LUM-201 Elicits Greater GH Response than Standard GH Secretagogues in Pediatric Growth Hormone Deficiency

摘要

Presentation Type: OralScience Type and Topic: Clinical Trial Introduction: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH-secretagogue that stimulates the GH secretagogue receptor (GHSR1a) in the hypothalamus and pituitary. LUM-201 is in development for long-term use in a subset of PGHD patients with moderate growth deficiencies. A diagnosis of PGHD is confirmed by low GH responses to standard GH secretagogues (clonidine, arginine, L-dopa, glucagon, insulin) so it is somewhat counter-intuitive to suggest that children who cannot respond to one GH secretagogue might have favorable responses to LUM-201. Objective: To determine if LUM-201 stimulates GH responses differently than standard GH secretagogues. Methods: 68 naïve-to-treatment, prepubertal children with GHD received two standard GH stimulation tests and a test with a single 0.8 mg/kg dose of LUM-201. The 68 subjects included 20 girls and 48 boys. The median (interquartile range) age was 9.2 years (7.2,10.8), bone age 6.0 years (4.5, 7.9), height SDS -3.3 (-4.5, -2.5), pretreatment height velocity 4.0 cm/y (3.2, 4.6), and baseline IGF-1 51 ng/mL (24,111). Results: The median (interquartile range) of maximal GH response to single dose LUM-201 was 15.0 ng/mL (3.5, 49) and to various pairs of standard stimuli was 5.4 ng/mL (1.8-7.6) (p< 0.00001). The median (IQR) for the difference between GH responses to LUM-201 and standard stimuli was 9.6 ng/ml (1.9, 42). In a multivariate analysis (r2 =0.73) differential GH increased with higher values of baseline IGF-I (p < 0.00001) and standard GH stimulation test (p = 0.047) but was not influenced by age (p = 0.16), sex (p = 0.28), baseline HV (p = 0.24), age-bone age differences (p = 0.33) or height-SDS (p = 0.75). Conclusion: In GHD children, the GH response to single dose LUM-201 greatly exceeds that observed with standard GH testing agents. The difference is greatest among patients with higher baseline values of IGF-I and higher GH responses to standard stimuli. The synergistic actions of LUM-201 on the physiological mechanisms regulating GH release explain why GH responses are greater in response to LUM-201 compared to traditional tests used to diagnose PGHD. Key words: LUM-201, GH deficiency, GH secretagogues, pediatrics, stimulation tests, short stature, pituitary, hypothalamus