sparsentan-treated patients achieved partial remission of proteinuria -- defined as a urinary protein-to-creatinine ratio of ≤1.5 and a >40% reduction in the ratio from baseline -- compared with irbesartan-treated patients (42% vs 26%; relative risk 1.55, 95% CI 1.10-2.18, P=0.009), according to the study findings, which were simultaneously published in the (NEJM).

Sparsentan, a dual endothelin-angiotensin receptor antagonist, was granted accelerated approval by the FDA in February for the treatment of proteinuria in IgA nephropathy, and was granted for FSGS. There are currently no approved treatments on the market specifically indicated for FSGS.

"There is a huge unmet clinical need for effective treatments for FSGS, and sparsentan represents a promising option based on preclinical and clinical data," Trachtman told 鶹ý. "Primary glomerular diseases are rare but have significant health consequences. It is important for the nephrology community to continue to conduct well-designed trials for patients with FSGS to develop effective treatments."

Trachtman said that he was a bit surprised by the findings, noting that "while there was a consistent antiproteinuric effect of sparsentan that was sustained for the entire duration of treatment, it did not translate into a significant reduction in the rate of decline in kidney function during the 2-year study period."

However, he added that "the findings overall point to a benefit of sparsentan in patients with FSGS. Longer-term treatment may be required to demonstrate the renoprotective effect of the drug and to identify patients who are more likely to respond to the drug."

In an , Julie Ingelfinger, MD, deputy editor of the NEJM, wrote that we're now "left to grapple with why the decreased proteinuria did not result in amelioration of decline in kidney function."

"The authors provide multiple speculative reasons as to why the results for the primary endpoint (the eGFR slope) were not found to be significant," she continued. "Perhaps 2 years is too little time to see a difference in eGFR decline in patients with FSGS. Other possibilities raised included the heterogeneity of the trial population; a greater decrease in eGFR at the time of treatment initiation in the sparsentan group than in the irbesartan group (which would have meant stabilization or recovery was needed); a better-than-anticipated response in the irbesartan group (the active control group); and the relapsing nature of FSGS."

Though there are still lingering questions, these findings add to those from the phase II DUET study, also led by Trachtman and presented at Kidney Week 2018, which showed significant reductions in urinary protein-to-creatinine ratio through 8 weeks at all studied doses of sparsentan (200, 400, and 800 mg/d).

In the , a total of 371 patients were included, ranging in age from 8 to 75, all with FSGS without known secondary causes. Mean age was 42, 53-55% were men, and 74-75% were white. At baseline, eGFR was 63-64 mL/min/1.73 m2, and median urinary protein-to-creatine ratio was 3.0-3.1.

Patients in the sparsentan group received a target dose of 800 mg/day, while those in the irbesartan group received a target dose of 300 mg/day.

Rates of adverse events were similar between the two groups, with four deaths occurring in the sparsentan group and three in the irbesartan group. One death in the sparsentan group from neuroendocrine carcinoma was considered to be potentially related to the trial drug. Acute kidney injury occurred more frequently in the sparsentan group (eight patients vs three in the irbesartan group).

Rates of fluid retention and use of diuretics were similar between the groups. Both groups also had increases in plasma potassium levels, and more sparsentan patients had adverse events associated with hyperkalemia (37 vs 21).

Developer Travere Therapeutics announced plans to "engage with regulators to explore a potential path forward" for a supplemental new drug application in the U.S.

  • author['full_name']

    Kristen Monaco is a senior staff writer, focusing on endocrinology, psychiatry, and nephrology news. Based out of the New York City office, she’s worked at the company since 2015.

Disclosures

The trial was funded by Travere Therapeutics.

Trachtman reported several relationships with industry, including with Travere Therapeutics.

Ingelfinger reported relationships with Springer and St. Martin's Press.

Primary Source

New England Journal of Medicine

Rheault MN, et al "Sparsentan versus irbesartan in focal segmental glomerulosclerosis" N Engl J Med 2023; DOI: 10.1056/NEJMoa2308550.

Secondary Source

New England Journal of Medicine

Ingelfinger JR "Sparsentan -- another arrow in the quiver for treatment of FSGS?" N Engl J Med 2023; DOI: 10.1056/NEJMe2312324.