Phase 1 Study of Oral N-Acetylmannosamine in Primary Podocytopathies

Introduction: Terminal sialic acid (SA) residues on glycoconjugates are essential for maintaining the glomerular filtration barrier's charge selectivity and podocyte ultrastructure. SA depletion affects key podocyte glycoproteins, contributing to podocytopathy and proteinuria. Glomerular hyposialylation is commonly seen in experimental podocytopathies and human renal biopsies. In nephrotic mouse models, oral administration of the metabolic SA precursor, N-acetylmannosamine (ManNAc) restored sialylation and reduced proteinuria, suggesting therapeutic potential. Methods: . Six subjects received a single 3g ManNAc dose followed by 5 days of 1.5 g twice-daily (BID) dosing. One subject received a single 6 g dose. Results: < 0.0001) was observed in subjects receiving ManNAc BID, correlating with glomerular hyposialylation in pre-study renal biopsies. Conclusion: Oral ManNAc demonstrated short-term safety and increased plasma SA levels in podocytopathy subjects. Early efficacy signals suggest that proteinuria reduction may correlate with glomerular hyposialylation, identifying a potential treatment biomarker. A phase 2 trial (NCT06664814) is underway to assess long-term outcomes.