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

We thank Dr. Malozowski for his comments on our recent publication (1). The heiGHt trial was designed to evaluate the safety, efficacy, and tolerability of the once-weekly long-acting growth hormone (LAGH) prodrug lonapegsomatropin (2). The primary efficacy objective of the trial was to demonstrate noninferiority of lonapegsomatropin to daily somatropin. The trial achieved its objective in the evaluation of treatment effect, and also demonstrated statistically greater growth in children treated with lonapegsomatropin compared with daily human growth hormone (hGH). This trial was not designed to address adherence to LAGH or differences in adherence to once-daily and once-weekly injectable treatments, and a hypothesis regarding the impact of adherence on outcomes was not tested.

According to the Growth Hormone Research Society the development of strategies to assess adherence is a particular challenge in growth hormone therapy, and “clinical trials select for motivated participants and the infrastructure of these studies enhance adherence” (3). Systematic reviews and meta-analyses across different chronic diseases report higher rates of treatment adherence from clinical trials compared with real-world data, and/or increased treatment adherence with simpler dosing regimens in real-word data (4-6). High and similar adherence was reported in both arms of the heiGHt trial and was not an unexpected result in the context of a clinical trial.

Lastly, it is important to note key differences in formulations between lonapegsomatropin and the previously marketed depot formulation mentioned in the letter (1, 2, 7). Lonapegsomatropin is a prodrug that releases unmodified somatropin (2). The depot preparation, however, was a highly viscous formulation with somatropin-containing microparticles and was associated with a high degree of injection site reaction (7). The depot preparation needed to be injected with a large-bore needle, often more than once at a given administration interval and leaving a visible subcutaneous lump (8). Lonapegsomatropin injections, in contrast, are well-tolerated and readily administered using an autoinjector and fine-gauge needle (2). While LAGHs are often and appropriately discussed as a group, it is paramount to assess each individual LAGH on its specific characteristics, including injection site tolerability and method of delivery.