Introduction: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH secretagogue receptor agonist under development for treatment of pediatric growth hormone deficiency (PGHD). Methods: The GH response to a single dose of LUM-201 and to other GH secretagogues used for diagnosis of PGHD were compared in 68 pediatric subjects participating in a trial for growth hormone deficiency. Results: LUM-201 elicited greater GH responses than observed in GHD diagnostic tests with arginine, glucagon, clonidine, L-dopa, and insulin-induced hypoglycemia [median and interquartile ranges 15.0 ng/mL (3.5, 49) vs. 5.5 ng/mL (1.8, 7.6) (p < 0.0001)]. The difference between responses was greatest in subjects with higher baseline IGF-I concentrations and higher GH responses to standard GH stimuli. Conclusion: LUM-201 elicits greater GH responses than standard stimuli in subjects with higher peak GH in response to conventional testing and is potentially an orally administered treatment alternative to injectable rhGH in a subset of patients with adequate responses to an acute dose of LUM-201.

The GH secretagogue receptor (GHSR1a, also known as the ghrelin receptor) is located in the hypothalamus and pituitary; stimulation by GHSR1a agonists can modulate both GHRH and somatostatin signaling to augment endogenous GH secretion [1]. There is renewed interest in GHSR1a agonists for the diagnosis and treatment of GH deficiency in adults and children [2, 3]. LUM-201 (ibutamoren mesylate, formerly MK-0677) is an orally administered GHSR1a agonist that stimulates GH secretion and endogenous GH pulsatility in healthy, elderly adult subjects [4]. Also, in pilot studies, LUM-201 stimulates GH and IGF-I responses and increases 6-month height velocities in children with moderate degrees of GHD [2, 5]. During the late 1990s, Merck conducted a double-blind, placebo-controlled study of LUM-201 in children with GHD. Prior to the onset of treatment, each subject received two standard GH stimulation tests and the GH response to a single, orally administered dose of LUM-201 was measured. We have recently analyzed these data to determine if differences were observed in the GH responses to LUM-201 and the standard GH stimulation tests [6].

Subjects

The analysis utilizes data from 68 prepubertal, naïve to treat children randomized to a multicenter trial for growth hormone deficiency. The cohort included 40 males and 28 females. Key inclusion criteria included age ≥4 years, prepubertal status, height <5th centile, a 6-month height velocity <10th centile for age and gender, bone age delay ≥1.0 years, peak GH response <10.0 ng/mL to two standard stimuli (arginine, clonidine, glucagon, insulin-induced hypoglycemia, and L-dopa), and a GH peak >1.9 ng/mL to a single oral dose of LUM-201. Pituitary imaging was not required or routinely reported. Exclusion criteria included pituitary tumors, cranial irradiation or surgery, and multiple pituitary hormone deficiencies with the exception of adequately treated hypothyroidism. Estrogen priming was not used for the standard GH stimulation tests. Baseline characteristics of the subjects are shown in Table 1. Written informed consent, and assent where applicable, was obtained prior to any study activities. The purpose of this analysis was to compare the maximal GH responses to single-dose LUM-201 (0.8 mg/kg) and two standard GH stimulation tests.

Table 1.

Baseline characteristics of the subjects (n = 68; 40 M, 28 F)

Baseline characteristics of the subjects (n = 68; 40 M, 28 F)
Baseline characteristics of the subjects (n = 68; 40 M, 28 F)

GH and IGF-I Assays

GH and IGF-I assays were performed at Esoterix (Calabasas Hills, CA, USA). GH was measured by a standard double-antibody radioimmunoassay, with a lower detection limit of 0.3 ng/mL, an intra-assay coefficient of variation (CV) of 3.4–10%, and an inter-assay CV of 7.2–13% for GH levels ranging from 0.92 to 8.9 ng/mL. IGF-I was determined by a competitive-binding radioimmunoassay, after acid ethanol extraction, with a lower limit of detection of 10 ng/mL, an intra-assay CV of 4.6–20%, and an inter-assay CV of 6.3–28% for IGF-I levels ranging from 24 to 580 ng/mL. The normative data supporting the IGF-I assay in the 1990s were considered insufficient by modern standards for accurate calculation of standard deviation scores (IGF-I SDS). Accordingly, data analysis for this report focuses only on IGF-I concentrations.

Statistical Analyses

Data from all 68 subjects were used in the analyses. There were no missing data. Values for the GH responses to LUM-201 and standard GH stimulation tests were not normally distributed. Consequently, the descriptive statistics are reported as medians and interquartile ranges. The null hypothesis of no difference between GH responses to LUM-201 and to standard GH stimuli was performed by a Kruskal-Wallis test. The differential GH response is defined as the difference in GH response to LUM-201 minus the maximal GH response to standard stimuli. Dependencies of the differential GH response on baseline characteristics of the subjects were examined using Pearson product-moment correlation matrices and multiple regression analyses of differential GH as the dependent variable and age, bone age, gender, height SDS, weight, GH stimulation test results, and baseline IGF-I concentration as potential covariates.

