ESPE2024 Free Communications Late Breaking (6 abstracts)
Amount and Pattern Of Pulsatile GH Secretion Induced By The Oral Growth Hormone Secretagogue LUM-201 Is Related To Growth And IGF-1 Responses In Moderate Pediatric Growth Hormone Deficiency (PGHD)
Amirul Roslan 1 , Rossana Román 2 , Alejandra Avila 2 , Daniela Said 2 , Ingrid Baier 2 , Erik L. Brincks 3 , Aleksandra Bruchey 3 , John C. McKew 3 , Pisit "Duke" Pitukcheewanont 3 , Michael L. Johnson4 , Terence Garner 1 , Michael O. Thorner 3,4 , Peter E. Clayton 1 , Adam Stevens 1 & Fernando Cassorla 2
1University of Manchester, Developmental Biology and Medicine, Manchester, United Kingdom. 2University of Chile, Institute of Maternal and Child Research, Santiago, Chile. 3Lumos Pharma, Inc., Austin, USA. 4University of VA - Emeritus, Charlottesville, USA
Background: Oral LUM-201 normalizes growth rates in moderate PGHD over 12 months (Phase 2 Trials: OraGrowtH210/OraGrowtH212) [FC-746 ESPE 2024]. In OraGrowtH212, GH profiles, based on 10-minute sampling over 12 hours (8am-8pm), showed significant increases in inter-pulse, pulsatile and total GH secretion in response to 1.6 and 3.2 mg/kg/day doses of LUM-201 over 6 months, with no difference between the doses [FC14.3, ESPE 2023].
Objectives: This study characterizes relationships between pulse profiles, growth and IGF-1 responses to oral LUM-201 (doses combined).
Methods: 22 prepubertal children with moderate GHD (peak GH >3 and <10ng/ml), IGF-1 >30ng/ml and an acute GH response to 0.8 mg/kg LUM-201 of ≥5ng/ml) were included. Subjects were grouped into tertiles based on 6 month (M6) Annualized Height Velocity (AHV). Pulsatile GH secretion profiles were characterized using (1) Approximate Entropy (ApEn, scale 0-1) examining degree of orderliness over the whole profile and (2) Functional Principal Component Analysis (FPCA) identifying where within the 12hr profile, divided into three 4hr periods, the dominant variation occurred.
Results: Mean baseline (D1) AHV was 4.5cm/yr with M6 AHVs in the tertiles (lower to upper) being 6.5, 7.4 and 8.8 cm/yr (all P <0.01). Mean D1 IGF-1 SD score was -0.9, and at M6 in the tertiles 0, +0.2 and +0.8 (all P <0.02). Pulsatile GH secretion increased in all three AHV tertiles by >50%, with no difference between tertiles at M6. ApEn in the whole cohort increased: D1 0.52, M6 0.72 (P <0.001), with no difference between tertiles at M6. In FPCA, the pattern of GH secretion, represented by the first principal component, was markedly modified by LUM-201: at D1 the upper AHV tertile had the highest variation in the first and third time periods, at M6 this had shifted to only the first period. In the lower AHV tertile at D1 the greatest variation was in the first and second periods, while at M6 this was in the third period. In the middle AHV tertile, greatest variation at M6 was in the first and third periods.
Conclusions: In response to oral LUM-201, pulsatile GH secretion, growth rate and serum IGF-1 increased. Additionally, LUM-201 induced both an increase in disorderliness (ApEn) of the pulse profiles and an alteration in time periods at which the greatest variation occurred, which differed between high and lower growth responders. Both amount and pattern of GH secretion are important for growth and IGF-1 responses to LUM-201.
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