Aceneuramic Acid Extended Release Administration Maintains Upper Limb Muscle Strength in a 48-week Study of Subjects with GNE Myopathy: Results from a Phase 2, Randomized, Controlled Study

Argov, Zohar; Caraco, Yoseph; Lau, Heather; Pestronk, Alan; Shieh, Perry B.; Skrinar, Alison; Koutsoukos, Tony; Ahmed, Ruhi; Martinisi, Julia; Kakkis, Emil

doi:10.3233/jnd-159900

Cited by 43 publications

(51 citation statements)

References 23 publications

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“…As stated above, with extended-release tablets being used for trials in overseas, increases in serum free aceneuramic acid concentration of two to three times that of without treatment were observed in Trial-2. The results are consistent with the overseas trials [35,36]. Thus, a long-term clinical trial to verify the efficacy and safety can be conducted in Japan as well, with the same dosing regimen as was used overseas.…”

Section: Discussionsupporting

confidence: 83%

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: 83%

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

et al. 2018

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“…There was a 6 ms increase in the mean baseline corrected QTcB interval for subjects receiving ManNAc that was not clinically significant. No other clinically relevant changes in the electrocardio[25] were noted.…”

Section: Resultsmentioning

confidence: 99%

“…While clinical trials for Neu5Ac (Ace-ER) in GNE myopathy patients are ongoing [25], we favored the development of ManNAc for patients with GNE myopathy after review of preclinical studies [26, 27]. ManNAc (MW 221.2 Da) is a naturally occurring uncharged monosaccharide, while Neu5Ac (MW 309.3 Da) is a negatively charged acidic monosaccharide.…”

Section: Discussionmentioning

confidence: 99%

Safety, pharmacokinetics and sialic acid production after oral administration of N -acetylmannosamine (ManNAc) to subjects with GNE myopathy

Wang

Latham

et al. 2017

Molecular Genetics and Metabolism

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GNE myopathy is a rare, autosomal recessive, inborn error of sialic acid metabolism, caused by mutations in GNE, the gene encoding UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase. The disease manifests as an adult-onset myopathy characterized by progressive skeletal muscle weakness and atrophy. There is no medical therapy available for this debilitating disease. Hyposialylation of muscle glycoproteins likely contributes to the pathophysiology of this disease. N-acetyl-D-mannosamine (ManNAc), an uncharged monosaccharide and the first committed precursor in the sialic acid biosynthetic pathway, is a therapeutic candidate that prevents muscle weakness in the mouse model of GNE myopathy. We conducted a first-in-human, randomized, placebo-controlled, double-blind, single-ascending dose study to evaluate safety and pharmacokinetics of ManNAc in GNE myopathy subjects. Single doses of 3 and 6 g of oral ManNAc were safe and well tolerated; 10 g was associated with diarrhea likely due to unabsorbed ManNAc. Oral ManNAc was absorbed rapidly and exhibited a short half-life (~2.4 h). Following administration of a single dose of ManNAc, there was a significant and sustained increase in plasma free sialic acid (Neu5Ac) (Tmax of 8-11 h). Neu5Ac levels remained above baseline 48 h post-dose in subjects who received a dose of 6 or 10 g. Given that Neu5Ac is known to have a short half-life, the prolonged elevation of Neu5Ac after a single dose of ManNAc suggests that intracellular biosynthesis of sialic acid was restored in subjects with GNE myopathy, including those homozygous for mutations in the kinase domain. Simulated plasma concentration-time profiles support a dosing regimen of 6 g twice daily for future clinical trials.

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“…Results at 24 weeks showed maintenance of upper extremity strength (as measured by composite upper extremity strength obtained by dynamometry) in the 6 g/day group compared to placebo, especially in subjects able to walk > 200 m on the 6-min walk test (6MWT) at baseline. At 48 weeks, there was significant improvement on upper extremity composite strength in the combined 6 g/day group compared to the combined 3 g/day group (+ 3.46 kg, p = 0.0031), but no other significant effect was measured on other tested endpoints, including lower extremity composite score, 6MWT, or GNEM-FAS [94].…”

Section: Sialic Acid (Neu5ac)mentioning

confidence: 88%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic Brimmed^vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.

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Aceneuramic Acid Extended Release Administration Maintains Upper Limb Muscle Strength in a 48-week Study of Subjects with GNE Myopathy: Results from a Phase 2, Randomized, Controlled Study

Cited by 43 publications

References 23 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

Safety, pharmacokinetics and sialic acid production after oral administration of N -acetylmannosamine (ManNAc) to subjects with GNE myopathy

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

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