This is a written summary of the conversation between Kirk Campbell, M.D., and Howard Trachtman, M.D., about FSGS, the DUPLEX trial, and sparsentan, sold under the brand name Filspari.
In this Managed Healthcare Executive “Between the Lines” video program, Kirk Campbell, M.D., and Howard Trachtman, M.D., discussed focal segmental glomerulosclerosis (FSGS) and how data from the phase 3 DUPLEX trial should inform clinical practice and payer policies for sparsentan, the first therapy approved specifically for the disease. The two nephrologists covered FSGS pathophysiology and subtypes, the historical treatment approach, the DUPLEX trial’s design and results, and how coverage criteria can align with the FDA label. Campbell is chief of the renal division at the University of Pennsylvania in Philadelphia. Trachtman is an adjunct professor of pediatrics at the University of Michigan in Ann Arbor.
Campbell explained that FSGS is not a single disease but a histologic pattern of injury marked by segmental scarring in some glomeruli, the kidney’s basic filtering units. It can arise from diabetes, obesity, sickle cell disease, infections and a range of genetic factors, but regardless of cause, the process culminates in injury to the podocyte, a key target cell in proteinuric kidney disorders. The presentation is nonspecific and variable. Many patients are identified incidentally through proteinuria on routine urinalysis, while others present with nephrotic syndrome, nephritic features or varying degrees of renal insufficiency, Campbell said.
Trachtman emphasized that FSGS affects patients of all ages. “The adverse consequences of this disease are the same whether you’re 10 or whether you’re 30 or whether you’re 50,” he said. It should capture the attention of nephrologists who care for patients of every age, he said.
The most recent Kidney Disease: Improving Global Outcomes (KDIGO) classification sorts FSGS into four categories. Campbell said it is due for an update. Primary FSGS is thought to have an immunologic origin, driven by a permeability factor that increases albumin leak into the urine, and is more often associated with full nephrotic syndrome. FSGS can also be secondary to drugs, infections or adaptive changes from hemodynamic strain on the filtration barrier, Campbell said. More than 60 genes have been associated with the disease, and polymorphisms in the APOL1 gene, though more of a genetic modifier than a monogenic cause, have a big impact on kidney disease in patients of African ancestry. Another category covers FSGS of undetermined cause.
Trachtman called the system a step in the right direction. He recalled that when pathologists first described FSGS in the 1950s, it was not intuitive that scarring in only some glomeruli would be harmful; clinicians observed that these patients counterintuitively did worse, but no one could predict who would. The classification is the first rational attempt to incorporate growing knowledge of kidney biology to guide evaluation and therapy, he said. “It begins to guide clinicians on how to evaluate a patient on what might be the best optimal therapy,” he said. The challenge now, he said, is to eliminate the unknown category.
Campbell added that albumin-dominant proteinuria is a central marker of disease activity and prognosis, with higher baseline levels signaling worse outcomes. A definitive diagnosis requires a kidney biopsy or a positive genetic test for a variant in a podocyte-associated gene.
Until recently, there were no FDA-approved therapies for FSGS, Campbell said. Immunosuppressants such as corticosteroids, calcineurin inhibitors (CNIs) and B-cell-depleting agents were the long-standing first-line approach for primary FSGS with nephrotic-range proteinuria, while angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) served as foundational antiproteinuric therapy. Sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, targets two pathways that both contribute to podocyte injury, fibrosis and glomerular hemodynamic stress. After approvals in IgA nephropathy in 2023 and 2024, sparsentan received full approval for FSGS in April 2026, becoming the first and only pharmacotherapy approved specifically for the disease.
Trachtman said that about one-third of patients respond to corticosteroids and a similar share of patients respond substantially to CNIs. RAS inhibitors — ACE inhibitors and ARBs — remain a fixture of care. Because endothelin and angiotensin signaling reinforce each other’s injury to the glomerulus, he suggested sparsentan may begin to replace RAS inhibitors as a first-line drug, with corticosteroids and/or CNIs added for patients who don’t respond adequately. Those agents have not lost their value, he said.
