Sparsentan Bests Irbesartan for Rare, Progressive Kidney Disease

LONG BEACH, Calif. -- Sparsentan (Filspari) led to more complete and partial remissions of focal segmental glomerulosclerosis (FSGS) compared with irbesartan (Avapro), the phase III DUPLEX trial showed.

Over the course of a 108-week double-blind treatment period, 18.5% of sparsentan-treated patients achieved complete remission of FSGS versus 7.5% of irbesartan-treated patients (relative risk [RR] 2.47, 95% CI 1.37-4.45), reported Michelle N. Rheault, MD, of the University of Minnesota Medical School in Minneapolis, and colleagues in a poster presented at the National Kidney Foundation (NKF) Spring Clinical meeting.

Of the patients on sparsentan, 37.5% had a partial remission compared with 22.6% of those on irbesartan (RR 1.60, 95% CI 1.13-2.25). Those taking sparsentan also had a significantly higher probability of achieving partial remission at the 36-week interim analysis point.

In addition, average change in urine protein-to-creatinine ratio (UPCR) was 50% and 32.3% for the sparsentan and irbesartan groups, respectively.

"There are no approved therapies for patients with FSGS and there is a high risk of progression to kidney failure," Rheault told MedPage Today. "I believe that sparsentan may be a useful treatment for patients with FSGS who have not responded to other therapies and deserves further study."

The current findings build upon those of the phase II DUET study, presented at Kidney Week 2018, in which more patients with FSGS treated with sparsentan had significant reductions in UPCR from baseline through 8 weeks compared with irbesartan.

The DUET trial tested sparsentan at three doses: 200, 400, and 800 mg. For DUPLEX, patients randomized to sparsentan were started on 400 mg and then were bumped up to 800 mg at week 2. Those on irbesartan were started on 150 mg and increased to 300 mg at week 2. Treatment was started after a 2-week washout period without renin-angiotensin system (RAS) inhibition.

An orally active, selective antagonist of the angiotensin II type 1 (AT1) receptor and the endothelin-A receptor, sparsentan has anti-inflammatory, anti-proliferative, and anti-fibrotic effects. In February 2023, it was the first non-immunosuppressive therapy approved for reducing proteinuria in IgA nephropathy, also know as Berger's disease.

However, in December 2023, the FDA told developer Travere Therapeutics that the DUPLEX study results alone were not sufficient to support a supplemental new drug application for sparsentan for an FSGS indication. "As a result, the company will be conducting additional analyses of FSGS data with plans to re-engage FDA in 2024," Travere said in a statement.

While sparsentan reduced proteinuria and boosted remission rates, it wasn't significantly better than irbesartan at preventing estimated glomerular filtration rate (eGFR) decline. From baseline to week 112, there was a 10.4 mL/min/1.73 m² reduction in eGFR compared with a 12.1 mL/min/1.73 m² drop with irbesartan.

"We were surprised that the effect on eGFR slope was not statistically significant," said Rheault. She said the 2-year study period may have been too short to show an effect.

"The patients were heterogeneous and included genetic and 'primary' FSGS, leading to larger eGFR confidence intervals compared to the PROTECT study of sparsentan in IgA nephropathy, for example," she added.

A smaller proportion of patients on sparsentan experienced two composite kidney endpoints or end-stage kidney disease (ESKD) during the trial, though differences between the two groups were not statistically significant:

• ≥40% eGFR reduction, ESKD, or death: 20.1% of sparsentan patients vs 23% of irbesartan patients (RR 0.87, 95% CI 0.60-1.26)
• ≥50% eGFR reduction, ESKD, or death: 11.4% vs 16.6% (RR 0.68, 95% CI 0.43-1.10)
• ESKD: 6.5% vs 11.2% (RR 0.58, 95% CI 0.31-1.07)

For inclusion in DUPLEX, participants had to have biopsy-proven or genetic FSGS (not from a secondary cause), have a UPCR of 1.5 g/g or more, and an eGFR of 30 mL/min/1.73 m² or more.

There were 184 and 187 participants included in the sparsentan and irbesartan groups, respectively. Average age was 42, mean eGFR was 63.7 mL/min/1.73 m², and mean UPCR was 3.72 g/g. Most were on RAS inhibitors prior to washout (83% of sparsentan patients and 76% of irbesartan patients). The groups had similar use of baseline immunosuppressive agents (27% and 25%) and diuretics (37% and 39%).

Both drugs had comparable safety profiles. The most common treatment-emergent adverse events in the sparsentan and irbesartan groups were fluid retention (26% vs 30%), hyperkalemia (20% vs 11%), hypotension (18% vs 11%), anemia (16% vs 8%), dizziness (13% vs 11%), and acute kidney injury (4% vs 7%).

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