ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab, 2022. 107(5): p. 1357-1367. PMID: 34964458

Brief Summary: This multicenter, randomized, controlled, phase 2 study compared the effects of once-weekly long-acting growth hormone (GH) somapacitan versus daily GH administered to GH-deficient (GHD) children over a period of 156 weeks. Efficacy estimates were height velocity (HV; cm/y) at year 3 and changes from baseline to end for height SDS, HV SDS, IGF-I SDS, and insulin-like binding protein-3 (IGFBP-3) SDS. Incidence of adverse events (AEs), bone age advancement, detection of anti-somapacitan and anti-GH antibodies after 3 years, and IGF-I/IGFBP-3 levels were assessed as safety endpoints. Somapacitan showed comparable safety and non-inferiority to daily GH over 3 years, with an improved sustainability for patients and families. Somapacitan appears promising as a valid alternative to daily GH treatment in children with GHD.

Currently approved GH treatment regimens are based on daily injections, which can be burdensome for patients and caregivers, leading to reduced treatment adherence and suboptimal clinical outcomes [1, 2]. Since 1999, long-acting GH (LAGH) formulations have been developed as a potential more bearable alternative for GH treatment, as they can be administered weekly, biweekly, or monthly [3]. Somapacitan, a once-weekly reversible albumin-binding GH derivative, has been approved for the treatment of adults in Europe, United States and Japan, and it is under scrutiny for treatment of children with GHD [4]. This study reports the results from a multicenter, randomized, controlled, phase 2 trial, comparing somapacitan and once-daily GH for 156 weeks (NCT02616562) in prepubertal children with GHD.

Fifty-nine children with GHD were randomized (1:1:1:1 ratio) to receive either once-weekly somapacitan (n=16,0.04; n=15, 0.08; n=14, 0.16 mg/ kg/wk) or daily GH (n=14, 0.034 mg/kg/d, equivalent to 0.238 mg/kg/wk) subcutaneously during the 26-week main trial period and the 26-week extension trial period. For the 104-week safety extension (total 3 years), all participants who received somapacitan during the first year continued with somapacitan dose of 0.16 mg/kg/wk. Daily GH doses remained unchanged for the whole duration of the trial.

At years 2 and 3, somapacitan at doses of 0.08/0.16 and 0.16/0.16 mg/kg/wk was non-inferior in terms of height velocity (HV) and change of height SDS, as compared to daily GH. During the first year of treatment, IGF-1 and IGFBP-3 levels increased in a dose-dependent manner in the somapacitan treatment arms. After 3 years of treatment, the mean increase in IGF-1 and IGFBP-3 SDS from baseline was similar across the somapacitan-treated and daily GH treated children. IGF-1 levels > +2 SDS were recorded in 39.5% of somapacitan treated children vs 28.6% of daily treated children. However, in the high dose somapacitan arm (0.16 mg/kg/wk) 57.1% of children showed IGF-1 > +2 SDS at least once during the trial. Of note, mean bone age advancement during the 3 years of the trial was 4.0 and 4.9 SD in the medium and high dose somapacitan arm, respectively (0.08 mg/kg/wk and 0.16 mg/kg/wk) vs 3.0 SD for daily GH. However, bone age/chronological age ratio remained < 1 in all treatment arms during the three years of the trial.

The impact of somapacitan on phsycological measures (emotional and social well-being, and physical functioning) was evaluated using the Growth Hormone Deficiency–Child Impact Measure (GHD-CIM). Total scores favored somapacitan over daily GH, without reaching statistical significance. Somapacitan was well tolerated with no new clinically significant safety or local tolerability issues.

In summary, the results of this phase 2 trial support the non-inferiority and comparable safety of somapacitan to daily GH over 3 years and suggest an improved sustainability in terms of treatment burden for patients and families. Somapacitan appears promising as a valid alternative to daily GH treatment in children with GHD.

References: 1. Cutfield, W.S., et al., Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One, 2011. 6(1): p. e16223. 2. Rosenfeld, R.G. and B. Bakker, Compliance and persistence in pediatric and adult patients receiving growth hormone therapy. Endocr Pract, 2008. 14(2): p. 143–54. 3. Pampanini, V., et al., Long-acting growth hormone preparations and their use in children with growth hormone deficiency. Horm Res Paediatr, 2022. 4. Battelino, T., et al., Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial. Clin Endocrinol (Oxf), 2017. 87(4): p. 350–358.