medwireNews: The heiGHt Trial investigators report that once-weekly treatment with lonapegsomatropin offers noninferior and indeed superior annualised height velocity (AHV) to that achieved with daily somatropin for children with growth hormone (GH) deficiency.
Aimee Shu, from Ascendis Pharma Inc in Palo Alto, California, USA, and co-workers explain that “[t]he fundamental challenge of developing a [long acting] GH is to create a more convenient dosing regimen while retaining the excellent safety, efficacy, and tolerability of daily somatropin.”
The prodrug lonapegsomatropin (TransCon hGH; Ascendis Pharma A/S, Hellerup, Denmark) has a half-life of approximately 25 hours, thus permitting a weekly dosing schedule, the team writes in The Journal of Clinical Endocrinology & Metabolism.
The primary endpoint of the phase 3, randomised controlled trial was AHV after 52 weeks of GH therapy given to treatment-naïve boys (age 3–12 years) or girls (age 3–11 years) at Tanner stage 1 with isolated GH deficiency, or GH deficiency as part of multiple pituitary hormone deficiency.
The least squares mean AHV was 11.2 cm/year for the 105 patients who were randomly assigned to receive open-label lonapegsomatropin 0.24 mg/kg per week versus 10.3 cm/year for the 56 patients instead given an equivalent weekly dose of somatropin on a daily basis.
This gave an estimated treatment difference of 0.9 cm at 52 weeks in favour of lonapegsomatropin that met the threshold for both noninferiority and superiority compared with daily treatment. The difference in AHV between the groups was apparent from week 5 of treatment and reached statistical significance at week 26.
In subgroup analyses, AHV favoured lonapegsomatropin over somatropin regardless of sex, age less than or at least 6 years, a baseline GH stimulation above or below the 5 ng/mL threshold, or the aetiology and extent of the GH deficiency.
The least squares mean height standard deviation scores (SDS) increased between baseline and week 52 by 1.10 for the lonapegsomatropin-treated group versus 0.96 for the daily somatropin group, again a significant difference.
Lonapegsomatropin-treated patients reached an insulin-like growth factor 1 (IGF-1) SDS range of 0–2 earlier than controls and continued to have a higher average IGF-1 SDS throughout the trial (+0.72 vs –0.02 at week 52), a finding that Shu et al say is “consistent with greater longitudinal growth”.
But the children given lonapegsomatropin had similar advancement on the ratio of bone age to chronological age as those given daily somatropin (0.75 vs 0.76), “suggesting that the increased rate of longitudinal growth did not occur at the expense of accelerated skeletal maturation”, they comment.
The average adherence rates were 99.6% for lonapegsomatropin and 98.6% for daily somatropin and there were no serious treatment-related adverse events (AEs) or AEs resulting in discontinuation or death.
Most AEs were mild or moderate and “represented usual ailments in a pediatric population”, such as upper respiratory tract infection, pyrexia and headache, the researchers say.
Treatment-related AEs occurred in 11.4% of patients given lonapegsomatropin and 17.9% of controls. The two groups had comparable rates of new onset or worsening deficiencies in the pituitary axes, such as secondary hypothyroidism (6.7 vs 7.1%), secondary adrenal insufficiency (1.9 vs 1.8%) and diabetes insipidus (1.0 vs 1.8%).
Anti-somatropin-binding antibodies were detected in 6.7% of the patients given lonapegsomatropin and 3.6% of those given daily somatropin, but none of the patients developed neutralising antibodies or AEs related to such antibodies.
“Building on the concept of releasing unmodified somatropin to maintain physiologic distribution, weekly lonapegsomatropin is the first [long acting] GH with data demonstrating superior efficacy compared to a daily somatropin, while maintaining similar bone age advancement, adverse event profile and immunogenicity”, Shu and co-authors conclude.
“Lonapegsomatropin may represent an important therapeutic option for children with GH [deficiency].”
By Lynda Williams
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J Clin Endocrinol Metab 2021; doi:10.1210/clinem/dgab529