Introduction: Idiopathic 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. Methods: A 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. Results: Seventeen 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. Conclusion: p38 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.
Bibliographical noteFunding Information:
Heather St Michael, of Fishawack Indicia Ltd. provided medical writing support, which was funded by GlaxoSmithKline (GSK). David M. Tenero, who is an employee of GSK, provided assistance with data modeling and simulation. This work was supported by GlaxoSmithKline (GSK study FSG117283; ClinicalTrials.gov NCT02000440). All authors contributed important intellectual content during manuscript drafting or revision, accept accountability for the work, and provided final approval of the submitted manuscript. Individual contributions of each author are as follows: DSG, MAH, RL, JRS, JCJ, BHR, and PHN contributed to the conception or design of the study, patient recruitment, the acquisition of data, and data analysis or interpretation. DLS and MP monitored study protocol, maintained study integrity and facilitated patient recruitment. DLS, MP, KST, FG, JART, SV, and RNW contributed to the conception or design of the study and data analysis or interpretation. Statistical analyses were conducted by FG. MCH contributed to data analysis or interpretation. AM and SJB contributed to the acquisition of data and data analysis or interpretation.
Heather St Michael, of Fishawack Indicia Ltd., provided medical writing support, which was funded by GlaxoSmithKline (GSK). David M. Tenero, who is an employee of GSK, provided assistance with data modeling and simulation.
This work was supported by GlaxoSmithKline (GSK study FSG117283; ClinicalTrials.gov NCT02000440).
- clinical trial
- nephrotic syndrome
PubMed: MeSH publication types
- Journal Article