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Due to very small patient numbers in IOPD and the high phenotypic heterogeneity observed in this population, a quantitative systems pharmacology (QSP)\u2010based \u201cdigital twin\u201d approach was developed to perform an\n                    <jats:italic>in silico<\/jats:italic>\n                    comparison of the efficacy of avalglucosidase alfa vs. the standard of care, in a virtual population of IOPD patients. A QSP model was developed that represents key elements of Pompe disease pathophysiology, including tissue glycogen accumulation and the elevation of the biomarker urine Hex4 in both LOPD and IOPD patients. In this approach, the QSP model was used to generate digital twins of each IOPD patient enrolled in the avalglucosidase alfa clinical program, considering their respective disease burden, demographics, and treatment history. This virtual cohort supplemented clinical observations by simulating and comparing tissue glycogen and urine Hex4 following avalglucosidase alfa treatment vs. the standard of care. The digital twin analysis supports the interpretation that the enhanced reduction in urine Hex4 observed following avalglucosidase alfa treatment is attributable to greater tissue glycogen clearance. Overall, this study provides mechanism\u2010based insight into avalglucosidase alfa efficacy across the phenotypic spectrum of Pompe disease and demonstrates the value of applying a QSP\u2010based digital twin analysis to support rare disease drug development.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3498","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T01:00:57Z","timestamp":1733360457000},"page":"579-588","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Quantitative Systems Pharmacology\u2010Based Digital Twins Approach Supplements Clinical Trial Data for Enzyme Replacement Therapies in Pompe Disease"],"prefix":"10.1002","volume":"117","author":[{"given":"Chanchala","family":"Kaddi","sequence":"first","affiliation":[{"name":"Translational Disease Modeling, Translational Medicine and Early Development Sanofi  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdi","family":"Tao","sequence":"additional","affiliation":[{"name":"Translational Disease Modeling, Translational Medicine and Early Development Sanofi  Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Bergeler","sequence":"additional","affiliation":[{"name":"Certara Applied Biosimulation  Lawrenceville New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"George","sequence":"additional","affiliation":[{"name":"Global Medical Affairs Sanofi  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Geerts","sequence":"additional","affiliation":[{"name":"Certara Applied Biosimulation  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet H.","family":"van der Graaf","sequence":"additional","affiliation":[{"name":"Certara Applied Biosimulation  Canterbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie L.","family":"Batista","sequence":"additional","affiliation":[{"name":"Rare Disease Registries Global Medical Affairs Sanofi  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Foster","sequence":"additional","affiliation":[{"name":"Rare Disease Registries Global Medical Affairs Sanofi  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Ortemann\u2010Renon","sequence":"additional","affiliation":[{"name":"Translational Precision Medicine Sanofi  Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atef","family":"Zaher","sequence":"additional","affiliation":[{"name":"Rare Diseases and Rare Blood Disorders, Clinical Development Sanofi  Quebec City Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"An Haack","sequence":"additional","affiliation":[{"name":"Rare Diseases and Rare Blood Disorders, Clinical Development Sanofi  Gentilly France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Zaph","sequence":"additional","affiliation":[{"name":"Translational Disease Modeling, Translational Medicine and Early Development Sanofi  Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21025"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.02.004"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36110"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35662"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-022-02517-0"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-023-09874-8"},{"key":"e_1_2_9_7_1","unstructured":"Yau E. 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