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PHILADELPHIA -- Sparsentan (Filspari) outperformed irbesartan in patients with IgA nephropathy over the 2-year phase III PROTECT trial.

Over a 110-week treatment period, those on sparsentan had an average 42.8% (95% CI -49.8 to -35.0) reduction in urine protein-to-creatinine ratio compared with a 4.4% (95% CI −15.8 to 8.7%) reduction with irbesartan (geometric least-squares mean ratio 0.60, 95% CI 0.50-0.72), reported Brad Rovin, MD, of The Ohio State University Wexner Medical Center in Columbus. The findings were simultaneously published in .

"Sparsentan met its primary endpoint of proteinuria change at 36 weeks in the interim analysis, with a sustained antiproteinuric effect over the course of the next 2 years," Rovin said in a presentation at the American Society of Nephrology (ASN) Kidney Week. "This led to accelerated approval for use in patients by the FDA."

This accelerated approval happened in February 2023, making sparsentan the first nonimmunosuppressive therapy for this rare condition. It's currently available under a risk evaluation and mitigation strategy (REMS) program that outlines specific requirements for prescriber, patients, and pharmacies.

At the end of the trial, 9% (18/202) of patients on sparsentan reached the composite kidney failure endpoint, whereas 13% (26/202) of the irbesartan group reached it. This translated to a 30% reduced relative risk with sparsentan for the composite of confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality (relative risk 0.7, 95% CI 0.4-1.2).

Sparsentan also did better to preserve kidney function, as patients on this treatment has a slower rate of eGFR decline than those on irbesartan according to the chronic 2-year slope (difference 1.1 mL/min/1.73 m²/year, 95% CI 0.1-2.1, P=0.037):

• Sparsentan: -2.7 mL/min/1.73 m²/year
• Irbesartan: -3.8 mL/min/1.73 m²/year

"Patients treated with sparsentan over 2 years exhibited one of the slowest annual rates of kidney function decline seen in recent IgA nephropathy trials," said Rovin.

The once-daily oral drug works by selectively targeting endothelin-1 and angiotensin II, two critical pathways in the disease progression of IgA nephropathy.

The 203 patients initially randomly assigned to the sparsentan group received a target dose 400-mg orally, once daily. The other 203 participants received target dose 300-mg oral irbesartan once daily. The average age of all participants was 46. They had biopsy-proven primary IgA nephropathy and proteinuria of at least 1.0 g/day despite maximized renin-angiotensin system inhibition for at least 12 weeks. At baseline, all also had an eGFR of at least 30 mL/min/1.73 m²/year, systolic blood pressure of 150 mm Hg or less, and diastolic blood pressure of 100 mm Hg or less.

More patients on sparsentan also achieved complete proteinuria remission, defined as urine protein excretion under 0.3 g per day (31% vs 11%). More also achieved partial proteinuria remission of under 1.0 g/day (78% vs 53%).

Rescue immunosuppressive medications were started sooner and more frequently with irbesartan than sparsentan (8% vs 3%), and these were mostly corticosteroids.

The most common treatment-emergent adverse events with sparsentan, occurring in at least 5% of patients, included dizziness (15% vs 6%) and hypotension (13% vs 4%).

Very few patients were also on SGLT2 inhibitors, Rovin pointed out.

"The PROTECT trial has an open-label extension now in which we are combining with SGLT2 inhibitors and we're running a de novo trial, which is starting up very shortly after the [ASN] meeting here called SPARTACUS, in which we're going to look at the addition of an SGLT2 inhibitor," he said. "And the expectation ... is that we would see additive effects since we're presumably working from different mechanisms."

Another trial presented here at Kidney Week -- the phase IIb ZENITH-CKD trial -- looked at combining the investigational endothelin A receptor antagonist (ERA) zibotentan with the SGLT2 inhibitor dapagliflozin (Farxiga) for reducing albuminuria in chronic kidney disease. ERAs as a class can cause fluid retention and edema and SGLT2 inhibitors have both diuretic effects and renoprotective properties.

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