PROTECTing the kidneys in IgA nephropathy

• Published in: The Lancet (British edition) Vol. 402; no. 10417; pp. 2046 - 2047
• Main Authors: Reich, Heather N, Barbour, Sean J
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 02.12.2023; Elsevier Limited
• Subjects: Angiotensin; Angiotensin II; Biomarkers; Biopsy; Complications; Congestive heart failure; Cost analysis; Drug development; Edema; Endothelin 1; FDA approval; Glomerulonephritis, IGA; Health risks; Humans; IgA nephropathy; Immunoglobulin A; Immunosuppression; Industrial development; Kidney; Kidneys; Patients; Proteinuria; Receptors; Reduction; Renal failure; United States > US
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(23)02418-2

Identification of earlier surrogate markers of beneficial treatment effect—proteinuria reduction and rate of kidney function decline—has improved trial feasibility and contributed to unprecedented industry interest in drug development in IgA nephropathy.2–4 The PROTECT study was designed to address a need for targeted, non-toxic therapies to improve the outcome of patients with IgA nephropathy, a leading cause of kidney failure.5 The PROTECT study is a double-blind, randomised, phase 3 study comparing the impact of sparsentan, a novel dual endothelin-1 and angiotensin II receptor antagonist (n=202), to treatment with the angiotensin II receptor antagonist irbesartan (n=202). The results of the PROTECT trial are eagerly anticipated by the kidney community because a prespecified interim analysis of the primary outcome of the trial (change in proteinuria at week 36) showed impressive relative reduction in proteinuria with sparsentan (−49·8% vs −15·1%).5 This finding was sufficient for accelerated approval of sparsentan by the US Food and Drug Administration for treatment of adults with IgA nephropathy at risk of rapid disease progression.6 Full approval from US and European regulatory and funding agencies would require additional evidence of an impact on the rate of kidney function decline. Importantly, no patients had to stop treatment as a result of oedema or heart failure,7 which are complications seen with other endothelin receptor antagonists.8 The marked proteinuria reduction observed with sparsentan compared with irbesartan was disproportionate to the relatively modest difference in loss of kidney function.7 Similar disconnect has been observed in a study of immunosuppression in IgA nephropathy and when sparsentan was studied in focal segmental glomerulosclerosis, another glomerular disease.9,10 Further research is required to elucidate the reasons for this disconnect, underscoring the need for better early biomarkers of treatment effect and the importance of validation of the surrogate indices of treatment effect with evidence of impact on kidney function decline.