Abstract
BackgroundGNE myopathy (distal myopathy with rimmed vacuoles) is a rare intractable muscle disease caused by the mutations in GNE gene, with no therapeutic agents at present. The mutations in GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene result in a deficiency of the biosynthesis of aceneuramic acid. Aceneuramic acid improves the phenotype of GNE myopathy model mice. We examined the pharmacokinetics and safety of aceneuramic acid therapy in a nonrandomized manner for patients with GNE myopathy for the first time in humans.MethodsThis article was based on the world’s first Phase I trial and the additional Phase I trial that began at a time when the intermediate results of an overseas Phase II trial were ascertained. In the first trial, conventional tablets without controlled release were administered orally in a single dose of 800 mg, in 800 mg/doses given three times in 1 day, and in 800 mg/doses given three times per day for 5 days. Serum and urinary concentrations of total aceneuramic acid including aceneuramic acid bound to proteins and lipids were measured. Subsequently, administering extended-release tablets to patients with GNE myopathy, we investigated the pharmacokinetics and safety of a single 2000 mg dose, three doses given for 1 day, and three doses per day for 7 days.ResultsThe results of the first trial showed no obvious increase in serum concentration after administration. Whereas the amount of aceneuramic acid excreted in the urine generally increased with all given doses, although there were variations among trial subjects. In the second trial, we measured free serum aceneuramic acid levels, and with all doses given there were obvious increases in the levels observed after administration. The degrees of increase were comparable with other studies conducted overseas, and there was no difference based on ethnicity. With regards to urinary excretion, free aceneuramic acid levels showed elevated levels in all patients, and total aceneuramic acid also increased in general, thus we could confirm the absorption of the investigational drug. In respect to safety, while some adverse events including abnormal laboratory test findings were observed, all events were mild and the causal relationship with the investigational drug was ruled out or unlikely.ConclusionThe elevated serum concentration of aceneuramic acid and safety were confirmed. We decided that the trial could shift to the next level to examine the long-term efficacy and safety for Japanese patients as well.Trial registrationNCT01236898, UMIN000011532. Registered 9 November 2010.
Highlights
GNE myopathy is a rare intractable muscle disease caused by the mutations in GNE gene, with no therapeutic agents at present
GNE myopathy is a rare intractable disease characterized by atrophy and degeneration of muscles starting from the distal area to the trunk, gradually developing into loss of motor control, with no therapeutic agents and for which treatment is limited to symptomatic treatment [1,2,3,4,5]
Trial overview The phase I trial of aceneuramic acid consisted of two trials, both of which were conducted at Department of Neurology, Tohoku University Graduate School of Medicine in accordance with the Good Clinical Practice (GCP) as investigator-initiated trials
Summary
GNE myopathy (distal myopathy with rimmed vacuoles) is a rare intractable muscle disease caused by the mutations in GNE gene, with no therapeutic agents at present. GNE myopathy is a rare intractable disease characterized by atrophy and degeneration of muscles starting from the distal area to the trunk, gradually developing into loss of motor control, with no therapeutic agents and for which treatment is limited to symptomatic treatment [1,2,3,4,5]. Muscles of the whole lower leg become affected, making gait difficult and the patient becomes wheelchair bound, whereas the quadriceps femoris are less likely to be affected. In Japan, there have been reports of decreased respiratory function [3], and some patients with severe GNE myopathy with early onset require artificial respiration during the night. A biochemical finding of this disease shows elevated creatinine kinase (CK) in the early stage; the degree of elevation is usually slight or within the normal range
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