Phase 1 Study of Oral N-Acetylmannosamine in Primary Podocytopathies.

Abstract

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: In this single-center, single-arm, ascending dose phase 1 trial, we evaluated safety and pharmacokinetics (PKs) of oral ManNAc in primary podocytopathies (ClinicalTrials.gov: NCT02639260). Eligible participants had urine protein-to-creatinine ratio (UPCR) > 1 g/g and estimated glomerular filtration rates (eGFR) > 15 ml/min per 1.73 m. 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: All enrolled participants had primary podocytopathy, with eGFR of 25 to 89 ml/min per 1.73 m and UPCR of 1.1 to 9.21 g/g. ManNAc was well-tolerated without serious adverse events (AEs). Maximum plasma ManNAc concentration was reached within 2 to 4 hours postdose, with dose-dependent increases in plasma SA. Subjects with eGFR < 45 ml/min per 1.73 m showed elevated maximum plasma ManNAc concentration and area under curve for both ManNAc and SA, reflecting reduced renal clearance. Proteinuria reduction of 12% to 52% (regression-adjusted mean 9.69%, < 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.

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Main findings

In a single-center, single-arm, ascending-dose phase 1 trial (n=7), oral ManNAc was well-tolerated with no serious adverse events. Peak plasma ManNAc occurred 2–4 hours postdose and plasma sialic acid increased in a dose-dependent manner; participants with eGFR <45 ml/min per 1.73 m had higher ManNAc/SA exposure consistent with reduced renal clearance. Among subjects receiving ManNAc twice daily, proteinuria reduction of 12%–52% (regression-adjusted mean 9.69%, P < 0.0001) was reported and described as correlating with glomerular hyposialylation in pre-study biopsies.

Outcomes measured

• Safety/adverse events
• Pharmacokinetics (plasma ManNAc concentration; time to Cmax; AUC)
• Plasma sialic acid (SA) levels
• Proteinuria (UPCR; percent reduction)
• Association with glomerular hyposialylation (from pre-study renal biopsies)

Limitations

• Phase 1 design focused on safety/PK rather than efficacy
• Single-center study
• Single-arm (no control group)
• Small sample size (n=7)
• Short duration of dosing (5 days BID after single dose)

{
    "study_type": "randomized_trial",
    "exposure": {
        "band": null,
        "source": null,
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": "Single dose (3 g or 6 g) followed by 5 days of 1.5 g twice daily (in 6 subjects); one subject single 6 g dose only"
    },
    "population": "Participants with primary podocytopathies (UPCR > 1 g/g; eGFR > 15 ml/min per 1.73 m)",
    "sample_size": 7,
    "outcomes": [
        "Safety/adverse events",
        "Pharmacokinetics (plasma ManNAc concentration; time to Cmax; AUC)",
        "Plasma sialic acid (SA) levels",
        "Proteinuria (UPCR; percent reduction)",
        "Association with glomerular hyposialylation (from pre-study renal biopsies)"
    ],
    "main_findings": "In a single-center, single-arm, ascending-dose phase 1 trial (n=7), oral ManNAc was well-tolerated with no serious adverse events. Peak plasma ManNAc occurred 2–4 hours postdose and plasma sialic acid increased in a dose-dependent manner; participants with eGFR <45 ml/min per 1.73 m had higher ManNAc/SA exposure consistent with reduced renal clearance. Among subjects receiving ManNAc twice daily, proteinuria reduction of 12%–52% (regression-adjusted mean 9.69%, P < 0.0001) was reported and described as correlating with glomerular hyposialylation in pre-study biopsies.",
    "effect_direction": "benefit",
    "limitations": [
        "Phase 1 design focused on safety/PK rather than efficacy",
        "Single-center study",
        "Single-arm (no control group)",
        "Small sample size (n=7)",
        "Short duration of dosing (5 days BID after single dose)"
    ],
    "evidence_strength": "very_low",
    "confidence": 0.7399999999999999911182158029987476766109466552734375,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "N-acetylmannosamine",
        "ManNAc",
        "sialic acid",
        "hyposialylation",
        "podocytopathy",
        "proteinuria",
        "nephrotic syndrome",
        "phase 1 trial",
        "pharmacokinetics",
        "safety"
    ],
    "suggested_hubs": []
}

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