DUET OLE supports long-term nephroprotection of sparsentan for FSGS patients

Results from the open-label extension (OLE) period of the phase II DUET trial demonstrated the long-term nephroprotective potential and safety of sparsentan for individuals with focal segmental glomerulosclerosis (FSGS).

“In the 8-week double-blind period [of DUET], we saw that sparsentan decreased proteinuria by almost 45 percent, in contrast to the 18 percent seen with irbesartan … [In the OLE,] sustained proteinuria reduction was observed in patients who continued sparsentan treatment,” said Dr Tarak Srivastava from the Children’s Mercy Hospital, Kansas City, Missouri, US, at ASN 2022. “Forty-three percent of subjects experienced ≥1 complete remission of proteinuria at any time.”

Looking at partial remission, there were 46, 59, and 59 percent of sparsentan-treated patients who achieved FPRE* at the respective 1-, 2-, and 3-year marks. By year 4, more than two-thirds (68 percent) have achieved this endpoint.

Mean change in eGFR** was –3.56 mL/min/1.73 m²/year for the first 108 weeks, based on the chronic slope estimate. At 240 weeks, the drop in eGFR was 4.16 mL/min/1.73 m²/year. “This is pretty good data,” Srivastava remarked.

Blood pressure (BP) reduction was also sustained, dropping by about 8–10 units for the systolic measurements and about 6–8 units for diastolic BP, he added.

DUET comprised 108 patients with biopsy-proven FSGS or documented genetic mutation associated with FSGS, urine protein/creatinine ratio (UP/C) ≥1 g/g, and eGFR >30 mL/min/1.73 m². In the double-blind phase, participants were randomized to receive sparsentan 200, 400, or 800 mg, or irbesartan 300 mg, for 8 weeks. In the OLE, those on sparsentan continued with the doses they were initially given, while placebo recipients transitioned to either of the three sparsentan doses.

Overall, the most common treatment-emergent adverse event was headache, with 11.7 cases per 100 patient-years (PY). “However, as a nephrologist, what we are really interested in are the rates of hyperkalaemia, hypotension, hypertension, or increase in blood creatinine,” Srivastava pointed out.

Indeed, there were increases in the rate of these events. Most of the hypotension and increase in serum creatinine cases occurred in the first year of follow-up (15.7 and 10.2 cases/100 PY, respectively). Hyperkalaemia and hypertension were more frequent during year 4 to <5 (11.1 cases/100 PY for both events).

The most common reasons triggering discontinuation in ≥2 subjects were decreased GFR (n=5), increased blood creatinine (n=3), and pregnancy (n=3). Median years to treatment discontinuation was 3.9 years.

“A fifth of participants discontinued by year 1. But by year 4, nearly half of the subjects were still on treatment, with only 6 percent discontinuing,” said Srivastava. There were no new or unexpected AEs observed with long-term sparsentan treatment.

Dual-pathway blockade

Sparsentan, a dual endothelin angiotensin receptor antagonist, is a novel investigational candidate being developed for the treatment of FSGS, a type of glomerular damage that could lead to kidney function decline and progression to end-stage kidney disease. [travere.com/our-science/our-pipeline/sparsentan-fsgs, accessed December 6, 2022]

Sparsentan selectively targets the endothelin A and angiotensin II subtype 1 receptors. [J Am Soc Nephrol 2018;29:2745-2754] Evidence shows that blocking both pathways in forms of rare chronic kidney disease reduces proteinuria, protects podocytes, and prevents glomerulosclerosis and mesangial cell proliferation. [Am J Physiol Regul Integr Comp Physiol 2016;310:R877-R884]

Half of individuals with nephrotic-range proteinuria who are not able to achieve even partial remission might require dialysis or kidney transplant within 5-10 years of diagnosis. [J Am Soc Nephrol 2012;23:1769-1776]

The current findings appear to align with the sparsentan programme’s objective of developing a well-tolerated, safe, and effective treatment for the sustainable reduction of proteinuria and to protect the long-term health of kidneys in individuals with FSGS.

The ongoing phase III DUPLEX study shall further elucidate the long-term antiproteinuric efficacy and safety of sparsentan.