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 by 99Tc-DTPA plasma clearance (mGFR) at 12weeks post-infusion. The trial was registered on ClinicalTrials.gov (NCT01843387).

Findings: 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/1.73m2 for eGFR and 4.1±2.75 and 3.9±2.75 for mGFR for the 150×106 and 300×106 cell groups, respectively.

Interpretation: 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.

Keywords: Diabetic nephropathy; Glomerular filtration rate; Inflammation; Mesenchymal precursor cells; Stem cell.

Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Disposition of patients.

Fig. 2

mGFR least squares mean change (SE) from baseline at 12 weeks by group (A). eGFR least squares mean change (SE) from baseline at 12 weeks by group (B). Values are least squares mean ± SE derived from ANCOVA model using treatment and eGFR strata as factors and baseline value as covariate.

Fig. 3

eGFR least squares mean change (SE) from baseline over 60 week study by group. Values are least squares mean ± SE derived from ANCOVA model using treatment and eGFR strata as factors and baseline value as covariate. MPC150M = rexlemestrocel-L 150 × 106; MPC300M = rexlemestrocel-L 300 × 106.