Weekly Somapacitan Is Effective and Well Tolerated in Children With GH Deficiency

The Randomized Phase 3 REAL4 Trial

Bradley S. Miller; Joanne C. Blair; Michael Højby Rasmussen; Aristides Maniatis; Rasmus Juul Kildemoes; Jun Mori; Michel Polak; Rikke Beck Bang; Volker Böttcher; Stefano Stagi; Reiko Horikawa

Disclosures

J Clin Endocrinol Metab. 2022;107(12):3378-3388. 

In This Article

Abstract and Introduction

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.

Introduction

GH is essential for longitudinal growth in children. GH deficiency (GHD) is characterized by the inadequate production or secretion of GH. Treatment with GH replacement therapy improves overall health and final adult height for children with GHD.[1,2] Normal growth can often be restored, but the short half-life of GH necessitates daily subcutaneous injections, which can be a burden for children and their caregivers, disrupting the daily lives and routines of families and resulting in low adherence.[3,4] In 1 study, one-quarter of children treated with daily GH therapy reported missing 2 or more injections per week.[5] Low adherence negatively affects growth outcomes[6] and is partly attributed to injection pain and frequency of injections.[5,7]

A long-acting GH (LAGH) should, at minimum, have the same excellent efficacy and safety profile as GH administered daily while also reducing the number of injections.[8] Somapacitan (Novo Nordisk A/S), a once-weekly treatment for GHD, is in clinical phase 3 development for GHD in children. It reduces injection frequency from 365 injections per year required for daily GH replacement to 52 injections per year.[9,10] This is expected to reduce distress associated with daily injections, decrease interference with daily life, and thereby potentially improve treatment adherence and, consequently, clinical outcomes.

Somapacitan is a 23.3-kDa human GH derivative (99% similarity to endogenous GH) linked to a small noncovalent albumin-binding moiety that facilitates reversible endogenous albumin binding to delay somapacitan elimination. Similar technologies enhance the half-life of other peptide drugs, such as long-acting insulin detemir,[11] glucagon-like peptide-1 molecules liraglutide,[12] and semaglutide.[13] In previous trials, somapacitan has been shown to be well tolerated in adults and children with GHD[9,10,14–16] and effective in adults with GHD.[17,18] A phase 2 dose-finding and safety trial in prepubertal children with GHD suggests 0.16 mg/kg/wk somapacitan has the same efficacy and safety profile as daily GH treatment (0.034 mg/kg/d Norditropin, Novo Nordisk A/S) for up to 3 years of treatment.[10,16]

The primary objective of the phase 3 REAL4 trial was to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan compared with daily GH in prepubertal, treatment-naïve children with GHD.

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