An Open Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy
Condition: GNE Myopathy
MeSH terms: Muscular Diseases; Distal Myopathies
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      Patients with GNE myopathy have progressive muscle weakness and can have difficulty walking
      and decreased mobility. The disease is a rare genetic disorder that results from a gene
      mutation in a key step in the body's production of a sugar called sialic acid, (also called
      N-acetylneuraminic acid, Neu5Ac). Researchers think decreased sialic acid bound to muscle
      proteins may be the cause of muscle wasting in GNE myopathy. Researchers are testing the drug
      ManNAc which is a precursor in the production of sialic acid within cells. ManNAc is provided
      as a powder dissolved in water to be administered orally.
    

Detailed description: 
      GNE myopathy is a rare genetic (autosomal recessive) disorder that causes progressive
      skeletal muscle atrophy and weakness. The disease presents in young adults typically between
      the ages of 20 and 40 years, and includes foot drop and difficulty walking. The disease
      progresses to involve all skeletal muscles, eventually leading to the use of a wheelchair
      and, in some cases, dependence on a caregiver. The causative gene, GNE, encodes the
      rate-limiting enzyme in the biosynthesis of CMP-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 oral N-acetyl-D-mannosamine (ManNAc) in mouse models of GNE myopathy. A
      first-in-human, Phase 1 single ascending dose study evaluated the safety, pharmacokinetics,
      and pharmacodynamics of a single dose of 3, 6, or 10 g of oral 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 ManNAc will be administered orally to 12
      subjects. The objectives of the study are to assess the long-term safety, tolerability,
      pharmacokinetics, and biochemical efficacy of oral ManNAc in GNE myopathy subjects. In the
      first phase of pharmacokinetic assessment, two cohorts of 6 subjects will receive ManNAc at
      doses of 3 g twice a day (6 g per day) or 6 g twice a day (12 g per day) for 7 days to assess
      safety and PK. In the second phase of the study, all subjects will receive treatment with
      ManNAc at a dose of 6 g twice daily (12 g per day) for the remainder of the study. The study
      was extended to include follow-up evaluations at 6, 12, 18, 24 and 30 months. During the 30
      month visit, PK of 4 g three times daily was assessed. Biochemical efficacy was assessed by
      change in the sialylation of proteins at 3 months compared to baseline. To evaluate the
      effect of ManNAc on clinical measures of GNE myopathy, a battery of clinical assessments was
      performed at every visit to identify clinical endpoints suitable for subsequent clinical
      trials.
    

Intervention name(s): ManNAc; ManNAc
Intervention type(s): Drug; Drug
Intervention description(s): At doses of 3 g and 6 g twice daily for a total dose of 6 and 12 g per day.; At doses of 6 g twice daily (12 g per day).
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hereditary Inclusion Body Myopathy (HIBM); Sialic Acid (N-acetylneuraminic acid, Neu5Ac); GNE Myopathy; N-Acetyl-D-mannosamine (ManNAc); GNE Gene