From a negative phase 3 readout and a seemingly tightening regulatory climate to a grueling three-month review extension, the path for Travere Therapeutics in its first-in-disease bid was anything but certain. Yet, the company has defied the odds, securing Filspari a landmark FDA approval in focal segmental glomerulosclerosis (FSGS) and delivering the first treatment for the rare kidney disease.
Monday’s FDA approval makes Filspari the first therapy specifically indicated for FSGS, a condition that represents a $1 billion-plus sales opportunity, according to Leerink Partners analysts. The drug was originally approved in 2023 for the treatment of IgA nephropathy, another kidney disease.
FSGS is estimated to affect more than 40,000 patients in the U.S. The disorder is characterized by scarring in the kidney’s filtering units as protein keeps leaking into the urine, often leading to further disease progression and kidney failure, sometimes quite rapidly.
Filspari is now indicated to reduce proteinuria for FSGS patients 8 years and older without nephrotic syndrome. This means over 30,000 patients in the U.S. could benefit from Filspari immediately, Travere CEO Eric Dube, Ph.D., told Fierce Pharma.
Three criteria are required to determine that a patient has nephrotic syndrome, who are considered sicker, Travere’s chief medical officer, Jula Inrig, M.D. explained in the same interview with Fierce. The patient must have significantly high protein in the urine at above 3.5 g per day, whereas the normal level is below 150 mg. At the same time, the patient must also have low albumin protein in their blood and swelling in the body.
If a patient with active nephrotic syndrome improves after treatment with standard immunosuppressants, they may still qualify for Filspari, Inrig noted.
In a big win for Travere, the FSGS green light is a traditional full approval. It follows several controversial FDA decisions that sparked fears of increased scrutiny if the agency in the rare disease field. However, the pendulum appears to be swinging back toward more regulatory flexibility lately. Filspari in FSGS joins the likes of Denali Therapeutics’ Hunter syndrome drug Avlayah and Rocket Pharmaceuticals’ hematopoietic stem cell-based gene therapy Kresladi among recent FDA endorsements for rare disease therapies.
The approval covers a “constellation of different” types of the FSGS, including primary, secondary, genetic and unknown causes, Dube said.
Travere had quite the ride before Monday’s approval. The FSGS decision was delayed by three months after the FDA requested additional information from the company to further characterize the clinical benefit of Filspari. The request was not surprising, given a shift in the main endpoint under review, Dube explained to Fierce in a separate interview ahead of the approval.
For this first-of-its-kind indication, Travere asked the FDA to essentially look past a phase 3 flop on a predetermined primary endpoint, and instead to consider mainly a newly emerged surrogate, which FDA staffers helped shape.
Back in 2023, Travere found that the phase 3 Duplex study pitting Filspari against off-label use of irbesartan, a drug sold by Sanofi as Avapro, failed to meet its primary endpoint of change in estimated glomerular filtration rate (eGFR), a measurement of kidney function over time, after two years. A favorable difference didn’t meet statistical significance.
Nevertheless, the study, like the phase 2 before it, proved Filspari’s ability to reduce the presence of excess protein in the urine, or proteinuria. At a prespecified interim analysis at 36 weeks, about 42% patients had partial remission of proteinuria, defined as a urinary protein-to-creatinine ratio (UPCR) of no more than 1.5 and a more-than-40% reduction from baseline. That rate was significantly better than the 26% recorded in the irbesartan group, according to results published in The New England Journal of Medicine.
Complete remission, defined as UPCR of less than 0.3 at any time during the double-blind period, was more frequent for Filspari (18.5%) than with irbesartan (7.5%).
In addition, 12 patients (6.5%) in the Filspari group and 21 patients (11.2%) in the control arm had kidney failure. Using the U.K.’s National Registry of Rare Kidney Diseases, which touts itself as the world’s largest of its kind, Travere extrapolated that this level of treatment effect would lead to a 24% reduction in the risk of kidney failure if patients were followed for five years, Inrig said in the pre-approval interview with Fierce.
The Duplex trial included fewer than 20% of patients with nephrotic syndrome. Although these patients also appeared to benefit from Filspari, those without this diagnosis experienced a greater treatment effect across trial endpoints, Inrig said. As a result, the FDA limited the approval to exclude the nephrotic subgroup, according to Inrig.
In the overall study population, patients treated with Filspari experienced a statistically significant 46% reduction in proteinuria from baseline to week 108, compared with 30% for those treated with the maximum labeled dose of irbesartan. In those without nephrotic syndrome, Filspari delivered a 48% reduction in proteinuria, compared with 27% with irbesartan.
Duplex’s favorable data, despite the primary endpoint miss, led to the formation of the PARASOL working group to elucidate endpoint selection for FSGS clinical trials. With participation from the FDA, the group found that eGFR slope was not an ideal endpoint in FSGS given, the heterogeneity of the disease. To show a clinically meaningful and statistically significant effect on that measure, a trial would need close to 2,000 patients, a requirement that’s infeasible for a rare disease, Inrig said. Instead, proteinuria showed similar behavior across patient subgroups and therefore can be supportive of regulatory approvals, the group found.
The FDA’s stance was made clearer when Dimerix and its new partner, Amicus Therapeutics, announced about a year ago that the agency had agreed on the use of proteinuria as an appropriate primary endpoint for traditional approval for their rival FSGS candidate, DMX-200.
Adding more optimism to Travere’s case, the FDA in September canceled a planned advisory committee meeting.
But toward the end of the year, accusations that the FDA was backpedaling on previously agreed-upon clinical development and regulatory plans started to emerge among rare disease drug developers. News of Filspari’s three-month extension arrived against this backdrop in January, raising doubts about the drug’s fate, despite the FDA’s involvement in the PARASOL project.
There have also been changes to Filspari’s review team at the FDA over the years, including some new names in the agency’s information requests for Travere, according to Dube. But Aliza Thompson, M.D., who was promoted last year to director of the FDA’s division of cardiology and nephrology responsible for the Filspari review, has been with the agency for a long time.
Meanwhile, Filspari has managed to hold its own in IgAN despite increased competition, including two drugs from Novartis. Full-year sales of Filspari grew 144% year over year to $322 million in 2025.
The FDA recently adjusted a liver monitoring requirement for Filspari, which Dube said simplifies access by allowing patients to align its frequency with how their kidney health is being followed, every three months.
The liver monitoring mandate also applies to the FSGS indication, Dube confirmed, stressing that it does not pose a barrier for doctors. In any case, most doctors are already used to Filspari, the chief executive said, pointing to an 85%-plus overlap in physicians that treat the two diseases.
In addition, an update to the KDIGO guidelines for IgAN last year recommended the use of Filspari, a dual endothelin angiotensin receptor antagonist, as a first-line treatment versus traditional renin-angiotensin system (RAS) inhibition. The guidelines also mentioned a potential combination of Filspari with immune-targeted therapies for patients whose disease is more difficult to treat.
“While there are other therapies that are made available, we are uniquely positioned and can be used in combination,” Dube said. “This is why we’ve seen an acceleration of demand for Filspari, and even with other therapies coming this year, we expect that our use [will] continue to grow.”
Editor's Note: The story was updated with the correct proteinuria level that's considered normal.