A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy

Hanns Lochmüller, Anthony Behin, Yoseph Caraco, Heather Lau, Massimiliano Mirabella, Ivailo Tournev, Mark Tarnopolsky, Oksana Pogoryelova, Catherine Woods, Alexander Lai, Jinay Shah, Tony Koutsoukos, Alison Skrinar, Hank Mansbach, Emil Kakkis, Tahseen Mozaffar, Hanns Lochmüller, Anthony Behin, Yoseph Caraco, Heather Lau, Massimiliano Mirabella, Ivailo Tournev, Mark Tarnopolsky, Oksana Pogoryelova, Catherine Woods, Alexander Lai, Jinay Shah, Tony Koutsoukos, Alison Skrinar, Hank Mansbach, Emil Kakkis, Tahseen Mozaffar

Abstract

Objective: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy.

Methods: UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results.

Results: Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs.

Conclusions: Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy.

Classification of evidence: This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. UX001-CL301 study design
Figure 1. UX001-CL301 study design
6MWT = 6-minute walk test; Ace-ER = aceneuramic acid extended-release; GNEM = GNE myopathy.
Figure 2. Percentage predicted muscle strength at…
Figure 2. Percentage predicted muscle strength at baseline
Ace-ER = aceneuramic acid extended-release.
Figure 3. Free serum sialic acid
Figure 3. Free serum sialic acid
Data are expressed as mean ± standard error. Gray lines indicate placebo; blue lines indicate aceneuramic acid extended-release (Ace-ER).
Figure 4. Change from baseline in primary…
Figure 4. Change from baseline in primary and key secondary efficacy assessments
(A–D) Data are expressed as mean change from baseline ± standard error. Gray lines indicate placebo; blue lines indicate aceneuramic acid extended-release (Ace-ER). GNEM-FAS = GNE myopathy–Functional Activity Scale; LEC = lower extremity composite; UEC = upper extremity composite.

