Once-Weekly Somapacitan vs Daily GH in Children With GH Deficiency: Results From a Randomized Phase 2 Trial

Abstract

Context: Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD).

Objective: The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH.

Design: REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562).

Setting: This study took place at 29 sites in 11 countries.

Patients: Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial.

Interventions: Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously.

Main outcome measures: The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS.

Results: At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week-daily GH): 1.7 [95% CI -0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, vs -0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH.

Conclusions: In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).

Keywords: growth hormone; growth hormone deficiency; growth hormone replacement therapy; long-acting growth hormone; somapacitan; treatment burden.

Figure 1.

Design of the REAL 3 trial and extensions. The pink shaded box indicates the phases reported in this paper. Time axis is not to scale. GH indicates growth hormone; GHD, growth hormone deficiency.

Figure 2.

Trial profile. The FAS was to contain all randomly assigned children who received at least 1 dose of randomized treatment. Only in exceptional cases, such as random assignment in error, could children be excluded from the FAS. PP set: children from the FAS who did not violate any inclusion/exclusion criteria and used the randomized treatment for at least 22 weeks (for children receiving somapacitan) or 154 days (for children receiving daily GH) during the main trial period. SAS: all randomly assigned children who received at least 1 dose of randomized treatment. ^aOne child in the daily GH group discontinued because of a nonserious adverse event (mild drug hypersensitivity), which was deemed probably related to treatment. ^bOne child was withdrawn by parents who declined further participation, and the other had a prior history or presence of malignancy and/or intracranial tumor. ^cOne child in the daily GH arm was excluded from the PP set because of not enough exposure (the patient referred to in footnote a). The other 3 children were excluded because of a violation of the height velocity (HV) inclusion criterion. FAS, full analysis set; GH indicates growth hormone; PP, per protocol analysis set; SAS, safety analysis set.

Figure 3.

Mean height velocity at week 26 (left) and 52 (right). Data are mean, SD, observed values, full analysis set. Statistical analysis of the end-of-treatment differences is reported in the text. ^aValue was 9.8 for the full analysis set. The value of 10.0 is from a post hoc-defined analysis that excluded visits after week 4 for the patient in the daily GH group who discontinued treatment prematurely at week 6. GH indicates growth hormone; wk, week.

Figure 4.

Mean height velocity SDS at baseline, week 26 and week 52 (left), and observed change in height velocity SDS from baseline to week 52 (right). Data are mean (SD), observed values, full analysis set. d, day; GH indicates growth hormone; HV SDS, height velocity SD score; wk, week.

Figure 5.

Mean height velocity SDS: change from baseline to week 26 (left) and week 52 (right). Data are estimated mean values. Numbers above brackets are estimated treatment differences (weekly somapacitan–daily GH) and 95% CI. *Denotes statistical significance. d, day; GH indicates growth hormone; HV SDS, height velocity SD score; wk, week.

Figure 6.

Visual predictive check for the population PK/PD model for somapacitan by dose level. Full red lines indicate observed median insulin-like growth factor-I (IGF-I) and dotted blue lines indicate the 5th to 95th percentile by visit. Yellow and blue areas indicate the model predicted 95% CI around the median and 5th to 95th percentile, respectively. Baseline samples (W0) were taken before first dose, trough samples (W4, W13, and W39) were taken 7 days after dose, and peak samples (W26 and W52) were taken 1 to 4 days after dose. PK/PD indicates pharmacokinetic/pharmacodynamic; W, week.

Figure 7.

Modeled IGF-I SDS fluctuations over the week. Insulin-like growth factor-I (IGF-I) SDS profiles for somapacitan were derived by population PK/PD modeling from the REAL 3 trial. Daily GH IGF-I SDS profiles are shown for reference and were derived by population PK/PD modeling of phase 1 data (daily GH model not published). d, day; GH indicates growth hormone; PK/PD, pharmacokinetic/pharmacodynamic; SDS, SD score; wk, week.

Figure 8.

Mean IGF-I SDS: observed and derived values. Somapacitan trough values are an average from values obtained 7 days after dose at weeks 4, 13, and 39. Somapacitan peak values are an average from values obtained 1 to 4 days after dose at weeks 26 and 52. Somapacitan average values were derived by population PK/PD modeling. Daily GH IGF-I levels from week 26 and 52 are shown for reference. Points and bars are means with SD. d, day; GH indicates growth hormone; PK/PD, pharmacokinetic/pharmacodynamic; SDS, SD score; wk, week.

Figure 9.

Change from baseline in Growth Hormone Deficiency—Child Impact Measure observer (GHD-CIM ObsRO) scores after 52 weeks of treatment (full analysis set). Patient and clinician ratings of severity of disease suggest a minimal important difference (MID) of 5 points for the total score, 7 for emotional well-being, 5 for physical health, and 5 for the social well-being domains, with a lower score representing an improvement. d, day; GH indicates growth hormone; wk, week.

Figure 10.

Most common adverse events, occurring in 10% or more of patients in any patient group (safety analysis set). % indicates percentage of patients; d, day; GH, growth hormone; R, event rate per 100 patient-years at risk; wk, week.

Figure 11.

Bone age progression vs chronological age, by visit. d, day; GH indicates growth hormone; wk, week.