Phase I clinical trial results of aceneuramic acid for GNE myopathy in Japan

Abstract

Background: 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. The mutations in GNE (UDP-Nacetylglucosamine 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. Methods: This 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. Results: The 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. Conclusion: The 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.

Recent advances in establishing a cure for GNE myopathy

“…In 2010, N-acetyl-neuraminic acid (NeuAc) was administered to six patients (NCT01236898). No clear increases in NeuAc serum concentration were observed at a dose of 800 mg three times daily for 5 days, probably because of rapid excretion of sialic acid [23].…”

Efficacy Confirmation Study of Aceneuramic Acid Administration for GNE Myopathy in Japan

“…Methods for blood sampling and determination of serum free and total aceneuramic acid concentrations were performed according to those described in the previous study [14]. Serum free and total aceneuramic acid concentrations (µg/mL) were measured at baseline and every 12 weeks before administration (trough concentration).…”

“…Mean and SD plots in serum free (a) and total (b) aceneuramic acid levels (FAS). Blood sampling and determination of serum free/total aceneuramic acid concentrations were performed as described previously [14]. FAS, full analysis set; SA-ER, sialic acid extended-release; SD, standard deviation.…”

“…To evaluate the safety and pharmacokinetics of orally administered aceneuramic acid in humans, we conducted phase I studies in GNE myopathy patients [14] and observed the elevated levels of serum free aceneuramic acid with no safety issues using an extended-release formulation of aceneuramic acid (SA-ER). The results were consistent with those of a prior international phase II study [15].…”

Advances in understanding of the natural history, mechanism, extra‐muscular manifestations and treatment of GNE myopathy

“…The efficacy of sialic acid supplementation in a mouse model led to clinical trials of sialic acid supplementation therapy. Tohoku University in Japan conducted the first trial in 2010 using regular NeuAc, which was rapidly excreted after oral administration (ClinicalTrials.gov: NCT01236898, Japan) 50 . Following this study, a NeuAc extended‐release tablet (Ace‐ER) was developed.…”