How effective is sparsentan in treating Iga nephropathy?

Time to market of sparsentan for the treatment of Iga nephropathy

Sparsentan, also known as Filspari, is indicated to reduce proteinuria in adults with IgA nephropathy who are at risk for rapid disease progression (usually with a urine protein to creatinine ratio (UPCR) greater than or equal to 1.5 g/g). Sparsentan was approved by the US FDA on February 17, 2023. Sparsentan has previously obtained orphan drug designation for the treatment of IgA nephropathy in the United States and the European Union, and received priority review status in the United States, with remarkable therapeutic effects.

The effect of FILSPARI on proteinuria was evaluated in a randomized, double-blind, active-controlled, multicenter, global study (PROTECT, NCT03762850) in adults with biopsy-confirmed IgAN, eGFR ≥30 mL/min/1.73 m2, and total urine protein ≥1.0 g/day who were treated with a maximum stable dose of a RAS inhibitor of at least 50% of the maximum labeled dose. Patients with other glomerulopathies or who had recently received systemic immunosuppressive therapy were excluded.

Patients were randomly assigned (1:1) to FILSPARI (400 mg once daily, 200 mg once daily for 14 days) or irbesartan (300 mg once daily, 150 mg once daily for 14 days). During the trial, salvage immunosuppressive therapy may be initiated at the investigator's discretion, but the use of SGLT2 inhibitors is prohibited.

The 36 patients who reached week 281 had a mean age of 46 years (range, 18 to 76 years); 69% were male, 62% were white, 35% were Asian, and 1% were black or African American. Approximately 77% had a history of hypertension, 12% diabetes or impaired fasting glucose, and 53% hematuria. Mean (SD) baseline eGFR was 56 (24) mL/min/1.73 m2.

The primary endpoint was the relative change from baseline in UPCR at week 36 (Table 1). The average percentage change over time compared to baseline is shown in Figure 1 .

Table 1: Geometric mean (GM) ratio of UPCR at week 36 relative to baseline (PROTECT, IAS)

	Filspari(sparsentan) N=141	Irbesartan N=140
Adjusted GM for UPCR*, g/g
baseline	1.2 (n=141)	1.2 (n=140)
Week 36	0.7 (n=135)	1.0 (n=128)
Adjusted GMPC from UPCR baseline at week 36 (95% CI)	45% (-51%, -38%)	15% (-24%, -4%)
FILSPARI vs. Irbesartan: Adjusted GM at Week 36 vs. Baseline (95% CI)	0.65 (0.55, 0.77)
p-value	<0.0001

*Adjusted GM for UPCR based on MMRM stratified by screening eGFR and total urinary protein excretion. The MMRM analysis included UPCR data from the double-blind period through week 36 from the first 281 randomized and treated subjects at the interim analysis. Baseline was defined as the last unmissed observation on or before the start of dosing.

Missing data were imputed using multiple imputation under the missing-at-random assumption. Data observed during randomized treatment and after treatment cessation were included in the analysis, regardless of treatment cessation and initiation of rescue therapy (Treatment Policy Strategy). Rescue immunosuppressive therapy was initiated in 1.4% and 5.7% of patients on FILSPARI and irbesartan, respectively.

Abbreviations: CI = confidence interval; GM = geometric mean; GMPC = geometric mean percent change; IAS = interim analysis set; MMRM = mixed model repeated measures; N = number of subjects per group; n = number of subjects with available data at the time of analysis; UPCR = urine protein to creatinine ratio.

Figure 1: Geometric mean percent change from baseline in UPCR by visit (PROTECT, IAS)

Adjusted GMPC of UPCR relative to baseline was based on the same MMRM analysis used in Table 3. Counts in the axis table represent the number of subjects with UPCR data by visit and treatment group.

BL=baseline; CI=confidence interval; FIL=FILSPARI; GMPC=geometric mean percent change; Irb=irbesartan; IAS=interim analysis data set; MMRM=mixed model repeated measures; N=number of subjects in each group; UPCR=urinary protein to creatinine ratio.

Treatment effects on UPCR at week 36 were consistent across subgroups of age, sex, race, baseline eGFR, and proteinuria levels.

References

[1.] English version of Filspari instructions on the official website of the U.S. National Library of Medicine February 17, 2023

Recommended related articles: