GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), is a rare, autosomal recessive myopathy with onset in early adulthood that is characterized by progressive muscle weakness and atrophy, which leads to wheelchair use and dependent care. The causative gene, GNE, encodes the rate-limiting enzyme in the biosynthesis of sialic acid. While the exact pathophysiology of GNE myopathy remains unknown, decreased sialic acid production and subsequent hyposialylation of muscle glycoproteins are thought to be key factors leading to muscle deterioration in GNE myopathy. This hypothesis is supported by prevention of disease after administration of N-acetyl-D-mannosamine (ManNAc) in mouse models of GNE myopathy. A recent first-in-human, Phase 1 single ascending dose study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single dose of 3,000, 6,000, or 10,000 mg drug product-grade ManNAc in subjects with GNE myopathy (ClinicalTrials.gov NCT01634750; IND No.78,091). ManNAc was safe and well-tolerated in all subjects who participated in this study. In this Phase 2, open-label, single-center study we propose to administer ManNAc orally to 12 subjects for 912 days (30 months). The objectives of the study are to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and biochemical efficacy of orally administered ManNAc in GNE myopathy subjects and to evaluate disease-related biomarkers and relevant clinical endpoints. In the first phase of pharmacokinetic assessment, two cohorts of 6 subjects will receive ManNAc at doses of 3,000 mg twice a day (6,000 mg per day) or 6,000 mg twice a day (12,000 mg per day) for 7 days while admitted to the NIH Clinical Center to assess PK and safety. Safety and tolerability will be assessed on an individual basis. In the second phase of the study, all subjects will receive treatment with ManNAc at a dose of 6,000 mg twice daily for the remainder of the study. Follow-up safety and efficacy evaluations will occur at 42 days, and at 91 (3 months), 182 (6 months), 365 (12 months), 548 (18 months), 730 (24 months) and 912 (30 months) days. Safety lab evaluation will be performed also at 456 (15 months), 638 (21 months) and 820 (27 months) days either at the NIH clinical center or subjects home laboratory or physician s office. Final dosing will occur at the 30-month visit. After the final dose, all Grade (Bullet)2 AEs at least possibly related to study drug will be followed to resolution. Safety will be evaluated by adverse events (AEs), clinical laboratory tests, vital signs, and physical examinations. PK will be assessed for plasma ManNAc and Neu5Ac. Biochemical efficacy will be measured by change in the sialylation of proteins and clinical efficacy will be assessed using a battery of clinical assessments deemed to be relevant based on disease natural history.