First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
22 Oct 2024
22 Oct 2024
Historique:
received:
10
05
2024
accepted:
18
09
2024
medline:
23
10
2024
pubmed:
23
10
2024
entrez:
23
10
2024
Statut:
aheadofprint
Résumé
Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and C
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 Maze Therapeutics. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Références
Adeva‐Andany, M.M., González‐Lucán, M., Donapetry‐García, C., Fernández‐Fernández, C. & Ameneiros‐Rodríguez, E. Glycogen metabolism in humans. BBA Clin. 5, 85–100 (2016).
van der Ploeg, A.T. & Reuser, A.J.J. Pompe's disease. Lancet 372, 1342–1353 (2008).
Sarah, B., Giovanna, B., Emanuela, K., Nadi, N., Josè, V. & Alberto, P. Clinical efficacy of the enzyme replacement therapy in patients with late‐onset Pompe disease: a systematic review and a meta‐analysis. J. Neurol. 269, 733–741 (2022).
Harlaar, L. et al. Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease. Neurology 93, e1756–e1767 (2019).
Schoser, B., Bilder, D.A., Dimmock, D., Gupta, D., James, E.S. & Prasad, S. The humanistic burden of Pompe disease: are there still unmet needs? A systematic review. BMC Neurol. 17, 202 (2017).
Gutschmidt, K. et al. STIG study: real‐world data of long‐term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa. J. Neurol. 268, 2482–2492 (2021).
Labella, B. et al. A comprehensive update on late‐onset Pompe disease. Biomolecules 13, 1279 (2023).
Douillard‐Guilloux, G., Raben, N., Takikita, S., Batista, L., Caillaud, C. & Richard, E. Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type II. Hum. Mol. Genet. 17, 3876–3886 (2008).
Douillard‐Guilloux, G. et al. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum. Mol. Genet. 19, 684–696 (2010).
Clayton, N.P. et al. Antisense oligonucleotide‐mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease. Mol. Ther. Nucleic Acids 3, e206 (2014).
Ullman, J.C. et al. Small‐molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders. Sci. Transl. Med. 16, eadf1691 (2024).
Kollberg, G. et al. Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0. N. Engl. J. Med. 357, 1507–1514 (2007).
Sukigara, S. et al. Muscle glycogen storage disease 0 presenting recurrent syncope with weakness and myalgia. Neuromuscul. Disord. 22, 162–165 (2012).
Musumeci, O. et al. A new phenotype of muscle glycogen synthase deficiency (GSD0B) characterized by an adult onset myopathy without cardiomyopathy. Neuromuscul. Disord. 32, 582–589 (2022).
Savage, D.B. et al. A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. PLoS Med. 5, e27 (2008).
Bruce, R.A. Methods of exercise testing. Step test, bicycle, treadmill, isometrics. Am. J. Cardiol. 33, 715–720 (1974).
An, Y., Young, S.P., Hillman, S.L., Van Hove, J.L., Chen, Y.T. & Millington, D.S. Liquid chromatographic assay for a glucose tetrasaccharide, a putative biomarker for the diagnosis of Pompe disease. Anal. Biochem. 287, 136–143 (2000).
Raben, N. et al. Targeted disruption of the acid α‐glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J. Biol. Chem. 273, 19086–19092 (1998).
Hagemans, M.L.C. et al. PAS‐positive lymphocyte vacuoles can be used as diagnostic screening test for Pompe disease. J. Inherit. Metab. Dis. 33, 133–139 (2010).
Tabatabaei, S.M. The Effect of Immune Cell Activation on Glycogen Storage in the Context of a Nutrient Rich Microenvironment. Masters. Concordia University. <https://spectrum.library.concordia.ca/id/eprint/980786/> (2016). Accessed April 19, 2024.
Parisi, D. et al. Vacuolated PAS‐positive lymphocytes on blood smear: an easy screening tool and a possible biomarker for monitoring therapeutic responses in late onset Pompe disease (LOPD). Front. Neurol. 9, 880 (2018).
Pascarella, A. et al. Vacuolated PAS‐positive lymphocytes as an hallmark of Pompe disease and other myopathies related to impaired autophagy. J. Cell. Physiol. 233, 5829–5837 (2018).
Shulman, G.I., Rothman, D.L., Jue, T., Stein, P., DeFronzo, R.A. & Shulman, R.G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non‐insulin‐dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N. Engl. J. Med. 322, 223–228 (1990).
Young, S.P. et al. Long‐term monitoring of patients with infantile‐onset Pompe disease on enzyme replacement therapy using a urinary glucose tetrasaccharide biomarker. Genet. Med. 11, 536–541 (2009).
Shulman, G.I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).
Befroy, D.E. & Shulman, G.I. Magnetic resonance spectroscopy studies of human metabolism. Diabetes 60, 1361–1369 (2011).
Buehler, T., Bally, L., Dokumaci, A.S., Stettler, C. & Boesch, C. Methodological and physiological test‐retest reliability of (13) C‐MRS glycogen measurements in liver and in skeletal muscle of patients with type 1 diabetes and matched healthy controls. NMR Biomed. 29, 796–805 (2016).
O'Sullivan, P.J., Gorman, G.M., Hardiman, O.M., Farrell, M.J. & Logan, P.M. Sonographically guided percutaneous muscle biopsy in diagnosis of neuromuscular disease: a useful alternative to open surgical biopsy. J. Ultrasound Med. 25, 1–6 (2006).
Barthelemy, F. et al. A well‐tolerated core needle muscle biopsy process suitable for children and adults. Muscle Nerve 62, 688–698 (2020).
Hayot, M. et al. Skeletal muscle microbiopsy: a validation study of a minimally invasive technique. Eur. Respir. J. 25, 431–440 (2005).
Prats, C. et al. Dual regulation of muscle glycogen synthase during exercise by activation and compartmentalization. J. Biol. Chem. 284, 15692–15700 (2009).
An, Y. et al. Glucose tetrasaccharide as a biomarker for monitoring the therapeutic response to enzyme replacement therapy for Pompe disease. Mol. Genet. Metab. 85, 247–254 (2005).