An Open Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy

Phase 2

Completed

Conditions: GNE Myopathy

Interventions: Drug: ManNAc

Registration Number: NCT02346461

Lead Sponsor: National Human Genome Research Institute (NHGRI)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort A	ManNAc	6 subjects on Cohort A will receive oral ManNAc 3 g twice daily (6 g/day) for 7 days and, if safe, continue on 6 g twice daily (12 g/day) for the remainder of the study.
Cohort B	ManNAc	6 subjects on Cohort B will receive oral ManNAc 6 g twice daily (12 g/day) for the duration of the study.

Primary Outcome Measures

Name	Time	Method
Mean Area Under the Curve (AUClast) of Plasma ManNAc (Baseline-adjusted)	Day 7	The mean area under the plasma ManNAc concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.
Maximum Observed Plasma Concentration (Cmax) of Neu5Ac (Baseline-adjusted)	Day 7	The maximum (or peak) plasma Neu5Ac concentration that the drug achieves in the body after the drug has been administrated.
Maximum Observed Plasma Concentration (Cmax) of ManNAc (Baseline-adjusted)	Day 7	The maximum (or peak) plasma ManNAc concentration that the drug achieves in the body after the drug has been administrated.
The Time to Cmax (Tmax) for Neu5Ac	Day 7	The time taken to achieve the maximum observed plasma concentration for Neu5Ac.
The Time to Cmax (Tmax) for ManNAc	Day 7	The time taken to achieve the maximum observed plasma concentration for ManNAc .
Mean Area Under the Curve (AUClast) of Plasma Neu5Ac (Baseline-adjusted)	Day 7	The mean area under the plasma Neu5Ac concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.
Half-life (t ½) for ManNAc	Day 7	The amount of time it takes for plasma ManNAc concentration to decline by half.