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Abstract: PO2640

Phase 2 Study of N-Acetylmannosamine (ManNAc) for Glomerular Diseases

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Huizing, Marjan, NIH, Bethesda, Maryland, United States
  • Blake, Jodi, NIH, Bethesda, Maryland, United States
  • Gahl, William, NIH, Bethesda, Maryland, United States
  • Kopp, Jeffrey B., NIH, Bethesda, Maryland, United States
Background

Sialic acid residues provide anionic charges to proteins, including those of the glomerular filtration barrier. Lectin analysis of kidney biopsies showed glomerular hyposialylation in nephrotic diseases, this may contribute to podocyte dysfunction and proteinuria. We showed in nephrotic mouse models that oral ManNAc, an uncharged precursor of sialic acid, normalized glomerular sialylation and markedly decreased proteinuria. ManNAc is also being studied to treat the rare hyposialylation disorder GNE myopathy (NCT04231266); it could be repurposed for patients with glomerular hyposialylation.

Methods

Phase 1 Results: A phase 1 study (NCT02639260; IND 125,192) of ManNAc in 7 nephrotic subjects showed that oral ManNAc was safe and well-tolerated. Plasma free sialic acid levels peaked ~10h after ManNAc dosing, remained elevated beyond 48h, and continued to increase during twice daily dosing, particularly in subjects with low eGFR. No adverse events occurred with increased plasma free sialic acid levels. Most subjects receiving ManNAc twice daily showed a 26-54% reduction in urine protein/creatinine ratio (UPCR), which appeared to correlate with the degree of glomerular hyposialylation.

Results

Phase 2 Design: An open-label phase 2 study will include assessment of longer-term pharmacokinetics, safety and efficacy. We will enroll 12 adults with focal segmental glomerulosclerosis, minimal change disease or membranous nephropathy, UPCR >2g/g, eGFR >45 ml/min/1.73m2 and glomerular hyposialylation. Glomerular sialylation will be assessed by lectin analysis of previous diagnostic biopsies. Subjects will receive oral ManNAc twice daily for 12 weeks, with clinical evaluations at baseline, interim and at the end of the study. Study outcomes will include safety and reduction of UPCR. Exploratory outcomes will include quality of life, patient-reported outcomes and improvement in eGFR.

Conclusion

Oral ManNAc therapy might benefit subjects with glomerular hyposialylation. ManNAc has minimal toxicity, is well tolerated, is easily administered, shows a trend to reduction of proteinuria, and could replace or augment existing therapies. The results of the planned phase 2 trial might offer a new therapeutic approach for primary and perhaps secondary glomerular diseases. Such results may change medical practice by including assessment of glomerular sialylation in the analysis of renal biopsies.

Funding

  • NIDDK Support