Dose-exposure-IGF-I response of once-weekly somapacitan in adults with GH deficiency

Abstract

Objective: Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose-responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose-insulin-like growth factor I (IGF-I) responses in AGHD patients.

Design: Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.

Methods: Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose-IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing.

Results: The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7-9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3-4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose-exposure-IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment.

Conclusions: This study extends the knowledge of the somapacitan dose-IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.

Figure 1

IGF-I sampling schedule for REAL 1 (A), REAL 2 (B) and REAL JP (C). Lines are means of individual model predictions obtained with the final PK/PD model. Symbols with error bars are mean IGF-I levels with 95% CIs and indicate sampling times. Symbols are coloured by sampling day after the latest dose. IGF-I, insulin-like growth factor I; PD, pharmacodynamic; PK, pharmacokinetic; SDS, standard deviation score. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1167.

Figure 2

Observed and predicted dose–IGF-I responses for somapacitan and somatropin by starting dose group. Open symbols (circles, squares and triangles) are observed dose–IGF-I response pairs at the phase 3 maintenance dose levels for somapacitan (A, B and C) or somatropin (D, E and F). Lines are individual (thin lines) and mean (thick lines) predicted dose–response relationships across the somapacitan (0.1–8 mg/week) or somatropin (0.05–1.1 mg/day) dose ranges. Intersects for starting dose groups; patients > 60 years: 0 SDS, somapacitan 1.1 mg/week and 2 SDS, 4.2 mg/week; patients ≤ 60 years: 0 SDS, 1.8 mg/week and 2 SDS, 5.5 mg/week; Females on oral oestrogen: 0 SDS, 5.5 mg/week and 2 SDS, above 8 mg/week. IGF-I_avg SDS, average insulin-like growth factor I during maintenance treatment standard deviation score. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1167.

Figure 3

Prediction of IGF-I distribution for various starting doses. Lines are means of individual dose–response curves by starting dose group. Symbols and bars are means and 5th to 95th percentiles at starting dose levels of 1.0, 1.5 or 2.0 mg/week used in phase 3 (A) and at higher doses of 1.5, 2.0 or 4.0 mg/week (B), for patients younger than 60 years, patients older than 60 years and females on oral oestrogen, respectively. IGF-I_avg SDS, average insulin-like growth factor I during maintenance treatment standard deviation score; wk, week. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1167.

Figure 4

Weekly IGF-I SDS profiles following somapacitan and somatropin dosing. Full lines are means of individual predictions in the fixed dose periods after titration as observed in phase 3 for somapacitan (mean dose, 2.4 mg weekly) and somatropin (mean dose, 0.3 mg daily). The dashed line represents the weekly average IGF-I SDS for somapacitan (0.09 SDS). IGF-I, insulin-like growth factor I; SDS, standard deviation score. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1167.

Figure 5

IGF-I SDS profiles following missed doses of somapacitan and somatropin. Lines are means of individual predictions in simulated scenarios with somapacitan dosing delayed or somatropin dosing missed for 1 (A) or 3 (B) days. Dotted vertical lines represent time of the first missed dose. IGF-I, insulin-like growth factor I; SDS, standard deviation score. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1167.

Figure 6

Somapacitan dose–exposure-IGF-I response in patient subgroups. Lines are dose–exposure, exposure–IGF-I response and dose–IGF-I response relationships for patient demographics and characteristics significantly impacting somapacitan PK and/or PD: Sex and oral oestrogen therapy (A-C), age (D-F), body weight (G-I) and race (J-L). The pre-specified reference subject was male, White, 85 kg, age 40 years. C_avg, average somapacitan exposure during maintenance treatment; IGF-I_avg SDS, average insulin-like growth factor I during maintenance treatment standard deviation score; PD, pharmacodynamic; PK, pharmacokinetic. A full colour version of this figure is available at https://doi.org/10.1530/EJE-21-1167.