{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T11:40:20Z","timestamp":1763811620873,"version":"3.45.0"},"reference-count":35,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Infantile\u2010onset Pompe disease (IOPD) is a rare, deadly, quickly\u2010progressing degenerative disease. Even with life\u2010sustaining treatment (e.g., alglucosidase alfa [ALGLU]), many patients experience continued motor impairment. The Mini\u2010COMET trial evaluated avalglucosidase alfa (AVAL) versus ALGLU on motor and other outcomes in IOPD. However, treatment groups were imbalanced at baseline and the trial was not powered to directly compare treatments. To supplement this limited data, we developed a modeling and simulation approach to compare AVAL versus ALGLU head\u2010to\u2010head in in silico (i.e., computer\u2010simulated) trials. We first developed a longitudinal clinical model to establish the relationship between changes in motor function and changes in urinary hexose tetrasaccharide (uHex4), an established biomarker in IOPD. This model was based on pooled data from Mini\u2010COMET (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200921) and COMET trials (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009100 patients with late\u2010onset Pompe disease, LOPD). We then conducted in silico trials mimicking Mini\u2010COMET. Simulated trials were informed by motor data generated from the clinical model and uHex4 profiles simulated in a quantitative systems pharmacology model. The virtual IOPD population was based on observed Mini\u2010COMET baseline characteristics but engineered to have well\u2010balanced baseline characteristics across treatment cohorts. In silico trials showed that patients with IOPD would have the greatest improvements in motor function with AVAL 40\u2009mg\/kg every other week (Q2W), suboptimal improvement with ALGLU 40\u2009mg\/kg Q2W, and no improvement with ALGLU 20\u2009mg\/kg Q2W. This study provides information on the relative efficacy of IOPD treatments and mitigates the confounding effects of imbalanced treatment cohorts. Our approach could also be applied in other rare diseases.\n                  <\/jats:p>","DOI":"10.1002\/psp4.13287","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T09:39:33Z","timestamp":1734082773000},"page":"1797-1809","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical modeling of motor function to predict treatment efficacy and enable in silico treatment comparisons in infantile\u2010onset Pompe disease"],"prefix":"10.1002","volume":"14","author":[{"given":"Fatiha","family":"Rachedi","sequence":"first","affiliation":[{"name":"Sanofi, R&amp;D, on behalf of IviData Life Sciences  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0607-2801","authenticated-orcid":false,"given":"Rana","family":"Jreich","sequence":"additional","affiliation":[{"name":"Sanofi, R&amp;D  Gentilly France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7469-6691","authenticated-orcid":false,"given":"Susan","family":"Sparks","sequence":"additional","affiliation":[{"name":"Sanofi  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atef","family":"Zaher","sequence":"additional","affiliation":[{"name":"Sanofi  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"an Haack","sequence":"additional","affiliation":[{"name":"Sanofi, R&amp;D  Gentilly France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"Granados","sequence":"additional","affiliation":[{"name":"Sanofi  Barcelona Catalunya Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoling","family":"Meng","sequence":"additional","affiliation":[{"name":"Sanofi  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,12,13]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_12_2_1","DOI":"10.1007\/s13311-018-0655-y"},{"doi-asserted-by":"publisher","key":"e_1_2_12_3_1","DOI":"10.1038\/sj.ejhg.5200367"},{"doi-asserted-by":"publisher","key":"e_1_2_12_4_1","DOI":"10.1016\/j.ncl.2014.04.010"},{"doi-asserted-by":"publisher","key":"e_1_2_12_5_1","DOI":"10.21037\/atm.2019.07.24"},{"doi-asserted-by":"publisher","key":"e_1_2_12_6_1","DOI":"10.1007\/s11940-022-00736-1"},{"doi-asserted-by":"publisher","key":"e_1_2_12_7_1","DOI":"10.1016\/j.jpeds.2005.11.033"},{"doi-asserted-by":"publisher","key":"e_1_2_12_8_1","DOI":"10.1016\/S0140-6736(00)02533-2"},{"unstructured":"US Food and Drug Administration.MYOZYME (alglucosidase alfa) prescribing information. 2006.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/125141s222lbl.pdf. Updated May 2019.","key":"e_1_2_12_9_1"},{"doi-asserted-by":"publisher","key":"e_1_2_12_10_1","DOI":"10.1203\/PDR.0b013e3181b24e94"},{"doi-asserted-by":"publisher","key":"e_1_2_12_11_1","DOI":"10.1212\/01.wnl.0000251268.41188.04"},{"doi-asserted-by":"publisher","key":"e_1_2_12_12_1","DOI":"10.1097\/GIM.0b013e31819d0996"},{"doi-asserted-by":"publisher","key":"e_1_2_12_13_1","DOI":"10.3233\/JND-230164"},{"doi-asserted-by":"publisher","key":"e_1_2_12_14_1","DOI":"10.21037\/atm.2019.04.70"},{"doi-asserted-by":"publisher","key":"e_1_2_12_15_1","DOI":"10.1016\/j.nmd.2018.12.004"},{"doi-asserted-by":"publisher","key":"e_1_2_12_16_1","DOI":"10.1016\/j.gim.2022.10.010"},{"doi-asserted-by":"publisher","key":"e_1_2_12_17_1","DOI":"10.1016\/S1474-4422(21)00241-6"},{"unstructured":"European Medicines Agency.Nexviadyme (avalglucosidase alfa) Product information. 2022.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/nexviadyme\u2010epar\u2010product\u2010information_en.pdf. Updated 23 May 2023. Accessed January 22 2024.","key":"e_1_2_12_18_1"},{"unstructured":"US Food and Drug Administration.NEXVIAZYME (avalglocoside\u2010alfa\u2010ngpt) prescribing information. 2021.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/761194s000lbl.pdf. Updated August 2021. 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