9318 Growth Response To Oral Growth Hormone Secretagogue LUM-201 In Children With Moderate GH Deficiency (GHD) Is Dependent On The Pattern Of Pulsatile GH Secretion Induced By LUM-201

Abstract

Disclosure: A. Roslan: None. R. Roman: None. A. Avila: None. D. Said: None. I. Baier: None. E. Brincks: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. J. McKew: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P. Pitukcheewanont: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc.. M. Johnson: None. T. Garner: Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P.E. Clayton: Advisory Board Member; Self; Lumos Pharma, Inc.. Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. A. Stevens: Consulting Fee; Self; Lumos Pharma, Inc. F. Cassorla: Consulting Fee; Self; Lumos Pharma, Inc..

Background: Oral GH secretagogue, LUM-201, increases growth rates in children with moderate GHD in Phase 2 trials (OraGrowtH210 and 212) [ENDO 2023, OR21-06]. GH pulse profiles at baseline (D1) and 6 months (6M) were assessed in OraGrowtH212. This study aims to understand relationships between pulse profiles and growth response to LUM-201. Methods: The OraGrowtH212 trial is being conducted at a single site (Chile). 22 prepubertal children (M 14: F 8) with moderate GHD (peak GH level on two stimulation tests >3 and <10ng/ml), who had basal IGF-I >30ng/ml and an acute GH response to 0.8mg/kg LUM-201 of ≥5ng/ml, were randomised to receive LUM-201 1.6 or 3.2 mg/kg/day. 10min samples over 12hrs (08.00-20.00) were collected at D1 and M6 for measurement of GH concentration (ng/ml), with GH secretion rates (ng/ml/min) derived by deconvolution analysis. A univariate Spearman’s rank correlation matrix was used to screen for relationships (significant at p<0.05) between D1 characteristics, D1 height velocity, 6M annualised height velocity (AHV) and interpulse, pulsatile and total GH secretion at D1 and M6.The pattern of pulsatile GH secretion in the 12hr profile was characterised using Functional Principal Component Analysis (FPCA) - used to explore the dominant modes of variation in functional data, in this case the GH time series. Subjects were grouped into tertiles based on 6M AHV (High [mean 8.9cm/yr], Medium [7.7], and Low [6.7]), and the 12hr profiles were divided into three 4hr intervals. The interquartile range (IQR) for mean GH secretion (representing variation in amount) and principal components [PCs] (variation in pattern) for all subjects in each AHV tertile at D1 and M6 were generated. Results: All GH secretion parameters increased significantly from D1 to M6 (p<0.01). Age was negatively associated with 6m AHV (r_s= -0.46), and D1 pulsatile GH secretion was positively associated with D1 AHV (r_s = +0.51). However, GH secretion at D1 and M6 was not correlated with 6m AHV. In the FPCA, the difference in IQR for mean GH secretion from D1 to 6M was highest over 0-4hrs for subjects in the high and medium AHV tertiles (5- and 3.3-fold greater respectively compared to the other time intervals), while subjects with low AHV had the highest difference over 8-12hrs (42-fold greater). Using the first PC (which accounts for ∼50% of total variation), the change in IQR was highest over 0-4 and 4-8hrs in the high AHV tertile (3-fold greater compared to other time intervals), over 0-4hrs in the medium tertile (46-fold greater) and over 8-12hrs in the low tertile (3.4-fold greater). Conclusions: Oral LUM-201 stimulates significant increases in GH secretion over 6 months in children with moderate GH deficiency. Complex relationships exist between growth response and both the amount and pattern of GH secretion, with the highest growth responses to LUM-201 associated with the greatest pulsatile activity early in the profile.

Presentation: 6/3/2024