Sparsentan fails to arrest deterioration of eGFR among patients with focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a rare and challenging kidney disorder that can lead to significant health consequences, including kidney failure. Currently, there are no approved treatments specifically indicated for FSGS, creating an unmet clinical need for effective therapeutic options.

In the pursuit of addressing this need, the phase III DUPLEX trial explored the potential of sparsentan, a dual endothelin-angiotensin receptor antagonist, to treat patients with FSGS. The researchers found that it fails to arrest deterioration of eGFR  and kidney function among patients with focal segmental glomerulosclerosis. However it led to greater reduction in proteinuria compared to irbesartan.

The trial was published in The New England Journal Of Medicine by Rheault MN and colleagues. The trial aimed to evaluate the effectiveness of sparsentan in slowing the progression of FSGS by assessing the estimated glomerular filtration rate (eGFR) slope, an essential measure of kidney function. Additionally, the study examined the impact of sparsentan on reducing proteinuria, a key marker of kidney disease. The findings of this study, presented during the American Society of Nephrology's Kidney Week, provide insights into the use of sparsentan for FSGS treatment.

The DUPLEX trial included 371 patients with FSGS who were divided into two groups. One group received sparsentan, while the other received irbesartan, an angiotensin receptor blocker used as an active control. The primary endpoint of the trial was the eGFR slope, a measure of the rate of kidney function decline.

At the final analysis, the results revealed no significant differences in the eGFR slope between the two groups. The total slope was -5.4 mL/min/1.73 m² per year for the sparsentan group and -5.7 mL/min/1.73 m² per year for the irbesartan group, indicating similar outcomes. Moreover, the chronic slope and mean change in eGFR from baseline to week 112 also showed no significant differences between the two treatment groups.

However, in a pre-specified interim analysis at 36 weeks, a noteworthy finding emerged. A higher percentage of patients treated with sparsentan achieved partial remission of proteinuria compared to those treated with irbesartan. Partial remission was defined as a urinary protein-to-creatinine ratio of ≤1.5 and a >40% reduction from baseline. This suggests that sparsentan has a more favorable effect on reducing proteinuria in FSGS patients.

The results of the DUPLEX trial shed light on the potential benefits of sparsentan in treating FSGS. While the trial did not demonstrate a significant difference in the eGFR slope, the reduction in proteinuria, an important marker of kidney disease, hints at the therapeutic potential of sparsentan for FSGS patients. It is worth noting that the study's two-year duration may have been insufficient to capture the full extent of sparsentan's impact on eGFR decline.

The pursuit of effective FSGS treatments remains crucial due to the substantial health consequences associated with the condition. The findings of this study underscore the importance of ongoing research in nephrology to develop treatments that can truly make a difference for FSGS patients. Longer-term studies may be necessary to evaluate the renoprotective effects of sparsentan fully and to identify patients who may benefit the most from this treatment.

In conclusion, sparsentan offers a promising option in the quest to address the unmet clinical need for effective FSGS treatments. Travere Therapeutics, the developer of sparsentan, has announced plans to seek traditional approval for an FSGS indication, providing hope for FSGS patients and the nephrology community alike.

Reference:

Rheault, M. N., Alpers, C. E., Barratt, J., Bieler, S., Canetta, P., Chae, D.-W., Coppock, G., Diva, U., Gesualdo, L., Heerspink, H. J. L., Inrig, J. K., Kirsztajn, G. M., Kohan, D., Komers, R., Kooienga, L. A., Lieberman, K., Mercer, A., Noronha, I. L., Perkovic, V., … Trachtman, H. Sparsentan versus irbesartan in focal segmental glomerulosclerosis. The New England Journal of Medicine,2023. https://doi.org/10.1056/nejmoa2308550