OBJECTIVE: Assess long-term safety, tolerability, pharmacokinetics, and biochemical effect of ManNAc in subjects with GNE myopathy and identify clinical endpoints suitable for subsequent clinical trials.
BACKGROUND: GNE myopathy is a rare, autosomal recessive myopathy caused by mutations in GNE, the gene encoding the rate-limiting enzyme in sialic acid biosynthesis. The disease manifests as an adult-onset myopathy characterized by progressive skeletal muscle weakness and atrophy. There is no approved therapy for this disease. Hyposialylation of muscle glycoproteins mediates the pathophysiology of the disease. ManNAc, an uncharged monosaccharide and the first committed precursor in sialic acid biosynthesis, is an oral therapeutic candidate that prevents muscle weakness in the mouse model of GNE myopathy. A first-in-human, randomized, placebocontrolled, double-blind, single-ascending dose study (NCT01634750) showed ManNAc is safe and restored sialic acid production in GNE myopathy patients.
DESIGN/METHODS: A Phase 2, open-label, single-center study (NCT02346461) enrolled twelve subjects with genetically-confirmed GNE myopathy. Subjects received oral ManNAc at 6 grams twice daily (12 grams/day) and were evaluated at baseline, 3, 6, 12, 18, 24 and 30 months.
RESULTS: Long-term administration of ManNAc at 6 grams twice daily is safe but was associated with decreased gastrointestinal tolerability. ManNAc resulted in a sustained increase in levels of plasma free sialic acid (Neu5Ac). Comparison of serial-sampled plasma ManNAc and Neu5Ac at 6 grams BID and 4 grams TID daily showed increased bioavailability with TID dosing. Biochemical efficacy was assessed by increase in muscle sialylation after 3 months of ManNAc administration. Measures of muscle strength (including quantitative muscle assessment), function, and patient-reported outcomes were evaluated for suitability to test clinical efficacy in future trials.
CONCLUSIONS: The findings of this study support further development of ManNAc as a therapy for GNE myopathy. A multicenter, randomized, placebo-controlled, double-blind trial of ManNAc in subjects with GNE myopathy is planned.
