ABSTRACT
Background & Aim: Funded in 2015, the NEPHSTROM EU-H2020 consortium aimed to translate pre-clinical evidence of efficacy of “off-the-shelf” intravenous (i.v.) allogeneic mesenchymal stromal cells (allo-MSC) in diabetic nephropathy to early-phase clinical investigation in patients with progressive diabetic kidney disease (DKD). Methods, Results & Conclusion: Methods: The trial IMP, NEPHSTROM ORBCEL-M, consists of cryopreserved, CD362-selected bone marrow allo-MSCs or matching placebo (cryopreservation fluid). The protocol for a multi-site, randomised, placebo-controlled, double- blind, dose-escalation phase-1b clinical trial in adults with DKD due to type 2 diabetes was designed collaboratively by a group of academic nephrologists and cell therapy specialists from Italy, the UK, Ireland and the Netherlands. Inclusion criteria included age 40-85 yrs and type 2 diabetes with evidence of progressive DKD [eGFR 25- 55mL/min/1.73m2, urine albumin creatinine ratio >88mg/g and rapid eGFR decline or ≥15% risk of ESRD within 5 years]. Three dose cohorts were planned, each with n=12 NEPHSTROM ORBCEL-M recipients + n=4 Placebo recipients and 18 months follow-up. Results: Following regulatory approval of the trial dossier through the EMA’s Voluntary Harmonisation Procedure and ethical approvals at the Sponsor site (Bergamo, Italy) and three other sites (Galway, Ireland;Birmingham and Belfast, UK), the NEPHSTROM trial (NCT02585622) opened March 2018. To date, 27 patients have been treated and 14 have completed the trial protocol. We report here our (as-yet blinded) experiences with the first fixed-dose cohort (80x10e6 cells/placebo i.v.), consisting of 16 subjects enrolled at 3 sites and followed for 18 months. The trial intervention proved safe, with one quickly-resolved infusion reaction and no subsequent SAEs ascribed to the IMP. Two patients died of unrelated causes between 12 and 18 months. Serial serum assays for anti-HLA antibodies indicated no persistent allo-immune sensitisation. NEPHSTROM ORBCEL-M effects on trends in eGFR, true GFR (iohexol clearance), albuminuria, serum/plasma inflammatory biomarkers and immune cell profiles will be analysed after unblinding. Following DSMB approval and COVID-19-related trial pauses, 11 second dose cohort subjects (160x10e6 cells/placebo i.v.) have been treated and are undergoing follow-up with no IMP-related adverse events to date. Conclusion: A novel, off-the-shelf, i.v. allo-MSC IMP has thus far proven safe and feasible in adults with progressive DKD.