title: Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled, Dose Escalation Study.
abstract: BACKGROUND
  Diabetic nephropathy is the most common cause of end stage renal failure. We assessed the safety, tolerability, and explored therapeutic effects of adult allogeneic bone-marrow derived mesenchymal precursor cells (MPC) in patients with moderate to severe diabetic nephropathy.
  
  
  METHODS
  Multicenter, randomized, double-blind, dose-escalating, sequential, placebo-controlled trial assessing a single intravenous (IV) infusion of allogeneic MPC (United States adopted name: rexlemestrocel-L) 150×106(n=10), 300×106(n=10) or placebo (n=10) in adults with diabetic nephropathy with an estimated glomerular filtration rate (eGFR) 20-50ml/min/1.73m2. Thirty patients at three Australian centers were enrolled between July 2013 and June 2014 and randomized 2:1, in two sequential dose cohorts, to receive rexlemestrocel-L or placebo. Study duration was 60weeks. Primary endpoint was safety and tolerability. Primary exploratory efficacy endpoint was change from baseline in eGFR and directly measured GFR by99Tc-DTPA plasma clearance (mGFR) at 12weeks post-infusion. The trial was registered on ClinicalTrials.gov (NCT01843387).
  
  
  RESULTS
  All patients completed the study and were included in analyses applied to the intention to treat population. There were no acute adverse events (AEs) associated with infusion and no treatment-related AEs or serious AEs were deemed treatment-related by investigators. No patients developed persistent donor specific anti-HLA antibodies. Relative to placebo, a single IV rexlemestrocel-L infusion showed trends of stabilizing or improving eGFR and mGFR at week 12. The adjusted least squares mean (LSM±SE) differences from placebo in changes from baseline at 12weeks in the rexlemestrocel-L groups were 4.4±2.16 and 1.6±2.15ml/min/1.73m2for eGFR and 4.1±2.75 and 3.9±2.75 for mGFR for the 150×106and 300×106cell groups, respectively.
  
  
  CONCLUSIONS
  This study demonstrates the safety of rexlemestrocel-L in diabetic nephropathy with suggestive effects on renal function to be confirmed in larger, appropriately powered trials.
authors.affiliation: Melbourne Renal Research Group, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: dmpackham@netspace.net.au.
authors.forename: David K
authors.initials: DK
authors.lastname: Packham
authors.affiliation: Epworth Medical Centre, Richmond, Victoria, Australia.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Fraser
authors.affiliation: Monash Medical Center, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kerr
authors.affiliation: Mesoblast, Inc., New York, NY, United States.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Segal
mesh_terms: D000368:Aged; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D016482:Urinalysis
keywords: Diabetic nephropathy; Glomerular filtration rate; Inflammation; Mesenchymal precursor cells; Stem cell