Development of a Predictive Enrichment Marker for the Oral GH Secretagogue LUM-201 in Pediatric Growth Hormone Deficiency

Abstract

Context We hypothesize, based on the degree of residual hypothalamic-pituitary function, that some, but not all, children with growth hormone deficiency (GHD) may have beneficial growth responses to the orally administered GH secretagogue LUM-201. Objective To determine if pretreatment testing can identify predictive enrichment markers (PEM) for subjects with adequate residual function that are responsive to LUM-201. Methods Analysis of a completed, randomized, placebo-controlled trial of LUM-201 a recombinant human growth hormone (rhGH) in which all randomized subjects had pretreatment testing Setting International multicenter study conducted in pediatric endocrinology clinics. Participants 68 naïve-to-treatment, prepubertal children with established diagnoses of GHD. Outcome Measures Sensitivity, specificity and predictive accuracy of potential markers to predict 6-month growth responses to oral LUM-201 and daily rhGH. Results Two PEM were identified: baseline insulin like growth factor- -I (IGF-I) concentration > 30 ng/mL and peak GH to single dose LUM-201 2: 5 ng/mL are defined as PEM-positive.PEM -positive status enriches a population for better growth responses to LUM-201.PEM -negative status enriches a population for better growth responses to rhGH. Conclusion The combination of peak GH to single-dose LUM-201 and baseline IGF-I concentration are effective PEMs for 6-month growth responses to LUM-201 and rhGH in prepubertal children with GHD.

RETRACTED: Effect of Weekly Long-Acting Growth Hormone Replacement Therapy Compared to Daily Growth Hormone on Children With Short Stature: A Meta-Analysis

“…A total of 1,245 unique studies were identified, of which 11 studies (between 2012 and 2021) fulfilled the inclusion criteria and were included in the study (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren

“…Relamorelin and anamorelin are two synthetic peptide agonists of GHSR that are in different stages of clinical trials to treat diabetic gastroparesis and cancer-related anorexiacachexia [12][13][14][15][16] . Ibutamoren, also known as MK-0677 or LUM-201, is a synthetic small-molecule GHSR agonist used as a growth hormone secretagogue in many disease settings 9,[17][18][19][20] .…”

Treatment of Pediatric Growth Hormone Deficiency With Oral Secretagogues Revisited

“…The studies by Bright et al and Blum et al add a new definition to the previously established diagnosis of idiopathic GHD with a moderate version [ 15 , 16 ]. They define moderate GHD as having insulin-like growth factor-1 (IGF-1) > 30 ng/mL although no upper limit is given and a peak GH response to stimulation >2 µg/L, which they estimate corresponds to a peak GH ≥ 5 ng/mL after ingestion of the oral secretagogue, LUM-201 [ 15 , 16 ].…”

“…The studies by Bright et al and Blum et al add a new definition to the previously established diagnosis of idiopathic GHD with a moderate version [ 15 , 16 ]. They define moderate GHD as having insulin-like growth factor-1 (IGF-1) > 30 ng/mL although no upper limit is given and a peak GH response to stimulation >2 µg/L, which they estimate corresponds to a peak GH ≥ 5 ng/mL after ingestion of the oral secretagogue, LUM-201 [ 15 , 16 ]. Reanalysis of data from the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) from 1995 to 2015 found that in individuals with moderate GHD as previously defined the average annualized growth velocity was 8.3 cm/year and less than the rate of 9.6 cm/year in those with severe GHD, defined as peak GH to stimulation <2 µg/L [ 17 ].…”

“…Children with GHD were treated for 6 months with different daily oral LUM-201 doses after measurement of peak GH response to a single dose of LUM-201 [ 15 ]. The mean annualized growth velocity for the LUM-201 groups (6.0, 6.9 cm/year) was modestly higher than the placebo group (4.5 cm/year) but lower than the rate in those treated with GH (11.1 cm/year).…”