The range of GH responses in the two standard GH stimulation tests was 0.8–10 ng/mL (median 5.4 ng/mL, IQR 1.8–7.6 ng/mL) but to a single oral dose of LUM-201 was 1.9–103 ng/mL (median 15.0 ng/mL, IQR 3.5–49 ng/mL). A Kruskal-Wallis test of the null hypothesis that no difference existed between the GH responses to the LUM-201 and the standard GH stimulation tests was rejected at a significance level <0.00001. The raw data are shown in Figure 1. Note that the Figure 1 presentation is log-linear. Also note that for standard stimulation test results <3 ng/mL, there are minimal differences between standard and LUM-201 tests.

Fig. 1.

Maximal GH responses (ng/mL) to two standard GH stimulation tests (x-axis) and to single oral dose of LUM-201 (y-axis).

Fig. 1.

Maximal GH responses (ng/mL) to two standard GH stimulation tests (x-axis) and to single oral dose of LUM-201 (y-axis).

Close modal

Potential correlations between the differential GH response and baseline characteristics of the individual subjects were examined initially by correlation matrices and then by multiple regression analyses of potentially informative covariates. The differential GH response was defined as the difference between GH response to single-dose LUM-201 and the GH response to standard stimulation tests. The differential GH response data were not normally distributed with a mean of 23 ng/mL, median of 9.6 ng/mL, an interquartile range of 1.9–42 ng/mL, and an absolute range from −1.9 to 97 ng/mL. Among the 68 subjects, only 3 had a higher GH response to standard GH stimulation tests than to single-dose LUM-201. The correlation matrix suggested that height SDS, weight, individual GH responses to standard GH stimulation tests, and baseline IGF-I might explain the distribution of differential GH responses. No correlations were found for gender or chronological age. As expected, some of the potentially informative factors were correlated to each other (e.g., bone age and height SDS). Accordingly, a stepwise multiple regression analysis was used to identify the most informative covariates. The final model was highly significant (p < 0.00001, adjusted r2 = 0.73). Despite a correlation between GH response to standard stimulation test and GH response to LUM-201 (adjusted r2 = 0.73, p < 0.00001), the multivariate analysis identified both baseline IGF-I (p < 0.000001) and standard GH stimulation test result (p = 0.013) as independent covariates (Table 2). The relationship between differential GH response and baseline IGF-I is shown in Figure 2, and the relationship between differential GH response and GH response to standard GH stimulation tests is shown in Figure 3.

Table 2.

Multiple regression analysis for factors affecting differences in peak GH response to single-dose LUM-201 and standard GH stimuli (adjusted r2 = 0.74, overall model p < 0.00001)

Multiple regression analysis for factors affecting differences in peak GH response to single-dose LUM-201 and standard GH stimuli (adjusted r2 = 0.74, overall model p < 0.00001)
Multiple regression analysis for factors affecting differences in peak GH response to single-dose LUM-201 and standard GH stimuli (adjusted r2 = 0.74, overall model p < 0.00001)
Fig. 2.

Relationship between differential GH response and baseline IGF-I concentrations. Note the data presentation is log-linear. The adjusted r2 value for log (differential GH) and baseline IGF-I was 0.63.

Fig. 2.

Relationship between differential GH response and baseline IGF-I concentrations. Note the data presentation is log-linear. The adjusted r2 value for log (differential GH) and baseline IGF-I was 0.63.

Close modal
Fig. 3.

Relationship between differential GH response and GH responses to standard GH stimulation tests. Note the data presentation is log-linear. The adjusted r2 value for log (differential GH) and GH response to standard GH stimulation tests was 0.61.

Fig. 3.

Relationship between differential GH response and GH responses to standard GH stimulation tests. Note the data presentation is log-linear. The adjusted r2 value for log (differential GH) and GH response to standard GH stimulation tests was 0.61.

Close modal

Note that the data in Figures 1-3 are log-linear presentations suggesting a sigmoid-type relationship with no differences among low values, a rapid increase, and a possible plateau at the highest values. Values for the GH differential were minimal for subjects with baseline IGF-I <30 ng/mL (mean GH differential 2.3 ng/mL) and for subjects with GH responses to standard stimulation tests <3 ng/mL (mean GH differential 2.1 ng/mL).

