{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T15:22:26Z","timestamp":1778599346413,"version":"3.51.4"},"reference-count":22,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"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":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:p>Selecting the right dose is a significant challenge in designing clinical development programs, especially for slowly progressing diseases lacking predictive biomarkers of efficacy that may require long\u2010term treatment to assess clinical benefit. Gantenerumab, a fully human monoclonal antibody (mAb) that binds to aggregated amyloid\u2010beta, was tested in two 24\u2010month phase III studies (NCT01224106, NCT02051608) in participants with prodromal and mild Alzheimer\u2019s disease (AD), respectively. Dosing in the first phase III study was suspended after a preplanned interim futility analysis in 2014. Subsequently, a dose\u2013response relationship was observed in a subgroup of fast AD progressors that, together with contemporary aducanumab (another anti\u2013amyloid\u2010beta mAb) data, indicated higher doses may be needed for clinical efficacy. The gantenerumab phase III studies were therefore transformed into dose\u2010finding, open\u2010label extension (OLE) trials. Two exposure\u2013response models were developed to support dose selection via simulations for the OLEs: a pharmacokinetics (PK)\/PET (positron emission tomography) model describing amyloid removal using PET data from low\u2010dose gantenerumab and high\u2010dose aducanumab, and a PK\/ARIA\u2010E (amyloid\u2010related imaging abnormalities\u2010edema) model describing the occurrence of ARIA\u2010E events leveraging an existing bapineuzumab model. Multiple regimens were designed to gradually up\u2010titrate participants to the target dose of 1,200\u00a0mg gantenerumab every 4 weeks to mitigate the increased risk of ARIA\u2010E events that may be associated with higher doses of anti\u2013amyloid\u2010beta antibodies. Favorable OLE data that matched well with model predictions supported the decision to continue the gantenerumab clinical development program and further apply model\u2010based analytical techniques to optimize the design of new phase III studies.<\/jats:p>","DOI":"10.1002\/cpt.2535","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T18:32:30Z","timestamp":1643653950000},"page":"857-866","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Disease Modeling and Model\u2010Based Meta\u2010Analyses to Define a New Direction for a Phase III Program of Gantenerumab in Alzheimer\u2019s Disease"],"prefix":"10.1111","volume":"111","author":[{"given":"Sylvie","family":"Retout","sequence":"first","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Clinical Pharmacology Roche Innovation Center Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald","family":"Gieschke","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Clinical Pharmacology Roche Innovation Center Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Serafin","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Clinical Pharmacology Roche Innovation Center Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia","family":"Weber","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Clinical Pharmacology Roche Innovation Center Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Frey","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Clinical Pharmacology Roche Innovation Center Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carsten","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Clinical Pharmacology Roche Innovation Center Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"World Health Organization (WHO).Dementia fact sheet<https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/dementia>. 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