This first in human study was designed to assess

This first in human study was designed to assess the overall safety of MPC and to explore its effects on renal function in patients with moderate to severe diabetic nephropathy as assessed by glomerular filtration rate measured directly by 99Tc DTPA plasma clearance (mGFR) and estimated (eGFR) from serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation (Levey et al., 1999).
Methods
Results
Discussion Therapies that delay or prevent progression of diabetic nephropathy to end stage renal failure would be of immense clinical and economic value. Because of the ability of allogeneic mesenchymal lineage cells to track to injured tissues (Togel & Westenfelder, 2011) and potentially exert anti-inflammatory, immunomodulatory and other paracrine effects these cells may represent such a candidate therapy. Paracrine effects of these cells in vivo are likely to explain their clinical potential (Psaltis et al., 2010; See et al., 2011) as there is little evidence of engraftment of systemically administered cells (von Bahr et al., 2012). This study represents the first double-blind, placebo-controlled trial of an allogeneic, bone-marrow derived mesenchymal lineage cell product in patients with chronic kidney disease due to type 2 diabetes. The study was designed to assess acute and chronic safety and immunological sensitization potential following a single infusion of rexlemestrocel-L. In addition, although the study was not powered for efficacy, a hypothesis-generating signal was observed with consistency between isotopically measured and creatinine-based estimations of renal function at the prespecified primary endpoint 12weeks post-infusion. The 12week timepoint was selected as the primary exploratory endpoint based on similar early phase clinical development studies in diabetic nephropathy (Pergola et al., 2011; Ruilope et al., 2014) and a previous study in subjects with type 2 diabetes that showed a trend for improved glycemic control at 8weeks which dissipated thereafter (Skyler et al., 2015). The infusions were well-tolerated and the safety profile we report is comparable across all treatment groups. Theoretical risks of an allogeneic cell therapy including allergic risks due to excipients such as fetal calf serum or immunogenic responses to human antigens (donor HLA) were not observed. Cross matching between donor cells and recipient was not performed prior to infusion. In addition, subjects were not excluded from participation based on assessment of order info to the donor HLA. Importantly in this patient population, no patients developed sustained antibodies specific to the donor HLA or showed clinically relevant sustained increases in Class I or Class II %PRA, consistent with the immune tolerant profile of this cell type and a previous study showing no evidence of rexlemestrocel-L induced antibodies or immune system events (Skyler et al., 2015). These cells are negative for HLA Class II and CD80 and CD86 co-immunostimulatory molecules, and exert potential immunomodulatory effects including inhibition of T-cell proliferation (Togel & Westenfelder, 2011). The observed lack of acute immunological responses to unmatched allogeneic MPC is particularly important in patients who may eventually require kidney transplantation. Possibly, repeated administration of this product may enhance the observed modest signal of GFR preservation, relative to placebo. Lack of any evidence of sustained sensitization and development of antibodies specific to the donor HLA suggests that repeat administration of this therapy may be a feasible option in this patient population. The design of future studies may include assessment of safety, tolerability and efficacy of single and repeated administration of the product. There are limitations to our study. First, the sample size was too small to demonstrate statistically significant effects on renal function. Moreover, the possibility of type 1 error cannot be excluded based on multiple exploratory statistical analyses performed without adjustment for multiplicity. In addition, the small sample size (N=30) while appropriate for a first in human investigation cannot exclude rarer safety events than would be detected over 60weeks following a single infusion. Second, the study duration (12weeks) to assess acute effects of a single administration with a 48week follow-up is too brief to evaluate a chronic disease with variable and frequently slow progression. Selection of patients with documented recent rapid progression of their chronic kidney disease may more likely show treatment effects, particularly over a brief study duration. Third, the wide range of baseline albuminuria and proteinuria (ACR 21 to 3000mg/g) as well as serum biomarkers in a small number of patients complicated the assessment of changes within and between groups in these parameters. Selection of subjects within a narrow range of baseline proteinuria may provide more useful information. With respect to serum biomarkers of inflammation, owing to within subject variability as well as sensitivity of the available assays, systemically measured inflammatory cytokines probably require substantially larger numbers of subjects per group to identify meaningful changes and treatment differences over time. Lastly, repeated isotopically measured GFR assessments beyond 12weeks to confirm eGFR findings were not performed because of radioisotope exposure. Serum-creatinine based eGFR equations may underestimate or overestimate GFR.