RESUMEN
INTRODUCTION: The phase 3 fliGHt Trial evaluated the safety and tolerability of once-weekly lonapegsomatropin, a long-acting prodrug, in children with growth hormone deficiency (GHD) who switched from daily somatropin therapy to lonapegsomatropin. METHODS: This multicenter, open-label, 26-week phase 3 trial took place at 28 sites across 4 countries (Australia, Canada, New Zealand, and the USA). The trial enrolled 146 children with GHD, 143 of which were previously treated with daily somatropin. All subjects received once-weekly lonapegsomatropin 0.24 mg human growth hormone/kg/week. The primary outcome measure was safety and tolerability of lonapegsomatropin over 26 weeks. Secondary outcome measures assessed annualized height velocity (AHV), height standard deviation score (SDS), and IGF-1 SDS at 26 weeks. RESULTS: Subjects had a mean prior daily somatropin dose of 0.29 mg/kg/week. Treatment-emergent adverse events (AEs) reported were similar to the published AE profile of daily somatropin therapies. After switching to lonapegsomatropin, the least-squares mean (LSM) AHV was 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS changed from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). Among switch subjects, the LSM for average IGF-1 SDS was sustained at Weeks 13 and 26, representing an approximate 0.7 increase from baseline (prior to switching from daily somatropin therapy). Patient-reported outcomes indicated a preference for weekly lonapegsomatropin among both children and their parents. CONCLUSIONS: Lonapegsomatropin treatment outcomes were as expected across a range of ages and treatment experiences. Switching to lonapegsomatropin resulted in a similar AE profile to daily somatropin therapy.
Asunto(s)
Sustitución de Medicamentos , Enanismo Hipofisario , Hormona del Crecimiento , Hormona de Crecimiento Humana , Estatura , Niño , Enanismo Hipofisario/tratamiento farmacológico , Trastornos del Crecimiento/tratamiento farmacológico , Hormona del Crecimiento/uso terapéutico , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/uso terapéuticoAsunto(s)
Proteínas de Unión al ADN/genética , Trastornos del Crecimiento/genética , Hormona de Crecimiento Humana/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/deficiencia , Proteínas de la Leche , Mutación Missense , Transactivadores/genética , Adolescente , Proteínas Portadoras/sangre , Proteínas de Unión al ADN/metabolismo , Femenino , Trastornos del Crecimiento/tratamiento farmacológico , Homocigoto , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/fisiología , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Receptores de Somatotropina/genética , Factor de Transcripción STAT5 , Análisis de Secuencia de ADN , Transducción de Señal , Transactivadores/metabolismoRESUMEN
Growth hormone insensitivity (GHI) has been attributable, classically, to mutations in the gene for the GH receptor. After binding to the GH receptor, GH initiates signal transduction through a number of pathways, including the JAK-STAT pathway. We describe the first patient reported with a mutation in the gene for STAT5b, a protein critical for the transcriptional regulation of insulin-like growth factor-I.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de la Leche/genética , Mutación , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Adolescente , Femenino , Humanos , Janus Quinasa 2 , Factor de Transcripción STAT5RESUMEN
To determine whether hyperinsulinemia and reduced insulin sensitivity in individuals born small for gestational age (SGA) could be related to persisting abnormalities of the GH/IGF-I axis, we assessed overnight GH secretory profiles and measured fasting glucose, insulin, intact and 32,33 split proinsulin, and IGF-I levels in 16 short SGA children (age range 2.3-8.0 y) and in controls. Insulin sensitivity was calculated using the homeostasis model. Compared with short normal-birthweight controls (n = 7, age range 2.3-5.0 y), short SGA children had higher fasting insulin levels (means: 26.8 vs 20.6 pmol/L, p = 0.02), lower insulin sensitivity [means: 204 vs 284 %homeostasis model assessment (HOMA), p = 0.01], and higher beta cell function (112 vs 89 %HOMA, p = 0.04). SGA children also had lower levels of IGFBP-1 (87.0 vs 133.8, p = 0.04), but similar IGF-I levels (IGF-I SDS: -1.1 vs -1.7, p = 0.4). Compared with normal-height controls (n = 15, age range 5.6-12.1 y), SGA children had higher overnight GH secretion (GH maximum: 55.9 vs 39.6 mU/L, p = 0.01; mean: 13.1 vs 8.9, p = 0.004; minimum: 1.2 vs 0.6, p = 0.02). Interestingly, among SGA children, fasting insulin levels and insulin sensitivity were significantly related to overnight GH secretion (insulin sensitivity vs maximum GH: r = -0.68, p = 0.01; vs GH pulse amplitude r = -0.71, p = 0.007). The only hormone level significantly related to current height velocity was C-peptide (r = 0.75, p = 0.008). In conclusion, elevated fasting insulin levels and reduced insulin sensitivity in short SGA children was related to elevated levels of overnight GH secretion. We hypothesize that resistance to the somatotropic actions of GH and IGF-I in short SGA children may contribute directly to reduced insulin sensitivity.