Gene Expression Signatures Predict First-Year Response to Somapacitan Treatment in Children With Growth Hormone...

Area of Science:

• Genomics
• Endocrinology
• Pediatrics

Background:

• The pretreatment blood transcriptome accurately predicts growth response to daily growth hormone (GH) therapy.
• Growth hormone deficiency (GHD) impacts child development.
• Novel long-acting GH formulations aim to improve treatment adherence and outcomes.

Purpose of the Study:

• To investigate the predictive capability of the pretreatment transcriptome for growth response in children with GHD treated with once-weekly somapacitan.
• To compare the predictive power of the transcriptome for somapacitan versus daily GH therapy.
• To identify a common set of predictive genes for both treatment modalities.

Main Methods:

• A randomized, multinational, open-label, phase 3 trial (REAL4) involving 128 treatment-naïve prepubertal children with GHD.
• Baseline blood transcriptome profiling using differential RNA-seq and machine learning.
• Randomization to subcutaneous somapacitan (once-weekly) or daily GH, with prediction of height velocity (HV) and other growth markers at 52 weeks.

Main Results:

• The pretreatment transcriptome demonstrated excellent prediction accuracy for height velocity (HV) and secondary growth markers (HV SDS, ΔHSDS, ΔIGF-I SDS) for both somapacitan and daily GH treatments (AUCs ranging from 0.83 to 0.99).
• Previously identified predictive genes for GH therapy were consistently effective in predicting the fastest growers in both treatment groups.
• Prediction accuracy was high for both treatments, with validation AUCs ranging from 0.61 to 0.88 for various growth parameters.

Conclusions:

• The pretreatment transcriptome is a reliable predictor of first-year growth response in children with GHD treated with once-weekly somapacitan.
• A shared set of genes can predict treatment response to both once-weekly somapacitan and conventional daily GH.
• This transcriptomic approach holds potential for development into a clinically applicable pretreatment test to optimize GHD management.