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Abstract: PO1887

Phase 1 Study of N-Acetylmannosamine (ManNAc) for Glomerular Disease

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Blake, Jodi, National Institutes of Health, Bethesda, Maryland, United States
  • Fuentes, Federico, National Institutes of Health, Bethesda, Maryland, United States
  • Huizing, Marjan, National Institutes of Health, Bethesda, Maryland, United States
  • Gahl, William, National Institutes of Health, Bethesda, Maryland, United States
  • Kopp, Jeffrey B., National Institutes of Health, Bethesda, Maryland, United States
  • Leoyklang, Petcharat, National Institutes of Health, Bethesda, Maryland, United States
  • Wilkins, Kenneth J., National Institutes of Health, Bethesda, Maryland, United States
Background


ManNAc is an uncharged monosaccharide and precursor of N-acetylneuraminic acid (NeuAc, sialic acid). It provides anionic charges to proteins, including those constituting the glomerular filtration barrier. Glomerular hyposialylation is common in nephrotic diseases and may contribute to podocyte foot process effacement and increased protein permeability. ManNAc showed benefit in nephrotic mouse models.

Methods

We performed a phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of ManNAc in nephrotic subjects (NCT02639260). Seven subjects were enrolled, 6 with focal segmental glomerulosclerosis and 1 with membranous nephropathy. Urine protein/creatinine ratio was 1.3 to 9.9 l g/g and estimated glomerular filtration rates were 29 to 89 ml/min/1.73m2. Six subjects completed a 11-day inpatient stay, receiving a 3 g single ManNAc dose, followed by 5 days 1.5 g twice daily. One subject received a single dose of 6 g ManNAc.

Results


ManNAc administration was well-tolerated. There were no serious adverse events. Most subjects (5 of 6) that received ManNAc twice daily showed a marked reduction in urine PCR (26-54%), which correlated with the degree of glomerular hyposialylation. Baseline plasma ManNAc levels in nephrotic subjects with normal eGFR were similar to those in subjects with normal renal function, but baseline plasma free NeuAc levels were elevated in nephrotic subjects with lower eGFR. This is consistent with NeuAc having high glomerular permeability and little tubular reabsorption. Plasma ManNAc levels peaked 2-4 h after dosing and returned to baseline after ~12h. Plasma free NeuAc levels peaked ~10h after dosing, remained elevated beyond 48h, and continued to increase during twice daily dosing, particularly in subjects with low eGFR. There appeared to be no adverse effects with increased free sialic acid levels, but confirmation is needed. These data support twice daily dosing, with reduced doses for subjects with low eGFR.

Conclusion


Oral ManNAc was safe and well tolerated in glomerular disease subjects. ManNAc supplementation showed a trend towards proteinuria reduction, possibly linked to the degree of glomerular hyposialyation. A phase 2 study is planned, to include assessment of longer-term pharmacokinetics, efficacy and safety.

Funding

  • NIDDK Support