Phase 2 Data Highlight SC0062’s Dose-Dependent Impact on Proteinuria in IgA Nephropathy

Hiddo Heerspink, PhD, PharmD

Credit: George Clinical

New phase 2 data suggest SC0062, a selective endothelin receptor antagonist, reduces urine protein-creatinine ratio (UPCR) in a dose-dependent manner when added to maximum tolerated angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) treatment in patients with IgA nephropathy (IgAN).¹

Findings from the phase 2, dose-finding, randomized, placebo-controlled clinical trial show treatment with SC0062 20 mg had the greatest impact on proteinuria reduction and that treatment with SC0062 at any dose was well-tolerated with an acceptable safety profile versus placebo.¹

“Endothelin-1 (ET-1) is a vasoactive peptide involved in the pathophysiology of IgA nephropathy. Upregulation of ET-1 and activation of endothelin type A receptor in the kidney contributes to endothelial dysfunction, podocyte damage, mesangial expansion, and tubular inflammation and fibrosis in experimental models of IgA nephropathy,” Hiddo J.L. Heerspink, PhD, PharmD, of University Medical Center Groningen, and colleagues wrote.¹ “Moreover, higher ET-1 levels measured in kidney biopsies of patients with IgA nephropathy correlated with more severe albuminuria and a faster rate of kidney function decline.”

Investigators pointed to additional support for targeting the endothelin axis in adults with IgAN based on findings from a phase 3 randomized controlled clinical trial of sparsentan (Filspari), a dual endothelin angiotensin receptor antagonist, demonstrating its impact on proteinuria and eGFR decline. On September 5, 2024, the US Food and Drug Administration granted full approval to sparsentan for slowing kidney function decline in adults with primary IgAN at risk of disease progression, making it the second therapeutic to receive full approval for IgAN following last year’s approval of budesonide (Tarpeyo) delayed-release capsules.^1,2

A novel, potent, and selective endothelin receptor type A antagonist, SC0062 is in development for the treatment of chronic kidney disease. In a phase 2 dose-finding trial conducted across 46 centers in China, its use was explored in patients with diabetic kidney disease and IgAN. For inclusion in the IgAN cohort, participants were required to be ≥ 18 years of age with eGFR ≥ 30 ml/min per 1.73 m2 and UPCR ≥ 750 mg/g in a 24-hour urine sample or 24-hour urine protein excretion ≥1000 mg per 24 hours despite using maximum tolerated doses of ACEI or ARB.¹

Participants were randomly assigned in a 1:1:1:1 ratio to 24 weeks of treatment with SC0062 5 mg, 10 mg, 20 mg, or matching placebo once daily. Of note, randomization was stratified according to eGFR at screening and SGLT2 inhibitor use.¹

The primary endpoint was the percent change from baseline in log-transformed UPCR measured in 24-hour urine samples at week 12. Secondary endpoints included the percent change from baseline in log-transformed UPCR and UACR at each study visit; change from baseline in eGFR at each study visit; percent change from baseline in 24-hour urinary protein excretion rate at week 12 and week 24; and proportion of participants with ≥30%, ≥40%, and ≥50% reduction in 24-hour UPCR from baseline at week 12 and week 24.¹

In total, 131 patients were randomly allocated to placebo (n = 34) or SC0062 5 mg (n = 33), 10 mg (n = 32), or 20 mg (n = 32), 127 (97%) of whom completed the 12-week double-blind period for the primary efficacy outcome and 122 (94%) completed the 24-week double-blind period on treatment. Among the cohort, the mean age was 42 years, the mean eGFR was 72 ml/min per 1.73 m2, and the median 24-hour UPCR was 1.2 g/g.¹

Results showed all SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, the placebo-corrected geometric mean changes from baseline in UPCR with SC0062 5 mg, 10 mg, and 20 mg were −27.6% (95% CI, −43.0 to −8.2), −20.5% (95% CI, −37.4 to 1.0), and −38.1% (95% CI, −51.4 to −21.0), respectively, and at week 24 they were−22.4% (95% CI, −42.2 to 4.3), −30.9% (95% CI, −48.6 to −7.0), and −51.6% (95% CI, −64.2 to −34.6), respectively.¹

Investigators noted the changes in 24-hour UACR were consistent with the observed changes in 24-hour UPCR, with the largest reduction in UACR observed with the greatest SC0062 dose (20 mg). Additionally, they pointed out eGFR changes fluctuated and were modest during double-blind follow-up in the placebo and all SC0062 treatment groups.¹

Of note, the proportion of participants with treatment-emergent adverse events or serious adverse events was balanced among treatment groups. Specifically, peripheral edema was reported by 2 (6%), 1 (3%), and 1 (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with 5 (15%) in the placebo group.¹

Investigators outlined multiple limitations to these findings, including the short follow-up period; the lack of generalizability to regions outside of China; the limited number of participants using SGLT2i in the study; the inability to assess the reversibility in UPCR after discontinuation of study medication; and the potential for random variation in clinical chemistry measurements due to use of local laboratories instead of a central laboratory.¹

“This study supports a larger randomized clinical trial to assess the long-term efficacy and safety of SC0062 in adults with IgA nephropathy,” investigators concluded.¹

References

1. ^{Heerspink HJL, Du X, Xu Y, et al. The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double-Blind Placebo-Controlled Clinical Trial. J Am Soc Nephrol. doi: 10.1681/ASN.0000000538.}
2. ^{Brooks, A. FDA Approves Travere Therapeutics’ Sparsentan to Slow Kidney Function Decline in Adult Primary IgAN. HCPLive. September 5, 2024. Accessed November 11, 2024. https://www.hcplive.com/view/fda-approves-travere-therapuetics-sparsentan-for-proteinuria-reduction-in-adult-primary-igan}