A Phase 1 Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ManNAc in Subjects With Primary Podocyte Diseases

Study Summary

Three kidney diseases that affect both children and adults are minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). These diseases are characterized by proteinuria (protein in the urine) and in the cases of FSGS and membranous nephropathy, a tendency to progressive scarring of the glomerulus (the filtering units of the kidneys) that leads to end-stage kidney disease. Several therapies are available for these diseases, but these therapies do not provide lasting reduction in proteinuria for many subjects. In the current study, carried out at the NIH Clinical Center, we are testing a new therapy, ManNAc. ManNAc is a naturally occurring uncharged sugar that cells use to produce negatively charged sialic acid. Kidney cells attach sugars such as sialic acids to proteins and lipids (resulting in glycans), and these assist in cell function. Mouse models of the inherited muscle disease GNE myopathy, which is due to sialic acid deficiency on muscle glycans, responded favorably to oral ManNAc therapy and a clinical trial of ManNAc is ongoing in GNE myopathy subjects. There is evidence that some subjects with MCD, FSGS or MN do not put enough sialic acids on glomerular proteins and so ManNAc therapy may increase sialic acid production and sialylation of glomerular proteins in these subjects. For the present study, we will recruit 12 subjects who have MCD, FSGS or MN. Each subject will stay at the NIH Clinical Center for 11 days to receive oral ManNAc. The primary purposes of the study are to determine: 1) the safety of ManNAc in subject s with kidney disease; and 2) the ManNAc and sialic acid metabolism related to ManNAc in subjects with kidney disease. Concentrations of ManNAc and sialic acid will be measured in plasma at various times before and after dosing. If this study suggests that ManNAc is safe in subject with kidney disease, the results will be used to plan a longer-term study to determine whether it is effective at

Primary Outcome

Safety by self-reported symptoms and by standard laboratory testing. The effects of reduced eGFR will be assessed. The effect of ManNAc therapy on proteinuria, from the baseline to the end of the extension phase, will be examined on a research basis.

Interventions

• DRUG N-acetyl D-mannosamine