Travere Misses Endpoint in Phase 3 Study of Sparsentan in Focal Segmental Glomerulosclerosis

Travere Misses Endpoint in Phase 3 Study of Sparsentan in Focal Segmental Glomerulosclerosis

Rare Daily Staff

Travere Therapeutics said its phase 3 study of sparsentan for the rare kidney disease focal segmental glomerulosclerosis missed the primary endpoint over 108 weeks of treatment.

Travere said it will engage with regulators to explore a potential path forward for a supplemental New Drug Application in the United States. Together with its collaborator CSL Vifor, the company also plans to engage with the European Medicines Agency to determine the potential for a subsequent variation to the Conditional Marketing Authorization of sparsentan for the treatment of FSGS, subject to a review decision on the pending application for the CMA of sparsentan in IgA nephropathy.

Focal segmental glomerulosclerosis (FSGS) is a rare proteinuric kidney disorder in both children and adults that is defined by progressive scarring of the kidney and often leads to kidney failure. FSGS is characterized by proteinuria, where protein leaks into the urine due to a breakdown of the normal filtration mechanism in the kidney. Once in the urine, protein is considered to be toxic to other parts of the kidney, especially the tubules, and is believed to contribute to further disease progression. Other common symptoms include swelling in parts of the body, known as edema, as well as low blood albumin levels, abnormal lipid profiles and hypertension. There is currently no approved pharmacologic indicated for the treatment of FSGS.

Sparsentan, marketed as Filspari, is an endothelin and angiotensin II receptor antagonist that was granted accelerated approval in the United States to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression. Because of the risks of hepatotoxicity and birth defects, it is available only through a restricted program called the Filspari REMS.

In the pivotal phase 3 DUPLEX study in FSGS, sparsentan achieved a mean reduction in proteinuria from baseline of 50 percent, compared to 32 percent for irbesartan at 108 weeks of treatment. Results from the two-year analysis demonstrated that sparsentan was well-tolerated and has shown a comparable safety profile to irbesartan.

“FSGS is a leading cause of kidney failure with no medicines currently approved for the condition. For the last several years we have been leading development efforts in this area which has culminated in the largest interventional study conducted to-date in FSGS, and the only one comparing a candidate against an active control,” said Eric Dube, president and CEO of Travere Therapeutics. “We are disappointed that we did not achieve the primary efficacy endpoint in this study, but we did see results that trended favorably for sparsentan that we are further exploring to determine a potential path forward in FSGS.”

The DUPLEX Study is the largest interventional study to date in FSGS. It is a global, randomized, multicenter, double-blind, parallel-arm, active-controlled phase 3 clinical trial assessing the efficacy and safety of sparsentan in 371 patients ages 8 to 75 years with primary FSGS. After a two-week washout period, patients are randomized 1:1 to receive either sparsentan or irbesartan, the active control, and subsequently dose titrated to the maximum dose of 800 mg of sparsentan or 300 mg of irbesartan, as tolerated.

In February 2021, Travere announced that the ongoing pivotal phase 3 DUPLEX Study of sparsentan in FSGS achieved its pre-specified interim FSGS partial remission of proteinuria (FPRE) endpoint with statistical significance. After 36 weeks of treatment, 42.0 percent of patients receiving sparsentan achieved FPRE, compared to 26.0 percent of irbesartan-treated patients.

Preliminary results from the interim analysis suggest that at the time of the interim assessment, sparsentan had been generally well-tolerated and shown a comparable safety profile to irbesartan. The study’s primary efficacy endpoint in the United States is the eGFR total slope from day 1 to week 108 of treatment. The primary efficacy endpoint in Europe is the eGFR chronic slope, from week 6 to week 108 of treatment, following the initial acute effect of randomized treatment. Patients that completed the DUPLEX double-blind portion of the study on treatment were eligible to participate in the open-label portion of the trial.

Photo: Eric Dube, president and CEO of Travere Therapeutics