The mean (SD) peak GH response to the various standard stimuli was 5.9 (2.5) for arginine, 4.8 (3.0) for clonidine, 5.6 (3.3) for glucagon, 5.5 (3.5) for insulin, and 4.2 (3.2) for L-dopa. No statistically significant comparison between test types was observed. The range of BMI values was 12.6–27.6 kg/m2. Peak GH to standard tests was somewhat lower in children with higher BMI but was not significant by linear regression analysis (p = 0.08). There was no apparent association between BMI and peak GH response to LUM-201 (p = 0.58).

In this study of 68 children with idiopathic GHD as defined by the eligibility criteria, the GH responses to a single dose of LUM-201 (0.8 mg/kg) were substantially higher than the GH responses to standard stimuli used for diagnostic tests of growth hormone deficiency (arginine, clonidine, L-dopa, glucagon, and insulin). The differences in GH responses were greatest in subjects with higher GH peaks to standard stimuli and higher baseline IGF-I concentrations. These data suggest a different mechanism of action on GH release for LUM-201 than for the standard diagnostic stimuli. In addition, the data suggest that LUM-201 may be effective in increasing GH exposure in some pediatric patients within the GHD spectrum, especially those with higher GH peaks to standard stimuli and higher baseline IGF-I. It should be mentioned that GH stimulation test results in the range of 5–10 ng/mL are not considered indicative of GHD by all pediatric endocrinologists, and subjects with organic forms of GHD (e.g., tumors) were not included in this study.

Substantially different magnitudes of GH secretory responses are commonly observed with different GH stimuli in growth hormone-deficient children and adults. GH-releasing peptide-2 (GHRP-2) is a hexapeptide that elicits substantially higher GH responses in GH-deficient children than the standard GH stimuli. Co-administered GHRP-2 and GHRH elicit greater GH responses than either GHRP-2 or GHRH alone, suggesting a synergistic effect in these patients and, perhaps, a separate signaling pathway for each [7]. GHRP-2 elicits greater GH responses than standard stimuli and is used as a diagnostic agent for adult and pediatric GHD in Japan, although the relatively short half-life of the GH response to a twice-daily, intranasal dose of GHRP-2 in children with GHD was inadequate to promote catch-up growth in a 6-month study [8]. In children with GHD, higher GH responses were observed with co-administered GHRH and arginine than with either agent alone [9, 10]. Macimorelin elicits higher GH responses than insulin-induced hypoglycemia [11] and has been approved as a diagnostic agent for adults with GH deficiency.

Available data suggest that LUM-201 acts to augment endogenous GH pulsatility in subjects with intact pituitary somatotrophs. Mean 24-h GH concentrations and serum IGF-I were increased in healthy elderly subjects treated with 10 and 50 mg doses of LUM-201 [4]. Augmented endogenous GH pulsatility has also been observed in children with GH deficiency after a 6-month treatment period with LUM-201 [5]. It is important to note that in these two studies, the augmentation of GH pulsatility was not uniform among all subjects: minimal changes in GH parameters were observed in some patients. As in the current study, the inference is that LUM-201 responsivity is present in some, but not all, patients within the spectrum of GH deficiency.

LUM-201 is an agonist of the GHSR1a located in the hypothalamus and pituitary. Stimulation of the GHSR1a evokes a number of responses including increased secretion of GHRH and decreased secretion of somatostatin from the hypothalamus, resulting in potentiation of the GHRH stimulus on pituitary somatotrophs and direct stimulatory effects on GH release on the somatotrophs [1]. In contrast, available studies suggest that the standard diagnostic stimuli for GHD may work through other mechanisms, possibly distinct from GHSR1a activation. In healthy adults, arginine co-administered with GHRH gave higher GH responses than either arginine or GHRH alone, suggesting that arginine effects are mediated via suppression of somatostatin [12]. However, treatment of healthy young men with a GHRH antagonist suppressed GH release to arginine, L-dopa, clonidine, insulin-induced hypoglycemia, and pyridostigmine, thus suggesting that GHRH is involved in GH release to standard stimuli, at least in healthy young adults [13]. A study in normal healthy adult males comparing GH responses to GHRH and insulin-induced hypoglycemia suggested different pathways for these stimuli, and that suppression of somatostatin by insulin was a probable mechanism for the GH secretory action of insulin-induced hypoglycemia [14]. Interpretations of results across these studies have not always been consistent although the choice of doses and routes of administered doses for these GH stimuli may have influenced the outcomes.

