Patients experience progressive scarring of the kidney, often resulting in failure. It is characterised by proteinuria, with protein leaking into the urine after the kidney’s normal filtration mechanism fails.
This protein is toxic to the rest of the kidney, particularly the tubules. Other common symptoms include oedema, low levels of blood albumin, abnormal lipid profiles and hypertension.
There are currently no approved drug treatments, but one potential therapy, sparsentan, is being developed by CSL Vifor and Travere Therapeutics. It is a dual endothelin angiotensin receptor antagonist that selectively targets the endothelin A receptor (ETAR) and the angiotensin II subtype 1 receptor (ATIR).
Preclinical studies indicated that blocking both these pathways could protect podocytes, prevent glomerulosclerosis and mesangial cell proliferation, and reduce proteinuria.
In a Phase II randomised, double-blind, active control trial, 109 FSGS patients aged 8–75 were given 200, 400 or 800 mg/day of sparsentan or 300 mg/day of irbesartan for 8 weeks, followed by open label sparsentan only.1
Those given sparsentan had greater reductions in their urinary protein to creatinine (UP/C) ratio than those given irbesartan. Partial remission was achieved in 28% of the sparsentan group and 9% of irbesartan recipients. It was safe and well tolerated.
In a Phase III study in 371 patients, after a 2-week washout period, subjects were randomised to receive sparsentan or irbesartan as an active control, with the dose titrated to a maximum of 800 mg of sparsentan or 300 mg of irbesartan.2
Preliminary results have been announced via press release. Although it failed to meet its primary efficacy endpoint of chronic or total eGFR slope during the 108-week double-blind treatment period, secondary and top-line exploratory endpoints were more favourable.
Notably, a reduction in proteinuria was sustained throughout the 108 weeks of treatment. The change from the baseline UP/C ratio was 50% with sparsentan and 32% with irbesartan, and 38% of sparsentan and 23% of irbesartan patients achieved the FSGS partial remission of proteinuria endpoint at week 108.
Complete remission, with the UP/C ratio falling below 0.3 g/g, was achieved by 18% on sparsentan and 7% on irbesartan (at any point during the double-blind period). It was well tolerated with a consistent safety profile (compared with irbesartan).
Sparsentan is also being evaluated in a Phase III trial in IgA nephropathy, an indication for which it was recently granted accelerated approval by the US FDA in patients at risk of rapid disease progression.
A prespecified interim analysis of its primary proteinuria efficacy has been released.3 Subjects were given once daily doses of sparsentan (400 mg) or irbesartan (300 mg). Of the 404 subjects in the interim analysis, the mean change from baseline in UP/C ratio was significantly greater with sparsentan (–49.8% compared with –15.1% for irbesartan).
Treatment-emergent adverse events were similar across both groups, with no severe oedema, heart failure or liver toxicity.
References
- H. Trachtman, et al., J. Am. Soc. Nephrol. 29, 2745 (2018).
- R. Komers, et al., Kidney Int. Rep. 5, 494 (2020).
- H.J.L. Heerspink, et al., Lancet 401, 1584 (2023).