Guillemette de la Borderie, Damien Chimits, Babak Boroojerdi, Melissa Brock, Petra W Duda, Fiona Grimson, Paul Mahoney, Foteini Strimenopoulou, Gary Cutter, Inmaculada Aban, Susanna Brauner, Malin Petersson, James F Howard, Nathan Bennett
{"title":"维持齐鲁霉素对全身性肌无力患者的疗效长达 24 周：一项基于模型的分析。","authors":"Guillemette de la Borderie, Damien Chimits, Babak Boroojerdi, Melissa Brock, Petra W Duda, Fiona Grimson, Paul Mahoney, Foteini Strimenopoulou, Gary Cutter, Inmaculada Aban, Susanna Brauner, Malin Petersson, James F Howard, Nathan Bennett","doi":"10.1177/17562864241279125","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available.</p><p><strong>Objectives: </strong>Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks.</p><p><strong>Design: </strong>A model-informed analysis (MIA) within a Bayesian framework.</p><p><strong>Methods: </strong>Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed.</p><p><strong>Results: </strong>At week 24, the predicted mean CFB in MG-ADL score was -4.55 (95% credible interval: -6.04, -3.13) with zilucoplan versus -2.00 (-3.35, -0.64) with control (difference: -2.55 [-3.76, -1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG.</p><p><strong>Conclusion: </strong>This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies.</p>","PeriodicalId":22980,"journal":{"name":"Therapeutic Advances in Neurological Disorders","volume":"17 ","pages":"17562864241279125"},"PeriodicalIF":4.7000,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418339/pdf/","citationCount":"0","resultStr":"{\"title\":\"Maintenance of zilucoplan efficacy in patients with generalised myasthenia gravis up to 24 weeks: a model-informed analysis.\",\"authors\":\"Guillemette de la Borderie, Damien Chimits, Babak Boroojerdi, Melissa Brock, Petra W Duda, Fiona Grimson, Paul Mahoney, Foteini Strimenopoulou, Gary Cutter, Inmaculada Aban, Susanna Brauner, Malin Petersson, James F Howard, Nathan Bennett\",\"doi\":\"10.1177/17562864241279125\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available.</p><p><strong>Objectives: </strong>Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks.</p><p><strong>Design: </strong>A model-informed analysis (MIA) within a Bayesian framework.</p><p><strong>Methods: </strong>Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed.</p><p><strong>Results: </strong>At week 24, the predicted mean CFB in MG-ADL score was -4.55 (95% credible interval: -6.04, -3.13) with zilucoplan versus -2.00 (-3.35, -0.64) with control (difference: -2.55 [-3.76, -1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG.</p><p><strong>Conclusion: </strong>This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies.</p>\",\"PeriodicalId\":22980,\"journal\":{\"name\":\"Therapeutic Advances in Neurological Disorders\",\"volume\":\"17 \",\"pages\":\"17562864241279125\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2024-09-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418339/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Therapeutic Advances in Neurological Disorders\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/17562864241279125\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Therapeutic Advances in Neurological Disorders","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/17562864241279125","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Maintenance of zilucoplan efficacy in patients with generalised myasthenia gravis up to 24 weeks: a model-informed analysis.
Background: Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available.
Objectives: Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks.
Design: A model-informed analysis (MIA) within a Bayesian framework.
Methods: Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed.
Results: At week 24, the predicted mean CFB in MG-ADL score was -4.55 (95% credible interval: -6.04, -3.13) with zilucoplan versus -2.00 (-3.35, -0.64) with control (difference: -2.55 [-3.76, -1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG.
Conclusion: This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies.
期刊介绍：
Therapeutic Advances in Neurological Disorders is a peer-reviewed, open access journal delivering the highest quality articles, reviews, and scholarly comment on pioneering efforts and innovative studies across all areas of neurology. The journal has a strong clinical and pharmacological focus and is aimed at clinicians and researchers in neurology, providing a forum in print and online for publishing the highest quality articles in this area.
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