Letter to the Editor From Sävendahl et al.: "Weekly Lonapegsomatropin in Treatment-Naïve Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial".

We read with interest the recent report by Thornton et al (1) on data from heiGHt, a phase 3 trial evaluating the efficacy and safety of once-weekly lonapegsomatropin (a prodrug for growth hormone [GH] treatment) vs the current standard of daily GH treatment in treatment-naïve prepubertal children with GH deficiency. The authors have demonstrated that the trial met its primary objective of noninferiority of lonapegsomatropin vs daily GH in annualized height velocity (AHV) after 52 weeks of treatment. In the discussion, the authors highlighted the importance of AHV in the first year of treatment as a predicting factor for final height and drew comparisons with efficacy data of 2 other long-acting GH preparations, somatrogon and somapacitan. However, when referring to our earlier report from the REAL 3 trial investigating the efficacy and safety of somapacitan (2), the authors cited data after 26 weeks, omitting published results after 52 weeks of treatment from this reference.

We wish to clarify the omitted efficacy data of somapacitan after 52 weeks, as we believe they provide a more appropriate comparison with the 52-week results with lonapegsomatropin. At week 52, mean (SD) AHV was 11.5 (2.6) cm/year in patients receiving somapacitan 0.16 mg/kg/week, vs 9.8 (2.3) cm/year for the comparator group receiving daily GH 0.034 mg/kg/day (2). The estimated treatment difference (ETD; somapacitan 0.16 mg/kg/week – daily GH) at week 52 was 1.8 (95% CI, 0.5; 3.1) (2), while, for lonapegsomatropin, the corresponding ETD was 0.9 (95% CI, 0.2; 1.5) (1). At week 26, the ETDs in AHV for somapacitan and lonapegsomatropin vs daily GH 0.034 mg/kg/day were 1.7 (95% CI, −0.2; 3.6) and 1.4 (95% CI, 0.5; 2.3), respectively (1, 2), although the ETD for somapacitan at week 26 was not statistically significant in the relatively small trial.

We acknowledge that REAL 3 is a phase 2 trial with fewer randomized patients (n = 59) than the phase 3 heiGHt study (n = 161). We would also like to note the molecular differences among the 3 long-acting GH compounds originating from different approaches to extending their in vivo half-life. Lonapegsomatropin consists of a GH molecule transiently bound to an inert carrier molecule and a TransCon linker, while somatrogon contains 3 C-terminal peptide segments from human chorionic gonadotropin, and somapacitan consists of a GH molecule and a moiety that reversibly binds to endogenous albumin (3). Thus, without a head-to-head comparison in clinical trials, direct comparison of these compounds would be speculative.

Nevertheless, as comparable efficacy and safety between lonapegsomatropin and daily GH were shown by Thornton et al (1), our data (2) have also supported similar efficacy and safety of somapacitan vs daily GH after 52 weeks of treatment, with a clear and expected dose- and time-dependent effect on AHV. In addition, the ongoing investigations of somapacitan will provide further information about the long-term effects of somapacitan treatment. The collective evidence of efficacy and safety of long-acting GH preparations is promising and will likely contribute to a decrease in treatment burden for children in need of GH therapy, and their parents/caregivers.