T.P.13 A phase 1 safety and pharmacokinetic study of sialic acid-extended release tablets in patients with Hereditary Inclusion Body Myopathy (HIBM or GNE myopathy)

Kakkis, Emil; Maurer, Martina; Shah, Pranav R.; Donikyan, Mardik; Ahmed, Ruhi

doi:10.1016/j.nmd.2012.06.159

Cited by 6 publications

(5 citation statements)

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“…Kakkis et al announced the results of their Phase I trial using extended-release tablets at the World Muscle Society of 2012 [34]. The results of our trial also demonstrated the consistent results with their trial in pharmacokinetics and safety in the Asian population.…”

Section: Discussionsupporting

confidence: 80%

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

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 80%

“…With regards to serum free aceneuramic acid concentration, it was almost the same as that of the overseas Phase I trial when without administration [34], and all nine cases, including three patients given the single dose, three doses per day, and three doses per day for 7 days, showed obvious increases in concentration after administration.…”

Section: Discussionsupporting

confidence: 61%

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

et al. 2018

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“…Following this study, a NeuAc extended‐release tablet (Ace‐ER) was developed. Ace‐ER (ClinicalTrials.gov NCT01359319, US) was well tolerated in a Phase I trial, 51 and upper extremity strength was better preserved in a group that received Ace‐ER 6 g/day than in a control group in a Phase II trial (ClinicalTrials.gov NCT01517880, US and Israel). In a Phase III trial, there was no observable effect on the primary or secondary endpoints, 52 and the company ceased development of Ace‐ER for GNE myopathy.…”

Section: Clinical Trialsmentioning

confidence: 99%

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

Yoshioka

Noguchi

Mori

et al. 2022

Neurology & Clinical Neurosc

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GNE myopathy has an estimated worldwide prevalence of 1/1 000 000 (Orphanet; https://www.orpha.net/conso r/cgi-bin/index.php) but is more common in Persian and Japanese populations. 1 It is an adultonset progressive myopathy which typically starts with foot drop and uniquely spares quadriceps until the late stage. [2][3][4][5] Rimmed vacuoles are frequently be found in atrophic fibers of affected muscles. 1 Model mice studies have led to the better understanding of molecular mechanism and multiple clinical trials. At the same time, natural history studies and patient registries have contributed much for the comprehension of GNE myopathy including extra-muscular manifestations. In this review, we summarize the evolving research on GNE myopathy and introduce more recently identified features.

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“…To overcome rapid excretion of NeuAc, Ultragenyx Pharmaceutical developed a slow released product, Ace-ER, the first trial (NCT01359319) of which began in 2011, where it appeared to be well tolerated and have no significant side effects. Blood-free sialic acid levels were elevated by two-fold above normal with a 6 g dose [24]. In 2012, a phase 2 double-blind trial (NCT01517880) including 47 patients was conducted (doses: 3, 6 g, placebo/day, 24 weeks).…”

Section: Neuac Extended Release Tablet (Ace-er)mentioning

confidence: 99%

Recent advances in establishing a cure for GNE myopathy

Yoshioka

Nishino

Noguchi

2022

Current Opinion in Neurology

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Purpose of review GNE myopathy is a rare autosomal recessive disease caused by biallelic variants in the GNE gene, which encodes an enzyme involved in sialic acid biosynthesis. No drugs are approved for the treatment of GNE myopathy. Following proof-of-concept of sialic acid supplementation efficacy in mouse models, multiple clinical trials have been conducted. Here, we review clinical trials of sialic acid supplementation therapies and provide new insights into the additional clinical features of GNE myopathy. Recent findingsClinical trials of sialic acid supplementation have been conducted in Europe, the USA, Japan, and South Korea. Some clinical trials of NeuAc-extended release tablets demonstrated amelioration of decline in upper extremity muscle strength; however, no significant improvement was observed in phase 3 trials in Europe and USA. A phase 2 trial of ManNAc showed slowed decline of both upper and lower extremity strength. GNE myopathy patient registries have been established in Europe and Japan, and have provided information on extramuscular manifestations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Sensitive and reliable biomarkers, and a disease-specific functional activity scale, have also been investigated.

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T.P.13 A phase 1 safety and pharmacokinetic study of sialic acid-extended release tablets in patients with Hereditary Inclusion Body Myopathy (HIBM or GNE myopathy)

Cited by 6 publications

References 0 publications

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

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

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

Recent advances in establishing a cure for GNE myopathy

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