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OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency

Disclosure: T. Garner: Grant Recipient; Self; Novo Nordisk. P.E. Clayton: Grant Recipient; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P. Murray: Grant Recipient; Self; Novo Nordisk. A. Stevens: Grant Recipient; Self; Novo Nordisk. Background: Growth...

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Autores principales: Garner, Terence, Clayton, Peter Ellis, Hojby, Michael, Murray, Philip, Stevens, Adam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555074/
http://dx.doi.org/10.1210/jendso/bvad114.1519
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author Garner, Terence
Clayton, Peter Ellis
Hojby, Michael
Murray, Philip
Stevens, Adam
author_facet Garner, Terence
Clayton, Peter Ellis
Hojby, Michael
Murray, Philip
Stevens, Adam
author_sort Garner, Terence
collection PubMed
description Disclosure: T. Garner: Grant Recipient; Self; Novo Nordisk. P.E. Clayton: Grant Recipient; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P. Murray: Grant Recipient; Self; Novo Nordisk. A. Stevens: Grant Recipient; Self; Novo Nordisk. Background: Growth hormone (GH) replacement therapy often requires daily subcutaneous injections that can be burdensome for patients and their caregivers. Somapacitan is a long-acting, once-weekly GH derivative in development for treating GH deficiency (GHD) in children. Somapacitan reduces treatment burden and shows a similar efficacy and safety profile as daily GH in children with GHD. Here, we investigate the prediction of first-year growth and insulin-like growth factor-I (IGF-I) response based on baseline blood transcriptome in children with GHD treated with somapacitan or daily GH. Methods: 200 treatment-naïve prepubertal children with GHD were enrolled into REAL4, a randomised, multinational, open-labelled, and active-controlled phase 3 trial. 128 consented to a baseline blood transcriptome profile. Children were treated with once-weekly somapacitan (n=81) or daily GH (n=47) for 52 weeks and categorised based on treatment response: the upper quartile of height velocity (HV; cm/year) was defined as good responders, and the lower quartile as poor responders. We split the somapacitan group into training (70%) and testing (30%) sets for prediction validation of HV and the GH response marker: ΔIGF-I standard deviation score (SDS). Gene expression was assessed between the target quartile and the remaining quartiles for both HV and ΔIGF-I SDS to identify the top 100 differentially expressed genes by adjusted p-value. Classes were balanced using a synthetic minority oversampling technique and Boruta, a feature selection algorithm, was used to refine gene lists. We performed random forest and calculated “out of box” (OOB) area under the curve (AUC) and OOB error rate (ER), measures of predictive accuracy and robustness, respectively. Results: HV prediction from the transcriptome was excellent for both treatments (AUC range: 0.95-0.99). It was more robust for identifying good responders (ER: 7.0-7.5%) than poor responders (ER: 13.2-17.5%). Genes previously identified as predictive of growth response for daily GH (Stevens et al., 2021. The Pharmacogenomics J., 21:594-607) were demonstrated to have high predictive value for once-weekly somapacitan and daily GH treatment in this study (AUC range: 0.84-0.97, ER <22%). Using the somapacitan group for validation, HV prediction (AUC range: 0.78-0.81) was stronger than ΔIGF-I SDS prediction (AUC range: 0.63-0.72). Conclusions: We demonstrate pre-treatment blood transcriptome predicts first-year growth response for somapacitan. This represents an independent validation of earlier observations and shows that genes predictive of growth response for daily GH treatment in children with GHD are also predictive for once-weekly somapacitan. Further, we demonstrate that the pre-treatment blood transcriptome predicts growth response better than it predicts IGF-I SDS response. Presentation: Saturday, June 17, 2023
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spelling pubmed-105550742023-10-06 OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency Garner, Terence Clayton, Peter Ellis Hojby, Michael Murray, Philip Stevens, Adam J Endocr Soc Pediatric Endocrinology Disclosure: T. Garner: Grant Recipient; Self; Novo Nordisk. P.E. Clayton: Grant Recipient; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P. Murray: Grant Recipient; Self; Novo Nordisk. A. Stevens: Grant Recipient; Self; Novo Nordisk. Background: Growth hormone (GH) replacement therapy often requires daily subcutaneous injections that can be burdensome for patients and their caregivers. Somapacitan is a long-acting, once-weekly GH derivative in development for treating GH deficiency (GHD) in children. Somapacitan reduces treatment burden and shows a similar efficacy and safety profile as daily GH in children with GHD. Here, we investigate the prediction of first-year growth and insulin-like growth factor-I (IGF-I) response based on baseline blood transcriptome in children with GHD treated with somapacitan or daily GH. Methods: 200 treatment-naïve prepubertal children with GHD were enrolled into REAL4, a randomised, multinational, open-labelled, and active-controlled phase 3 trial. 128 consented to a baseline blood transcriptome profile. Children were treated with once-weekly somapacitan (n=81) or daily GH (n=47) for 52 weeks and categorised based on treatment response: the upper quartile of height velocity (HV; cm/year) was defined as good responders, and the lower quartile as poor responders. We split the somapacitan group into training (70%) and testing (30%) sets for prediction validation of HV and the GH response marker: ΔIGF-I standard deviation score (SDS). Gene expression was assessed between the target quartile and the remaining quartiles for both HV and ΔIGF-I SDS to identify the top 100 differentially expressed genes by adjusted p-value. Classes were balanced using a synthetic minority oversampling technique and Boruta, a feature selection algorithm, was used to refine gene lists. We performed random forest and calculated “out of box” (OOB) area under the curve (AUC) and OOB error rate (ER), measures of predictive accuracy and robustness, respectively. Results: HV prediction from the transcriptome was excellent for both treatments (AUC range: 0.95-0.99). It was more robust for identifying good responders (ER: 7.0-7.5%) than poor responders (ER: 13.2-17.5%). Genes previously identified as predictive of growth response for daily GH (Stevens et al., 2021. The Pharmacogenomics J., 21:594-607) were demonstrated to have high predictive value for once-weekly somapacitan and daily GH treatment in this study (AUC range: 0.84-0.97, ER <22%). Using the somapacitan group for validation, HV prediction (AUC range: 0.78-0.81) was stronger than ΔIGF-I SDS prediction (AUC range: 0.63-0.72). Conclusions: We demonstrate pre-treatment blood transcriptome predicts first-year growth response for somapacitan. This represents an independent validation of earlier observations and shows that genes predictive of growth response for daily GH treatment in children with GHD are also predictive for once-weekly somapacitan. Further, we demonstrate that the pre-treatment blood transcriptome predicts growth response better than it predicts IGF-I SDS response. Presentation: Saturday, June 17, 2023 Oxford University Press 2023-10-05 /pmc/articles/PMC10555074/ http://dx.doi.org/10.1210/jendso/bvad114.1519 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Pediatric Endocrinology
Garner, Terence
Clayton, Peter Ellis
Hojby, Michael
Murray, Philip
Stevens, Adam
OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency
title OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency
title_full OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency
title_fullStr OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency
title_full_unstemmed OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency
title_short OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency
title_sort or21-01 pre-treatment blood transcriptome predicts first-year growth and igf-i response to somapacitan treatment in children with gh deficiency
topic Pediatric Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555074/
http://dx.doi.org/10.1210/jendso/bvad114.1519
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