PMID- 32775822
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220416
IS  - 2468-0249 (Electronic)
IS  - 2468-0249 (Linking)
VI  - 5
IP  - 8
DP  - 2020 Aug
TI  - Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental 
      Glomerulosclerosis.
PG  - 1228-1239
LID - 10.1016/j.ekir.2020.05.024 [doi]
AB  - 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 m(2); 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.
CI  - (c) 2020 Published by Elsevier, Inc., on behalf of the International Society of 
      Nephrology.
FAU - Gipson, Debbie S
AU  - Gipson DS
AD  - Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Hladunewich, Michelle A
AU  - Hladunewich MA
AD  - Department of Internal Medicine, Sunnybrook Health Sciences Centre, Toronto, 
      Ontario, Canada.
FAU - Lafayette, Richard
AU  - Lafayette R
AD  - Department of Internal Medicine, Stanford University, Stanford, California, USA.
FAU - Sedor, John R
AU  - Sedor JR
AD  - Department of Internal Medicine, Cleveland Clinic Lerner College of Medicine, 
      Case Western Reserve University, Cleveland, Ohio, USA.
FAU - Rovin, Brad H
AU  - Rovin BH
AD  - Department of Internal Medicine, Ohio State University Wexner Medical Center, 
      Columbus, Ohio, USA.
FAU - Barbour, Sean J
AU  - Barbour SJ
AD  - Department of Internal Medicine, University of British Columbia, Vancouver, 
      British Columbia, Canada.
FAU - McMahon, Alan
AU  - McMahon A
AD  - Department of Internal Medicine, University of Alberta Hospital, Edmonton, 
      Alberta, Canada.
FAU - Jennette, J Charles
AU  - Jennette JC
AD  - Department of Pathology, University of North Carolina, Chapel Hill, North 
      Carolina, USA.
FAU - Nachman, Patrick H
AU  - Nachman PH
AD  - Department of Internal Medicine, University of North Carolina, Chapel Hill, North 
      Carolina, USA.
AD  - Department of Internal Medicine, University of Minnesota, Minneapolis, Minnesota, 
      USA.
FAU - Willette, Robert N
AU  - Willette RN
AD  - PoC Pharma Consulting, LLC, Pottstown, Pennsylvania, USA.
FAU - Paglione, Marcella
AU  - Paglione M
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Gao, Feng
AU  - Gao F
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Ross Terres, Jorge Alfonso
AU  - Ross Terres JA
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Vallow, Sue
AU  - Vallow S
AD  - Worldwide Clinical Trials, Morrisville, North Carolina, USA.
FAU - Holland, M Claire
AU  - Holland MC
AD  - Teva Pharmaceuticals, Frazer, Pennsylvania, USA.
FAU - Thorneloe, Kevin S
AU  - Thorneloe KS
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Sprecher, Dennis L
AU  - Sprecher DL
AD  - BioView Consultants, LLC, Blue Bell, Pennsylvania, USA.
LA  - eng
PT  - Journal Article
DEP - 20200526
PL  - United States
TA  - Kidney Int Rep
JT  - Kidney international reports
JID - 101684752
PMC - PMC7403548
OTO - NOTNLM
OT  - *FSGS
OT  - *clinical trial
OT  - *glomerulosclerosis
OT  - *nephrotic syndrome
OT  - *proteinuria
EDAT- 2020/08/11 06:00
MHDA- 2020/08/11 06:01
PMCR- 2020/05/26
CRDT- 2020/08/11 06:00
PHST- 2019/12/02 00:00 [received]
PHST- 2020/05/12 00:00 [revised]
PHST- 2020/05/18 00:00 [accepted]
PHST- 2020/08/11 06:00 [entrez]
PHST- 2020/08/11 06:00 [pubmed]
PHST- 2020/08/11 06:01 [medline]
PHST- 2020/05/26 00:00 [pmc-release]
AID - S2468-0249(20)31285-7 [pii]
AID - 10.1016/j.ekir.2020.05.024 [doi]
PST - epublish
SO  - Kidney Int Rep. 2020 May 26;5(8):1228-1239. doi: 10.1016/j.ekir.2020.05.024. 
      eCollection 2020 Aug.