FDA Approves Sparsentan as First FSGS Treatment

The FDA expanded the indication of sparsentan (Filspari) to make it the first treatment for focal segmental glomerulosclerosis (FSGS), developer Travere Therapeutics announced on Monday.

A once-daily oral tablet, sparsentan is fully approved to reduce proteinuria in patients ages 8 and older with FSGS who do not have nephrotic syndrome. The non-immunosuppressive therapy features a dual mechanism of action, targeting both endothelin A and angiotensin II receptors.

FSGS is estimated to affect more than 40,000 patients in the U.S., over 30,000 of whom do not present with nephrotic syndrome.

The progressive kidney disease causes irreversible scarring of the kidney and chronic proteinuria, often leading to kidney failure. Treatment options included off-label use of ACE inhibitors, angiotensin receptor blockers (ARBs), SGLT2 inhibitors, and immunosuppressive regimens.

“For decades, treatment options have been limited, often relying on off-label therapies such as long-term steroids that can carry a significant burden for patients,” said Kirk Campbell, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, in a company press release.

The regulatory path wasn’t as smooth for FSGS as it was for sparsentan’s initial indication for IgA nephropathy in February 2023. Yesterday’s approval followed a 3-month FDA delay while the agency reviewed additional information about sparsentan’s clinical benefit, following mixed results from the pivotal trial.

The DUPLEX study missed its primary endpoint, showing no significant difference at week 112 in total estimated glomerular filtration rate (eGFR) slope with sparsentan versus irbesartan (P=0.75). The phase III trial enrolled 371 patients ages 8 to 75 years with biopsy-proven or genetic FSGS.

Despite failing to meet the primary endpoint, sparsentan showed it could reduce proteinuria in a secondary analysis. Sparsentan-treated patients had a 46% reduction in proteinuria compared with a 30% reduction with irbesartan (P=0.0299).

The benefit was more pronounced in a subgroup of patients without nephrotic syndrome who had a 48% reduction in proteinuria with sparsentan versus 27% with irbesartan (P=0.0075). Sparsentan-treated patients without nephrotic syndrome had a slightly lower total eGFR decline compared with irbesartan.

Sparsentan “delivered rapid and sustained reductions in proteinuria compared to irbesartan, with particularly meaningful effects in patients without nephrotic syndrome. This is consistent with KDIGO guidance, which emphasize[s] reducing proteinuria as a key strategy to slow disease progression in FSGS,” Campbell noted. “For patients without active nephrotic syndrome, where optimizing foundational therapy is critical, [sparsentan] represents an important new option.”

The most common adverse events (occurring in ≥5%) in patients treated with sparsentan were peripheral edema, hypotension including orthostatic hypotension, hyperkalemia, dizziness, and anemia.

Sparsentan is available only through a risk evaluation and mitigation strategies (REMS) program due to hepatotoxicity. The drug’s label carries a boxed warning for that and embryo-fetal toxicity and warnings about acute kidney injury and fluid retention.

The treatment is contraindicated with endothelin receptor antagonists (ERAs) or aliskiren and in pregnancy. Patients must discontinue renin-angiotensin-aldosterone system inhibitors and ERAs before starting sparsentan.