For patients switching, Trachtman expects most clinicians will replace enalapril or losartan outright, with monitoring not much different from what patients already receive. He cautioned that “we have to make sure we’re not doing any harm.” He noted that the level of proteinuria patients can safely tolerate varies by disease, and an approved drug will help the field learn how low proteinuria must go in FSGS. “We will learn about this with FSGS, and having a drug that’s approved and that can be used rationally can enable us as a community to learn how low do we need to lower the proteinuria level,” he observed.
DUPLEX was a phase 3, international, double-blind trial that randomly assigned patients 1-to-1 to sparsentan or the active comparator irbesartan, an ARB, said Campbell as he explicated the design of the trial. Enrollment required biopsy or genetic evidence of FSGS, proteinuria above 1.5 grams, and a glomerular filtration rate (GFR) of at least 30 milliliters per minute. Patients with FSGS caused by another disease or drug were excluded. The primary end point was the estimated GFR (eGFR) slope at week 108, with a prespecified interim end point at week 36 based on FSGS partial remission, defined as a urine protein-creatinine ratio (UPCR) below 1.5 grams with more than a 40% reduction from baseline. The secondary end point was eGFR change from baseline to week 112.
Asked about excluding secondary FSGS, Trachtman said, “I think the world always looks different with a 10-year gap.” When the trial was designed approximately in 2018 and 2019, secondary FSGS was seen as less threatening and controllable by treating the underlying disorder, a view that nephrologists are now rethinking, he said. “From the vantage point of the planning committee 10 years ago, I think it made sense [based on] what they knew about the state of nephrology at the time.” Campbell agreed there is a rationale for using sparsentan in secondary FSGS “because we know now that it’s not as benign as we previously thought.”
On the 1.5-gram threshold, which the label does not impose, Trachtman noted that DUPLEX patients had that proteinuria despite standard care, including corticosteroids and CNIs. In retrospect, he said, the eGFR slope was a weak end point because its variability is much greater in glomerular diseases.
Trachtman called the safety profile of sparsentan “remarkably reassuring,” citing nearly 1,000 patients who have received sparsentan across several trials, including the DUET trial he was involved in. He said he is comfortable prescribing it for persistent proteinuria of 1 to 1.5 grams despite ongoing therapy.
At week 108, the between-group difference in eGFR slope was not significant, acknowledged Campbell. “At the time, that was the headline,” he said. But the mean eGFR change to week 112 was -10.4 milliliters per minute per year with sparsentan compared with -12 milliliters per minute per year with irbesartan. Even though the primary analysis end point did not meet its target, the secondary analysis did, he said.
The proteinuria data were more striking. At week 36, 42% of patients on sparsentan reached FSGS partial remission versus 26% on irbesartan, and mean UPCR fell 50% versus 32% through week 108. Under the classic partial remission definition of more than a 50% reduction, 37.5% of patients on sparsentan responded versus 22.6%, and complete remission at week 108 was 18.5% versus a little over 7%. The time to first partial remission was 14.1 weeks versus 109 weeks. A post hoc analysis showed that, regardless of treatment arm, reaching partial or complete remission reduced progression to kidney failure. Campbell said he was highlighting that “reducing proteinuria in FSGS is an important treatment target.”
Trachtman said missing the primary end point was “hardwired” into the tremendous variability of FSGS. Though some journal clubs viewed the drug as a failure, he said, the proteinuria end point has profound meaning and the field must recalibrate how it assesses efficacy. He called the FDA’s decision “brave.”
“What we learned from the DUPLEX trial is that we need to recalibrate how we assess the efficacy of an agent, and the proteinuria is likely to be a very reliable indicator of long-term outcomes beyond the two-year time frame of a clinical trial,” Trachtman said. Campbell agreed, saying “that the biological plausibility linking podocyte injury to proteinuria is just so compelling for FSGS.”
