乌鸦传媒

SAN DIEGO -- Sparsentan effectively reduced proteinuria after 8 weeks in patients with focal segmental glomerulosclerosis (FSGS), a rare and progressive kidney disorder, according to results from a phase II trial presented here.

In the DUET study, compared with irbesartan (Avapro), more patients treatment with sparsentan saw significant reductions in urinary protein-to-creatinine ratio (UP/C) from baseline through 8 weeks (primary endpoint) at all studied doses (200, 400 and 800 mg/d), reported Howard Trachtman, MD, of New York University School of Medicine in New York City, and colleagues:

• Sparsentan: -44.8% (95% CI -52.7% to -35.7%)
• Irbesartan: -18.5% (95% CI -34.6% to 1.7%)

When narrowed down to just patients who received one of the two higher doses of sparsentan (400 or 800 mg/d), 47.4% of patients experienced a significant decline in UP/C from baseline compared with only 19% of patients on 300 mg/d of irbesartan (P=0.011), they reported at the American Society of Nephrology (ASN) Kidney Week 2018 and in the .

Partial remission of FSGS was also achieved by significantly more patients on any dose of sparsentan versus irbesartan (28% vs 9%, P=0.04).

Sparsentan is an orally active, selective antagonist of the angiotensin II type 1 (AT₁) receptor and the ET_A receptor, the authors noted, adding that "findings indicate that short-term dual blockade of the AT₁ and ETA receptors with sparsentan produced greater reduction in proteinuria than blockade of the AT₁ receptor alone."

A total of 96 patients, ages 8-75 years, had either biopsy-proven FSGS or a disease-causing genetic mutation that was tied to FSGS were enrolled. These patients also had a UP/C ratio of ≥1.0 g/g and an eGFR >30 ml/min/1.73 m².

There was a prespecified plan of a 3:1 randomization of sparsentan to irbesartan within each of the cohorts, with 20-40-40 allocation of patients to the 200-, 400-, and 800-mg doses of sparsentan. However, due to a computer error during the 8-week blinded portion of the study, there ended up being 13 patients who received 200 mg of daily sparsentan compared with eight patients on 300-mg irbesartan, 26 on 400-mg sparsentan compared with 20 on irbesartan, and 34 on 800-mg sparsentan compared with eight on irbesartan.

After unblinding, patents were able to receive sparsentan in an open-label period for an additional 144 weeks.

A significant greater mean change in both systolic and diastolic blood pressure (BP) was also seen with sparsentan treatment when compared with irbesartan from baseline to the end of 8 weeks of treatment:

• Systolic BP: -7.2 (95% CI -11.8 to -2.6, P=0.003)
• Diastolic BP: -5.6 (95% CI -9.0 to -2.2, P=0.002)

However, eGFR did not differ between the treatments at the end of 8 weeks, and remained stable for all patients through the double-blind period.

Sparsentan was also safe and generally well tolerated, with a similar number of treatment-emergent adverse events seen with both agents, although more patients on sparsentan experienced hypotension, dizziness, edema, nausea, and gastrointestinal side effects. Hyperkalemia, muscle spasms, fatigue, and respiratory-related adverse events were more common with irbesartan.

In the entire study, there were only 15 black patients enrolled, which was a limitation, according to Marva Moxey-Mims, MD, of Children's National Health System in Washington.

"How is this generalizable to a population that tends to have more FSGS and maybe more aggressive FSGS," she asked during the ASN presentation. Moxey-Mims, who was not involved with the study, also commented that although there were no significant outcomes differences seen between the various doses of sparsentan, the low number of patients randomized to each dose was likely too small to have the power to show any potential between-group differences.

The phase III DUPLEX study assessing sparsentan is currently underway, which drugmaker said will serve as the basis for the NDA filing. If FDA approved, sparsentan would be the first pharmacologic treatment for FSGS.

Comment