Work

Alternative Dosing Strategies to Enhance the Absorption of N-Acetyl-d-Mannosamine Monohydrate (ManNAc) in Healthy Adult Males

Year: 2026

Type: article

Study designs: Randomized Controlled Trial, Clinical Trial

Abstract: BACKGROUND: GNE myopathy is a rare autosomal recessive muscle disease caused by biallelic mutations in GNE, a gene which encodes the bifunctional enzyme that catalyses the rate-limiting step of intracellular sialic acid biosynthesis. Whilst there is no current marketed therapy to treat the disease, current investigations focus on supplementation with N-acetyl-D-mannosamine monohydrate (ManNAc), a precursor in the biosynthesis of N-acetylneuraminic acid (Neu5Ac), the most abundant sialic acid. ManNAc possesses a low oral bioavailability, likely owing to poor absorption, and exhibits non-linearity across the therapeutic range, possibly due to saturation of intestinal transporter systems. OBJECTIVES: The study was conducted to examine if the absorption of ManNAc could be improved by administering a smaller (non-saturating) oral dose, more frequently, or by co-administering ManNAc with dietary salt, which might facilitate carrier-mediated transport. METHODS: This was an open-label, randomised, cross-over study in 12 healthy male participants. Participants were administered 4 x 1 g doses of ManNAc every hour, 4 g ManNAc as a single dose with 1 g dietary salt or 4 g ManNAc alone. RESULTS: The pharmacokinetic analysis population comprised 11 participants who received all three study treatments. Administration of ManNAc as split doses, more frequently, resulted in a 1.7-fold increase in ManNAc plasma exposure compared to a single 4 g dose, with a corresponding 1.9-fold increase in systemic Neu5Ac concentrations. In comparison, co-administration of ManNAc with dietary salt had no impact on ManNAc absorption. CONCLUSIONS: This study suggests that strategies to slow down the delivery of ManNAc to the small intestine may significantly improve its overall bioavailability and therefore reduce total daily dose requirements. CLINICAL TRIAL REGISTRATION: The clinical trial was registered on the Australian New Zealand Clinical Trials Registry (ID: ACTRN12620001127998).

Source: Clinical Drug Investigation

DOI: 10.1007/s40261-026-01546-y