Gene expression signatures predict first-year response to somapacitan treatment in children with GH deficiency
Terence Garner, Peter Clayton, Michael Højby, Philip Murray, Adam Stevens- Biochemistry (medical)
- Clinical Biochemistry
- Endocrinology
- Biochemistry
- Endocrinology, Diabetes and Metabolism
Abstract
Context
The pre-treatment blood transcriptome predicts growth response to daily GH therapy with high accuracy.
Objective
Investigate response prediction using pre-treatment transcriptome in children with GH deficiency (GHD) treated with once-weekly somapacitan, a novel long-acting GH.
Design
REAL4 is a randomised, multinational, open-labelled, active-controlled parallel group phase 3 trial, comprising a 52-week main phase and an ongoing 3-year safety extension (NCT03811535).
Patients
128/200 treatment-naïve prepubertal children with GHD consented to baseline blood transcriptome profiling.
Interventions
Randomized 2:1 to subcutaneous somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day).
Methods and main outcome measures
Differential RNA-seq analysis and machine learning to predict therapy response.
Results
121/128 samples passed quality control. Children treated with somapacitan (n = 76) or daily GH (n = 45) were categorised based on fastest and slowest growing quartiles at week 52. Prediction of height velocity (HV; cm/year) was excellent for both treatments (OOB AUC: 0.98–0.99; validation AUC: 0.83-0.84), as was prediction of secondary markers of growth response: HV SD score (SDS) (0.99-1.0; 0.75-0.78), change from baseline height SDS (ΔHSDS) (0.98-1.0; 0.61-0.75) and change from baseline insulin-like growth factor-I SDS (ΔIGF-I SDS) (0.96-1.0; 0.85-0.88). Genes previously identified as predictive of GH therapy response were consistently better at predicting the fastest growers in both treatments in this study (OOB AUC: 0.93-0.97) than the slowest (0.67-0.85).
Conclusions
Pre-treatment transcriptome predicts first-year growth response in somapacitan-treated children with GHD. A common set of genes can predict the treatment response to both once-weekly somapacitan and conventional daily GH. This approach could potentially be developed into a clinically-applicable pre-treatment test to improve clinical management.