Abstract
PurposeTo evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. MethodsWe conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. ResultsMost drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. ConclusionManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.
Highlights
GNE myopathy (OMIM 605820) is a rare autosomal recessive inborn error of sialic acid biosynthesis that manifests as progressive skeletal muscle atrophy in young adults [1]
GNE myopathy is caused by variants in the UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE) gene that result in decreased activity of this bifunctional enzyme responsible for initiating and regulating the intracellular biosynthesis of Nacetylneuraminic acid (Neu5Ac, sialic acid) [4,5,6,7]
GNE myopathy is a genetic muscle disease caused by decreased activity of the rate-limiting bifunctional enzyme in the intracellular pathway of Neu5Ac biosynthesis, resulting in impaired Neu5Ac production and cell surface hyposialylation [5, 7, 9, 14, 30]
Summary
GNE myopathy (OMIM 605820) is a rare autosomal recessive inborn error of sialic acid biosynthesis that manifests as progressive skeletal muscle atrophy in young adults [1]. Preclinical studies have shown that ManNAc increases Neu5Ac biosynthesis and sialylation in various unaffected and disease models [7, 9, 13,14,15,16,17,18,19]. Oral administration of ManNAc increased Neu5Ac biosynthesis, improved muscle sialylation, and prevented skeletal muscle deterioration in a mouse model that recapitulates the human disease [17]. A first-in-human, randomized, placebocontrolled, double-blind study (NCT01634750) showed that single doses of oral ManNAc were safe and led to a sustained increase in plasma Neu5Ac levels in patients with GNE myopathy [20]. Secondary outcome measures of strength and function were evaluated for clinical efficacy in patients with GNE myopathy
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