Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis

Debbie S. Gipson, Michelle A. Hladunewich, Richard Lafayette, John R. Sedor, Brad H. Rovin, Sean J. Barbour, Alan McMahon, J. Charles Jennette, Patrick H. Nachman, Robert N. Willette, Marcella Paglione, Feng Gao, Jorge Alfonso Ross Terres, Sue Vallow, M. Claire Holland, Kevin S. Thorneloe, Dennis L. Sprecher

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1228-1239
Number of pages12
JournalKidney International Reports
Volume5
Issue number8
DOIs
StatePublished - Aug 2020

Keywords

  • FSGS
  • clinical trial
  • glomerulosclerosis
  • nephrotic syndrome
  • proteinuria

PubMed: MeSH publication types

  • Journal Article

Fingerprint Dive into the research topics of 'Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis'. Together they form a unique fingerprint.

  • Cite this

    Gipson, D. S., Hladunewich, M. A., Lafayette, R., Sedor, J. R., Rovin, B. H., Barbour, S. J., McMahon, A., Jennette, J. C., Nachman, P. H., Willette, R. N., Paglione, M., Gao, F., Ross Terres, J. A., Vallow, S., Holland, M. C., Thorneloe, K. S., & Sprecher, D. L. (2020). Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis. Kidney International Reports, 5(8), 1228-1239. https://doi.org/10.1016/j.ekir.2020.05.024