References

    1. Nishino I, Carrillo-Carrasco N, Argov Z. GNE myopathy: current update and future therapy. J Neurol Neurosurg Psychiatry 2015;86:385–392.
    1. Nonaka I, Noguchi S, Nishino I. Distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy. Curr Neurol Neurosci Rep 2005;5:61–65.
    1. Pogoryelova O, Cammish P, Mansbach H, et al. . Phenotypic stratification and genotype-phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients: first report from the GNE myopathy Disease Monitoring Program, registry portion. Neuromuscul Disord 2017;28:158–168.
    1. Behin A, Mozaffar T, Tarnopolsky M, et al. . GNE-myopathy (HIBM): upper and lower extremity muscle strength declines over time in a prospective study. Neuromuscul Disord 2017;27(suppl 2):S51–S270.
    1. Varki NM, Varki A. Diversity in cell surface sialic acid presentations: implications for biology and disease. Lab Invest 2007;87:851–857.
    1. Chan YM, Lee P, Jungles S, et al. . Substantial deficiency of free sialic acid in muscles of patients with GNE myopathy and in a mouse model. PLoS One 2017;12:e0173261.
    1. Malicdan MC, Noguchi S, Hayashi YK, Nonaka I, Nishino I. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 2009;15:690–695.
    1. Yonekawa T, Malicdan MC, Cho A, et al. . Sialyllactose ameliorates myopathic phenotypes in symptomatic GNE myopathy model mice. Brain 2014;137:2670–2679.
    1. Malicdan MC, Noguchi S, Tokutomi T, et al. . Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy. J Biol Chem 2012;287:2689–2705.
    1. Argov Z, Caraco Y, Lau H, et al. . 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. J Neuromuscul Dis 2016;3:49–66.
    1. Argov Z, Caraco Y, Lau H, et al. . Oral sialic acid extended release (SA-ER) stabilizes upper extremity muscle strength in human GNE myopathy: a phase 2 study. Neurology 2014;83:e35.
    1. Lau H, Argov Z, Caraco Y, et al. . GO 27: randomized controlled phase 2 study of GNE myopathy subjects treated with placebo, 6 g or 3 g doses of extended-release sialic acid (SA-ER) and an extension study at a higher 12 g dose of combination extended and immediate release sialic acid (SA). Neuromuscul Disord 2014;24:923.
    1. Argov Z, Bronstein F, Esposito A, et al. . Characterization of strength and function in ambulatory adults with GNE myopathy. J Clin Neuromuscul Dis 2017;19:19–26.
    1. Mayhew J, Bonner N, Arbuckle R, Turnbull A, Bowden A, Skrinar A. Development and preliminary evidence of the psychometric properties of the GNE myopathy functional activity scale. J Comp effectiveness Res 2017;7:381–395.
    1. Agarwal S, Kiely PD. Two simple, reliable and valid tests of proximal muscle function, and their application to the management of idiopathic inflammatory myositis. Rheumatology 2006;45:874–879.
    1. Ozalevli S, Ozden A, Itil O, Akkoclu A. Comparison of the Sit-to-Stand Test with 6 min walk test in patients with chronic obstructive pulmonary disease. Respir Med 2007;101:286–293.
    1. Chetta A, Zanini A, Pisi G, et al. . Reference values for the 6-min walk test in healthy subjects 20–50 years old. Respir Med 2006;100:1573–1578.
    1. Vincent KA, Carr AJ, Walburn J, Scott DL, Rose MR. Construction and validation of a quality of life questionnaire for neuromuscular disease (INQoL). Neurology 2007;68:1051–1057.
    1. Izumi R, Niihori T, Suzuki N, et al. . GNE myopathy associated with congenital thrombocytopenia: a report of two siblings. Neuromuscul Disord 2014;24:1068–1072.
    1. Sillanaukee P, Ponnio M, Jaaskelainen IP. Occurrence of sialic acids in healthy humans and different disorders. Eur J Clin Invest 1999;29:413–425.
    1. Bohannon RW. Reference values for extremity muscle strength obtained by hand-held dynamometry from adults aged 20 to 79 years. Arch Phys Med Rehabil 1997;78:26–32.
    1. NIMS. Muscular weakness assessment: use of normal isometric strength data: The National Isometric Muscle Strength (NIMS) Database Consortium. Arch Phys Med Rehabil 1996;77:1251–1255.
    1. Mathiowetz V, Kashman N, Volland G, Weber K, Dowe M, Rogers S. Grip and pinch strength: normative data for adults. Arch Phys Med Rehabil 1985;66:69–74.
    1. Bohannon RW, Peolsson A, Massy-Westropp N, Desrosiers J, Bear-Lehman J. Reference values for adult grip strength measured with a Jamar dynamometer: a descriptive meta-analysis. Physiotherapy 2006;92:11–15.
    1. Palmio J, Udd B. Myofibrillar and distal myopathies. Rev Neurol 2016;172:587–593.
    1. Noguchi S, Keira Y, Murayama K, et al. . Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. J Biol Chem 2004;279:11402–11407.
    1. Saito F, Tomimitsu H, Arai K, et al. . A Japanese patient with distal myopathy with rimmed vacuoles: missense mutations in the epimerase domain of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene accompanied by hyposialylation of skeletal muscle glycoproteins. Neuromuscul Disord 2004;14:158–161.
    1. Andrew CG, Appel SH. Macromolecular characterization of muscle membranes I: proteins and sialic acid of normal and denervated muscle. J Biol Chem 1973;248:5156–5163.
    1. Ervasti JM, Burwell AL, Geissler AL. Tissue-specific heterogeneity in alpha-dystroglycan sialoglycosylation: skeletal muscle alpha-dystroglycan is a latent receptor for Vicia villosa agglutinin b4 masked by sialic acid modification. J Biol Chem 1997;272:22315–22321.
    1. Harazi A, Becker-Cohen M, Zer H, Moshel O, Hinderlich S, Mitrani-Rosenbaum S. The interaction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) and alpha-actinin 2 is altered in GNE myopathy M743T mutant. Mol Neurobiol 2017;54:2928–2938.
    1. Xu X, Wang AQ, Latham LL, et al. . Safety, pharmacokinetics and sialic acid production after oral administration of N-acetylmannosamine (ManNAc) to subjects with GNE myopathy. Mol Genet Metab 2017;122:126–134.
    1. Nemunaitis G, Jay CM, Maples PB, et al. . Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex. Hum Gene Ther 2011;22:1331–1341.
    1. Nemunaitis G, Maples PB, Jay C, et al. . Hereditary inclusion body myopathy: single patient response to GNE gene Lipoplex therapy. J Gene Med 2010;12:403–412.

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