A multiplicity of signaling effects may be the reason for the substantial GH responses to LUM-201 in subjects with minimal ability to respond to standard GH stimuli. Importantly, the combined data suggest that GH responsiveness to GHSR1a stimulation is retained in some subjects with likely idiopathic GHD as defined by the eligibility criteria used in this study, and that LUM-201 more effectively stimulates GH release compared to the standard GH stimulation diagnostic agents, at least in the subset of subjects with higher GH peaks to standard stimuli and higher baseline IGF-I.

The mechanism of action of GH secretagogues may affect another aspect of GH responses, namely, the reproducibility of the results in a subsequent test. Concordance, the percentage of results above and below specified cut-off points, is a measure of test reproducibility. In one study, concordance rate was only 56.5% with two standard GH stimulation tests in short children [15]. In another study of children with short stature, GH stimulation tests were performed 1–6 months apart (and with no intervening treatment) and the majority (>80%) of subjects tested above the specified GH cut-off value, indicating poor test-retest reproducibility [16]. In its registration studies, the test-retest paradigm for macimorelin was evaluated in a subgroup of 33 subjects. The overall reproducibility rate was 94%. Concordance rates and reproducibility may be affected by the degree of GH deficiency. In the macimorelin study, reproducibility was greatest in the subjects with lowest results on standard GH stimulation tests [15]. The reproducibility of the macimorelin test-retest is higher than with standard GH stimuli, which may reflect its mechanism of action. GH responses to given stimuli occur in a setting of opposing GHRH and somatostatin tone; the GH response may be affected by the relative strengths of GHRH and somatostatin signaling at any given time. GHSR1a agonists influence both GHRH and somatostatin; this multiplicity of action may contribute to the high overall reproducibility rate, as well as the magnitude of the GH response.

The current study indicates that LUM-201 can elicit greater GH responses than standard GH secretagogues in some subjects, possibly via its agonist activity on the GHSR1a and subsequent modulation of GHRH and somatostatin signaling. Confirmation of this finding and evaluation of the reproducibility of GH responses to LUM-201 are underway in a study of children with GH deficiency (Clinical Trials.gov, NCT04614337). NCT04614337 is also a Phase 2 study to determine if LUM-201 and daily rhGH give comparable 6-month height velocity responses in prepubertal children from the GHD spectrum selected by higher baseline IGF-1, higher GH responses to standard GH stimuli, and peak GH responses to single-dose LUM-201. The GH response to single low-dose LUM-201 has additional value. In a recent analysis of a completed trial of LUM-201 and rhGH in children with growth hormone deficiency, the GH response to single-dose LUM-201 mg/kg and the baseline concentration of IGF-I were found to be predictive enrichment markers (PEMs) for 6-month height velocity responses. Children with higher baseline IGF-1 and GH responses to LUM-201 (PEM positive) had higher height velocities to LUM-201 than PEM-negative children. Children with lower baseline IGF-I and GH responses to LUM-201 (PEM negative) had higher height velocities with rhGH than the PEM-positive children [2]. If confirmed in an independent second population, the single-dose LUM-201 test may be an effective way to predict favorable treatment responses to the oral GH secretagogue, LUM-201.

Data for these analyses were provided by Lumos Pharma, Inc. The original study was conducted by Merck. The authors wish to acknowledge the participants and institutions who conducted the Merck study: H. Yu, University of Qingdao, China; F. Cassorla, University de Chile, Santiago, Chile; A. Tiulpakov, Russian Academy of Medical Sciences, Moscow, Russia; Y.-F. Shi, Beijing University Medical College, Beijing, China; N. Setian, Instituto da Crianca, Sao Paolo, Brazil; B. Bercu, University of South Florida, Tampa, FL, USA; A. Arango, Universidad Pontificia Bolivariana, Medellin, Columbia; G. Kletter, University of Washington, Seattle, WA, USA; O. Pescovitz, Indiana University, Indianapolis, IN; J. DiMartino, Albert Einstein College of Medicine New York, NY, USA; D. Krupa, M Cambria; and MA Bach, Merck and Company, Rahway, NJ, USA.

The study protocol was reviewed and approved by the IRB at each participating center. Written informed consent was obtained from the parent/legal guardian prior to a subject’s participation in study activities.

G.M.B. and M.O.T. are consultants to Lumos Pharma, Inc. M.O.T. has equity in Lumos Pharma, Inc.

Lumos Pharma, Inc provided funding support for the analyses and preparation of the manuscript.

Data management and analysis were performed by G.M.B. Data interpretation was completed by both authors. G.M.B. provided the initial draft of the manuscript, and both authors contributed to the final version of the manuscript.

All data sets used for these analyses are the property of Lumos Pharma, Inc. The data used to support the figures and text of this manuscript are property of Lumos Pharma, Inc. and are not publicly available. Specific inquiries about the data may be made by contacting Lumos Pharma at https://lumos-pharma.com/contact/.

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