In the post hoc analysis of the phase III PROTECT trial, the non-immunosuppressive dual endothelin angiotensin receptor antagonist sparsentan remains superior to irbesartan for the treatment of immunoglobulin A nephropathy (IgAN).

The initial study results have shown the superiority of sparsentan over maximum-labelled dose irbesartan in terms of proteinuria reduction and kidney function preservation in these patients. [Lancet 2023;401:1584-1594; Lancet 2023;402:2077-2090; Clin Sci (Lond) 2024;138:645-662]

“While sparsentan was favoured vs irbesartan across multiple prespecified PROTECT subgroups, it is not known whether time from biopsy to informed consent affects the efficacy of sparsentan treatment in PROTECT,” noted the investigators, led by Dr Shikha Wadhwani from the University of Texas Medical Branch, Galveston, Texas, US, at ASN Kidney Week 2025.

“[In the current analysis,] sparsentan showed greater efficacy than irbesartan, regardless of time from biopsy, with greater reduction of proteinuria and preservation of kidney function with shorter time from biopsy,” said Wadhwani and colleagues.

Sparsentan showed rapid (as early as week 4) and greater UPCR* reductions than irbesartan, which were sustained through week 110 among patients who had ≤12 months from biopsy (geometric least-squares mean [GLSM] percent change, -49.8 percent vs -11.8 percent), translating to a 43-percent reduction. A similar pattern was observed among those who had >12 months from biopsy (GLSM percent change, -41.2 percent vs -1 percent; 41-percent reduction).

There were more sparsentan than irbesartan recipients who achieved complete remission of proteinuria (urine protein excretion <0.3 g/day), irrespective of time from biopsy (39 percent vs 14 percent [≤12 mos] and 28.6 percent vs 10.5 percent [>12 mos]). [ASN Kidney Week 2025, abstract FR-PO0807]

The estimates of UPCR percent change at week 110 across different years from biopsy to informed consent (0.5, 2, 8, and 10 years) also showed that proteinuria reduction was greater and more consistent with sparsentan (LSM percent change, -48.1, -46.9, -41.8, and -39.9 percent, respectively) than with irbesartan (LSM percent change, -5.8, -5.3, -3.5, and -2.9 percent).

There were also slower rates of decline in estimated glomerular filtration rate (eGFR) with the active drug than the comparator when looking at both the chronic (LSM, -2.2 vs -3.7 mL/min/1.73 m²/year [≤12 mos] and -3 vs -4 mL/min/1.73 m²/year [>12 mos]) and total (LSM, -2.3 vs -3.6 mL/min/1.73 m²/year and -3.2 vs -4 mL/min/1.73 m²/year, respectively) eGFR slopes. The chronic eGFR slope started from week 6 through 110, while the total started from day 1 to week 110.

Supports early Tx initiation

In this 110-week trial, 404 adults with biopsy-proven IgAN were randomized 1:1 to receive sparsentan 200 mg or irbesartan 150 mg daily. The daily dose for both agents was doubled at week 2. A majority of participants (n=313) had >12 months elapse between their kidney biopsy and informed consent, while the remaining 91 patients had ≤12 months. The mean age at informed consent was approximately 46 years, over two-thirds of the participants were men, and about 30 percent were Asian.

Based on the initial PROTECT findings, sparsentan was approved in the US and Europe for the treatment of adults with primary IgAN at risk of disease progression, the researchers noted.

“[In this post hoc analysis,] sparsentan showed greater efficacy than maximum-labelled dose irbesartan across all time-from-biopsy groups, with greater absolute responses when initiated sooner after biopsy, supporting early sparsentan initiation,” they said.

In individuals with IgAN, significant nephron loss may have already occurred by the time of diagnosis. As such, the KDIGO** guidelines highlight early diagnosis and treatment when proteinuria is ≥0.5 g/day. [https://kdigo.org/wp-content/uploads/2024/08/KDIGO-2025-IgAN-IgAV-Guideline.pdf, accessed November 27, 2025]

“These results, especially in the context of the 2025 KDIGO guidelines for IgAN, emphasize the clinical benefit of early initiation of sparsentan treatment,” the investigators added.

*UPCR: Urine protein-to-creatinine ratio

**KDIGO: Kidney Disease: Improving Global Outcomes