FDA Asks Travere for Additional Data Ahead of Marketing Application for FSGS Therapy

Rare Daily Staff

Travere Therapeutics said the U.S. Food and Drug Administration told the company that interim data from its ongoing phase 3 study of sparsentan in focal segmental glomerulosclerosis would not be adequate to support an accelerated approval at this time.

The FDA’s decision came after a pre-NDA meeting in which the agency acknowledged the high unmet need for approved therapies for the treatment of focal segmental glomerulosclerosis (FSGS). Travere was pursuing accelerate approval submissions in the United States and European Union.

Based on this feedback, Travere said it no longer expects to submit for accelerated approval for FSGS in the United States during the second half of 2021. The FDA has indicated that it may be possible to submit an application for accelerated approval after additional data accrue in the study. Subject to further discussion with the FDA, Travere believes that it may be possible to provide sufficient additional estimated glomerular filtration (eGFR) data from the DUPLEX study in the first half of 2022. The FDA has encouraged the company to request a follow-up meeting to further explore this option in greater detail, and a Type A meeting is expected to occur in the third quarter of 2021.  

“We remain very confident in the profile of sparsentan and believe it supports the ability to ultimately become a new treatment standard for FSGS, but we are disappointed that we will not be able to submit for accelerated approval this year and deliver it to patients on our original targeted timeline,” said Eric Dube, CEO of Travere Therapeutics. “Based upon our ongoing dialogue with FDA, we believe the eGFR data need to further mature to support our New Drug Application for accelerated approval in this indication. We remain optimistic that we still have a potential opportunity to pursue a path to an accelerated approval submission in the United States next year.”

FSGS is a rare proteinuric kidney disorder that is estimated to affect up to 40,000 patients in the United States with similar prevalence in Europe. The disorder is defined by progressive scarring of the kidney and often leads to end-stage kidney disease. 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 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, as well as low blood albumin levels, abnormal lipid profiles and hypertension.

Reduction in proteinuria appears to be beneficial in the treatment of FSGS and may be associated with a decreased risk of progression to end-stage kidney disease. FSGS is currently managed with angiotensin receptor blockers, angiotensin converting enzyme inhibitors, steroids or calcineurin inhibitors.

Sparsentan is an experimental product candidate that functions as a high affinity dual-acting antagonist of both the endothelin type A and angiotensin II type 1 receptors, in a single molecule. Preclinical data have shown that blockade of both pathways in forms of rare chronic kidney disease reduces proteinuria, protects podocytes and prevents glomerulosclerosis and mesangial cell proliferation.

In February 2021, Travere reported that the ongoing pivotal phase 3 DUPLEX Study of sparsentan in FSGS achieved its pre-specified interim FPRE endpoint with statistical significance. FPRE is a clinically meaningful endpoint defined as urine protein-to-creatinine ratio (UP/C) ≤1.5 g/g and a >40 percent reduction in UP/C from baseline. 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 DUPLEX study is fully enrolled with 371 participants and is scheduled to continue as planned on a blinded basis to assess the confirmatory estimated glomerular filtration rate (eGFR) endpoint after 108 weeks of treatment. Topline results from the confirmatory endpoint are expected in the first half of 2023.

Travere also conducted initial MAA pre-submission interactions with the European Medicines Agency. In that meeting, the company said it received administrative support for proceeding as planned with a conditional marketing authorization submission in the second half of 2021. As a result its interactions, Travere said it will continue its preparations for an MAA submission of sparsentan in FSGS and seek confirmation of its plans with the assigned rapporteurs and co-rapporteurs in an upcoming meeting.

Sparsentan is also currently being evaluated in the pivotal phase 3 PROTECT Study for the treatment of IgAN. If approved for both indications, sparsentan could potentially be the first medicine approved for both FSGS and IgAN. It has been granted Orphan Drug designation for the treatment of FSGS and IgAN in the United States and Europe.

Photo: Eric Dube, CEO of Travere Therapeutics