By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a first-in-class combination endothelin and angiotensin II receptor antagonist to treat adults with immunoglobulin A nephropathy (IgAN).1 Sparsentan received an accelerated approval based on the ability to alleviate proteinuria. Continued approval may be contingent on verification and description of clinical benefit in a confirmatory clinical trial.2
Sparsentan is distributed as Filspari. Because of the potential risks, the drug will be available only through an FDA Risk Evaluation and Mitigation Strategy program.2
INDICATIONS
Sparsentan can be prescribed to alleviate proteinuria in adults with primary IgAN who are at risk of rapid disease progression — generally, a urine protein-to-creatinine ratio (UPCR) ≥ 1.5 mg/g.2
DOSAGE
The recommended initial dose is 200 mg, administered orally once daily.2 After 14 days, increase the dose to 400 mg once daily as tolerated.
If dose is interrupted (e.g., elevation of aminotransferase three times the upper limit of normal), resumption of treatment should start with the 200 mg daily dose.2 Sparsentan is available as 200 mg and 400 mg tablets.
POTENTIAL ADVANTAGES
Sparsentan provides a non-immunosuppressive treatment option, and was found to be more effective then irbesartan in improving UPCR.2
POTENTIAL DISADVANTAGES
Based on animal studies, sparsentan can cause major birth defects if used during pregnancy.2 In women who can become pregnant, an effective contraception method must be used before, during, and one month after treatment. Endothelin receptor antagonists have been reported to cause elevation of aminotransferase, hepatotoxicity, and liver failure.2 Elevation of more than three times the upper limit of normal has been observed in up to 2.5% of sparsentan-treated patients. Other possible adverse reactions include hypotension, acute kidney injury, hypokalemia, fluid retention, and lower hemoglobin levels.2 Avoid concomitant use with a strong inhibitor or a strong inducer of CYP3A.2
COMMENTS
Endothelin-1 and angiotensin II are believed to contribute to the pathogenesis of IgAN.2 The blockage of their respective receptors is a rational therapeutic approach. The efficacy of sparsentan on alleviating proteinuria in patients with biopsy-proven IgAN was evaluated in a randomized, double-blind, parallel-group, active-controlled study (PROTECT).2,3 Subjects were considered to be at high risk of progressing to renal failure. They were randomized to sparsentan or irbesartan (target dose = 300 mg daily). The primary efficacy endpoint was change from baseline in UPCR (based on a 24-hour urine sample) at week 36. From a baseline of 1.2 mg/g, sparsentan reduced UPCR to 0.7 mg/g in 141 patients vs. 1 mg/g for irbesartan in 140 patients (-45% vs. -15%, respectively; risk reduction, 0.65; 95% CI, 0.55-0.77; P < 0.0001). Sparsentan has not been shown to slow decline in kidney function or provide long-term nephroprotection. However, secondary efficacy endpoint assessments from PROTECT, including eGFR over a 52-week period (week 58 post-randomization) and eGFR over a 104-week period (week 110 post-randomization), are in progress.3 Researchers are evaluating sparsentan against irbesartan for treating focal segmental glomerulosclerosis, too.4
CLINICAL IMPLICATIONS
IgAN, an autoimmune disease, is the most common type of glomerulonephritis, leading to end-stage kidney disease in 15% to 20% of patients within 10 years from disease onset.5,6 One of the mainstays of therapy is to alleviate proteinuria. To block the renin-angiotensin system, initiate an angiotensin-converting enzyme inhibitor or an angiotensin receptor antagonist in all IgAN patients.5 The efficacy of corticosteroids has not been established, and immunosuppressives (e.g., azathioprine, rituximab) are not recommended.5 Sparsentan offers an option that is more effective than irbesartan in alleviating proteinuria. In a subanalysis of the larger dapagliflozin study in subjects with chronic kidney disease (DAPA-CKD study), the SGLT2 inhibitor dapagliflozin reduced UPCR by 26% relative to placebo from a median ratio 900 mg/g after a median follow-up of 2.1 years.7 As part of PROTECT, sparsentan and dapagliflozin will be evaluated as a combination.3 The cost for a 30-day supply of sparsentan is $9,900.
REFERENCES
1. Travere Therapeutics. Travere Therapeutics announces FDA accelerated approval of FILSPARI (sparsentan), the first and only non-immunosuppressive therapy for the reduction of proteinuria in IgA nephropathy. Feb. 17, 2023.
2. Travere Therapeutics. Filspari prescribing information. February 2023.
3. ClinicalTrials.gov. A study of the effect and safety of sparsentan in the treatment of patients with IgA nephropathy (PROTECT). Last update posted Feb. 3, 2023.
4. Komers R, Diva U, Inrig JK, et al. Study design of the phase 3 sparsentan versus irbesartan (DUPLEX) study in patients with focal segmental glomerulosclerosis. Kidney Int Rep 2020;5:494-502.
5. Floege J, Rauen T, Tang SCW. Current treatment of IgA nephropathy. Semin Immunopathol 2021;43:717-728.
6. Natale P, Palmer SC, Ruospo M, et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev 2020;3:CD003965.
7. Wheeler DC, Toto RD, Stefánsson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021;100:215-224.
Sparsentan can be prescribed to alleviate proteinuria in adults with primary immunoglobulin A nephropathy who are at risk of rapid disease progression — generally, a urine protein-to-creatinine ratio 1.5 mg/g or higher.
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