ESPE Abstracts

Treating short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that are burdensome for patients and caregivers. Results from REAL5 (ongoing randomised, multinational, open-label, controlled, dose-finding phase 2 trial; NCT03878446) indicate that somapacitan (0.24 mg/kg/week) has an efficacy, safety, and tolerability profile similar to daily GH (0.067 mg/kg/day) after 52 weeks of treatment in children born SGA. Predicting GH treatment response from gene expression has the potential to improve clinical management of short stature. Here, we investigate the prediction of growth response based on baseline blood transcriptome in children born SGA treated with either daily GH or somapacitan in the REAL5 study. 62 GH-treatment-naïve, prepubertal children born SGA were randomized (1:1:1:1:1) to receive somapacitan (0.16, 0.20 or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day) for 52 weeks. 44 consented to a baseline blood transcriptome profile [n=9, 10, and 10 in somapacitan 0.16, 0.20 and 0.24 mg/kg/week arms; n=6 and 9 in daily GH 0.035 and 0.067 mg/kg/day arms]. Children were categorised based on treatment response: the upper and lower quartiles of height velocity (HV; cm/year) were defined as good and poor responders, respectively. Differential expression analysis identified genes associated with HV in a continuous manner across all arms separately. Boruta was used to identify which of the top 100 genes, ranked by false discovery-rate corrected P-values, were informative in distinguishing good from poor responders. Random forest classifier was used to predict good/poor responders vs. remaining three quartiles, across all doses, using expression from these genes. Performance of the classification models was assessed using out of box area under the curve (OOB AUC) and error rate (ER). Growth response prediction from baseline (pre-treatment) blood transcriptome was strong following treatment with either daily GH (OOB AUC: 0.97-1.00; ER: 0-5.3%) or somapacitan (0.91-0.93; 13.5-14%). Genes predictive of growth response to daily GH in children with GH deficiency (GHD) and Turner syndrome (Stevens et al. 2021, Pharmacogenomics J.) had strong predictive value in children born SGA with either daily GH (OOB AUC: 0.81-0.90; ER: 15.8-21%) or somapacitan (0.84-0.88; 21-24%) treatment. We demonstrate pre-treatment blood transcriptome predicts first-year growth response for somapacitan in children born SGA. However, growth response was less predictive than equivalent prediction in children with GHD. This may reflect a greater heterogeneity of the short stature SGA study population.