Weekly Somapacitan is Effective and Well Tolerated in Children With GH Deficiency: The Randomized Phase 3 REAL4 Trial

Abstract

Context: Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD).

Objective: To demonstrate efficacy and safety of somapacitan vs daily GH.

Methods: REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535).

Setting: Eighty-six sites across 20 countries.

Patients: 200 treatment-naïve patients were randomized and exposed.

Interventions: Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (Norditropin; 0.034 mg/kg/d), administered subcutaneously.

Main outcome measures: The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures.

Results: Estimated mean HV at week 52 was 11.2 and 11.7 cm/y for somapacitan and daily GH, respectively. Noninferiority was confirmed. Changes in HV SDS, height SDS, bone age, and IGF-I SDS from baseline to week 52 were similar between treatment groups. At week 52, mean IGF-I SDS values were similar between treatment groups and within normal range (-2 to +2). Safety of somapacitan was consistent with the well-known daily GH profile. Low proportions of injection-site reactions were reported for somapacitan (5.3%) and daily GH (5.9%). Both treatments similarly reduced disease burden from baseline to week 52, whereas a greater treatment burden reduction was observed for somapacitan.

Conclusions: Similar efficacy for somapacitan compared to daily GH was demonstrated over 52 weeks of treatment with comparable safety and mean IGF-I SDS levels in treatment-naïve children with GHD.

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

Figure 1.

Trial overview. Design of the REAL4 trial and extension. Results from main trial (52 weeks) are reported in this paper. Time axis is not to scale. Abbreviation: GHD, GH deficiency.

Figure 2.

Trial profile. The full analysis set (FAS) represents all randomly assigned children in the trial to either weekly somapacitan or daily GH (Norditropin). The safety analysis set (SAS) contains all randomly assigned children who received at least 1 dose of randomized treatment. *One patient receiving somapacitan discontinued treatment because of violation of inclusion/exclusion criteria but was included in the FAS and SAS.

Figure 3.

Observed height velocity from baseline to week 52. Mean observed HV (cm/year) at baseline and week 52 for 0.16 mg/kg/wk somapacitan and 0.034 mg/kg/d daily GH (Norditropin) treatment groups. Error bars represent SD. Abbreviation: HV, height velocity.

Figure 4.

IGF-I SDS profiles following somapacitan administration. (A) Observed mean IGF-I SDS for 0.16 mg/kg/wk somapacitan and 0.034 mg/kg/d daily GH (Norditropin). Samples collected at week 0 were taken prior to first dose. To characterize the weekly IGF-I profile, week 4 and 26 samples were collected in a window designed to characterize the peak between 1 and 4 days after dosing: mean sampling times after dosing were 45 and 44 hours (1.9 and 1.8 days), respectively. Trough samples at weeks 13 and 39 were taken on day 7. Week 52 samples taken 4 to 6 days after dosing captured expected weekly averages: mean sampling time after dosing was 113 hours (4.7 days). Error bars represent SD. Time axis is not to scale. (B) Estimated IGF-I SDS profile over the week were derived by population PK/PD modeling. The solid line represents mean profiles based on population PK/PD modeling. Dotted gray lines represent 5th to 95th percentile. Abbreviations: PK/PD, pharmacokinetic/pharmacodynamic; SDS, SD score.

Figure 5.

Patient reported outcomes at week 52. (A) Change from baseline to week 52 between somapacitan and daily GH (Norditropin) in disease burden (GHD-CIM) domain scores and total score (FAS). A lower number indicates a greater burden reduction. (B) Estimated treatment differences from baseline to week 52 between somapacitan and daily GH (Norditropin) in disease burden (GHD-CIM) domain scores and total score (FAS). Estimated treatment difference at week 52 between somapacitan and daily GH (Norditropin®) in treatment burden domain scores and total score (FAS) for (C) child (GHD-CTB) and (D) parent/caregiver (GHD-PTB). Abbreviations: CI, confidence interval; CIM, Child Impact Measure; CTB, Child Treatment Burden; FAS, full analysis set; GHD, GH deficiency; PTB, Parent Treatment Burden.