Unlocking the Potential of SC0062

We have read with great interest the article by Heerspink et al.1 titled "The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double-Blind Placebo-Controlled Clinical Trial," published in JASN, which presents the findings of a phase 2 dose-finding trial assessing the efficacy and safety of the highly selective endothelin receptor antagonist SC0062 in 131 patients with IgA nephropathy across multiple centers in China over a 6-month treatment period. According to the findings, SC0062 reduced the urine protein-creatinine ratio (UPCR) in a dose-dependent manner. Interestingly, over 71% and 51.6% of patients in the SC0062 treatment group at a dose of 20 mg experienced a 30% and 50% reduction in UPCR at week 24, respectively, compared with the baseline UPCR level. However, only 33.3% and 12.1% of placebo-treated patients experienced the same percentage reduction in UPCR. In general, throughout the same treatment period, the net UPCR reduction of SC0062 was similar to the other endothelin receptor antagonists, including sparsentan, which demonstrated a reduction of roughly 48.8% at week 24 (48.8% versus 13.9%),2 and atrasentan, which showed a reduction of 35.7% at week 24 (35.7% versus 2.8%).3 In addition, the safety profile of SC0062 appears favorable, with no significant differences between treatment groups in treatment-emergent adverse events or serious adverse events. The clinical data from the phase 2 study indicate that SC0062 has demonstrated the ability to significantly reduce proteinuria in patients with IgA nephropathy, showing potential as a treatment option that warrants further investigation. However, several questions arise from the study. First, the pathological results of kidney biopsies, specifically the Oxford mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, were not provided, and it remains unknown whether these parameters are comparable among the four groups. Second, we noticed that the selected patients had an average eGFR >70 ml/min per 1.73 m2. It remains unclear whether patients with moderate-to-severe kidney impairment would experience similar benefits from the SC0062 treatment. More importantly, the main goal of treating IgA nephropathy is to prevent the progression of the disease to kidney failure.4 There is still uncertainty as to whether SC0062 has a protective role in preserving eGFR, which is essential for having a 2-year observation period and enrolling more participants. Finally, the small sample size limits the power of subgroup analyses, preventing us from determining whether the benefits are consistent across different populations, such as sex, age, and grading of different kidney pathologies. While the study suggests that the effects of SC0062 are consistent regardless of sodium-glucose cotransporter 2 inhibitor use, future studies with a larger number of participants, including those using sodium-glucose cotransporter 2 inhibitors, are necessary to fully elucidate any potential synergistic or antagonistic effects between these two drug classes. In conclusion, the study by Heerspink et al.1 provides promising initial evidence for the use of SC0062 in IgA nephropathy. Although the results are encouraging, they also underscore the need for larger, longer-term, and geographically diverse studies to fully assess the role of SC0062 in the treatment of IgA nephropathy.