OR03-06 Acutely regulated genes in children born small for gestational age following daily and weekly growth hormone are predictive of first-year growth response

Abstract Disclosure: T. Garner: Grant funding from Novo Nordisk. P. Murray: Grant funding from Novo Nordisk. M. Højby: Employee and shareholder of Novo Nordisk. R. Ard: Employee and shareholder of Novo Nordisk. P.E. Clayton: Grant funding from Novo Nordisk. A. Stevens: Grant funding from Novo Nordisk.. Background: Daily growth hormone (GH) and a long-acting GH (once-weekly somapacitan) are associated with improved growth response in children with GH deficiency and those born small for gestational age (SGA). Accurate growth response predictions have been demonstrated in both cases using the baseline blood transcriptome [Garner et al., JCEM 2024 & ENDO 2024]. Acute gene expression changes following treatment with GH have not yet been investigated. It is therefore unknown whether GH-responsive genes are useful predictors of growth response following GH treatment. Methods: Here we assessed, using RNA-sequencing, differentially expressed genes (DEGs) identified from blood sampling at baseline and 8 weeks after treatment in the REAL5 study, a global phase 2 trial (Clinicaltrials.gov: NCT03878446) investigating somapacitan versus daily GH in children born SGA [Juul et al., JCEM 2024]. We used DEGs as a marker of acute response to either treatment. Identified genes were compared to baseline gene expression previously identified as predictive of growth response and an independent analysis was performed to determine whether these DEGs were also predictive. Additionally, expression differences from baseline to week 8 were calculated for each patient. Correlation between the most variable genes (upper quartile: 3921) in both groups was determined. A hypergraph approach was employed wherein clusters of genes were identified by the number of correlations shared by a pair of genes. The significance of the number of these genes that overlapped between daily GH and somapacitan treatments was assessed using a hypergeometric test. Results: Limited commonality (<5%) was observed between GH-responsive genes and baseline gene expression previously identified as predictive of first-year growth response in SGA. Few acute GH-responsive DEGs were informative in predicting first-year response to GH, however these genes do predict both daily GH and somapacitan treatment (OOB AUCs=0.84-1.00). In contrast to previous analyses using baseline transcriptome, fast responders (validated AUC=0.75) were better predicted than slow responders (0.625). GH-responsive elements (STAT binding sites) were associated with identified genes in both groups: 5/5 and 3/7 for daily GH and somapacitan, respectively. Hypergraph modelling differences in expression after 8 weeks revealed a core group of 960 genes common to daily GH and somapacitan treatment (out of 3921). 371 of these were within a central cluster representing highly significant overlap (p<1e-21; 1.55-fold enrichment). Conclusions: Our results suggest that fast response is potentially more strongly associated with acute regulation of response to GH, and that coordinated gene expression implies common GH responses for daily GH and somapacitan. Presentation: Saturday, July 12, 2025