Trachtman added, “As a pediatric nephrologist, I frequently prescribe calcineurin inhibitors, and I would be forced to wait three to six months before you'd really be able to make a sound decision about whether the drug was effective or not. And the fact that sparsentan, within a two-to-three-month period of time, is able to lower proteinuria to a meaningful level, should be very heartening to the clinician, that you're doing the right thing and to be able to buck up the commitment of the patient to say, ‘We're heading in the right direction.’”
Safety was comparable between arms, with 93.5% of patients on sparsentan and 93% of patients on irbesartan reporting at least one side effect, Campbell said. Common events such as COVID-19, peripheral edema, hypotension and hyperkalemia were balanced, and no hepatotoxicity signal was reported despite the theoretical liver risk with endothelin receptor antagonists.
Trachtman said sparsentan had been haunted by earlier endothelin antagonists linked to substantial liver injury, but its high selectivity for the endothelin type A receptor compared with endothelin type B was likely key to its lower rate of serious side effects. The patients he cared for in the DUET and DUPLEX trials tolerated it beautifully, he said, and clinicians “shouldn’t be losing too much sleep over the thought of whether to prescribe this or not.”
Sparsentan still requires a Risk Evaluation and Mitigation Strategy (REMS) program. Liver function testing has already moved from monthly to quarterly, which he said is not dramatically different from how often nephrologists see patients with FSGS. Stable real-world results could support even fewer visits, but only if the community collects systematic postapproval data.
Campbell clarified that the FDA approved sparsentan to reduce proteinuria in patients 8 years and older with FSGS without nephrotic syndrome, defined as a documented history of the syndrome or concurrent nephrotic-range proteinuria, serum albumin below 3.0 grams per deciliter, and edema at baseline. Campbell noted that the label is consistent with KDIGO guidelines for managing FSGS, sets no minimum UPCR and does not exclude any FSGS type, so primary, secondary, genetic and undetermined cases are all eligible.
In the 68% of DUPLEX patients without nephrotic syndrome, sparsentan reduced UPCR by 48% versus 27% with irbesartan, Campbell said, while in the 32% with nephrotic syndrome, reductions were similar at 39% and 37%.
Campbell and Trachtman discussed ruling out patients with the classic nephrotic syndrome triad, which includes edema, from being treated with sparsentan. Trachtman said he wondered whether trial patients with edema had less stable, more active disease, and he left the door open to treating patients with edema with the new drug if they are clinically stable and monitored carefully.
“I think that patients with nephrotic syndrome with edema should not automatically be excluded, and I think that the data would support the consideration of the use of the drug regardless of what you clinically think is the triggering factor,” he said.
Campbell responded that clinicians will have to decide “in a patient-centered manner” which patients are most appropriate for sparsentan therapy, noting the benefit that there is an approximate timeline for efficacy signals from the drug.
Trachtman said he hopes payers will authorize sparsentan when a physician prescribes it for a patient with a given level of proteinuria, leaving the decision to clinical judgment, with careful, timely follow-up to justify continued coverage. Rather than closing the door on the drug, payers could place more of the burden on practitioners to verify it is working and doing no harm. Campbell stressed that patients should not be excluded based on the study’s strict inclusion criteria, because the label is more inclusive.
For clinicians seeking coverage, Trachtman pointed to the DUPLEX summary data and urged providers to speak for their patients. A patient with confirmed FSGS, regardless of age, has a roughly 40% to 50% chance of progressing to kidney failure within five to 10 years, he said, and sparsentan is the only approved drug. He encouraged clinicians, patients and advocacy groups to collect postapproval data on proteinuria and kidney function to keep the FDA and payers informed.
In closing, Trachtman applauded the sponsor, investigators and patients for a monumental accomplishment. “It’s not the answer to our prayers, but it’s the beginning of an ongoing dialogue between patients, the FDA and payers,” he said. He urged payers to remember that unresponsive FSGS is not an inexpensive condition to treat. Society saves money when patients avoid lost work and school time and end-stage disease, he said.
Campbell agreed that the impact of untreated FSGS far exceeds the cost of new agents. He sounded a note of optimism about drug development that may result in multiple treatment options as nephrology enters the precision medicine era.
Artificial intelligence was used to help prepare this article from a transcript of the conversation.
