INTRODUCTIONIdiopathic focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. In preclinical models and biopsies of human FSGS kidneys, p38 mitogen-activated protein kinase (MAPK) has demonstrated enhanced activity; and p38 MAPK inhibition has improved disease markers. This proof-of-concept trial aimed to assess efficacy, safety, tolerability, and pharmacokinetics of losmapimod, an oral p38 MAPK inhibitor, in humans with FSGS.METHODSA single-arm, multicenter, open-label, Phase II trial (NCT02000440) was conducted in adults with FSGS; proteinuria ≥2.0 g/d; estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2; blood pressure <140/90 mm Hg. Collapsing and genetic forms of FSGS were excluded. The primary endpoint was number of patients with ≥50% proteinuria reduction and eGFR ≥70% of baseline after receiving losmapimod twice-daily for 16 to 24 weeks.RESULTSSeventeen patients received ≥1 losmapimod dose. No patients achieved the primary endpoint; therefore, the study was terminated following a prespecified interim analysis. At week 24, proteinuria reductions between 20% and <50% were observed in 4 patients and proteinuria increases >20% in 3 patients. One patient achieved a proteinuria response (≥50% reduction) at week 2 but subsequently relapsed. Losmapimod pharmacokinetics were consistent with prior studies. No serious adverse events (AEs) were reported.CONCLUSIONp38 MAPK inhibition with losmapimod did not result in ≥50% reduction of proteinuria in patients with FSGS. However, study population heterogeneity may have contributed to our negative findings and therefore this does not eliminate the potential to demonstrate benefit in a population more sensitive to p38 MAPK inhibition if identifiable in the future by precision-medicine methods.