Weekly Lonapegsomatropin in Treatment-Naïve Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial

Abstract

Context: For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD.

Objective: The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin.

Design: The heiGHt trial was a randomized, open-label, active-controlled, 52-week Phase 3 trial (NCT02781727).

Setting: This trial took place at 73 sites across 15 countries.

Patients: This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD.

Interventions: Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/week or an equivalent weekly dose of somatropin delivered daily.

Main outcome measure: The primary end point was annualized height velocity (AHV) at week 52. Secondary efficacy end points included change from baseline in height SD scores (SDS).

Results: Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs 10.3 (0.3) cm/year for daily somatropin (P = 0.009), with lonapegsomatropin demonstrating both noninferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to week 52 by 1.10 (0.04) vs 0.96 (0.05) in the weekly lonapegsomatropin vs daily somatropin groups (P = 0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups.

Conclusions: The trial met its primary objective of noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.

Figure 1.

Transient conjugation. Lonapegsomatropin is a long-acting prodrug consisting of the parent drug, unmodified somatropin; an inert carrier; and a proprietary linker that temporarily binds the somatropin and carrier. The carrier has a shielding effect that minimizes renal excretion and receptor-mediated clearance. Following autocleavage of the linker under physiologic conditions, lonapegsomatropin predictably releases somatropin within therapeutic levels over one week.

Figure 2.

Screening, randomization, and follow-up.

Figure 3.

Subgroup analysis of annualized height velocity. Lines represent 95% CI.

Figure 4.

Change from baseline in height SD score.

Figure 5.

(A) Insulin-like growth factor 1 (IGF-1) weekly profile following lonapegsomatropin administration. (B) Average IGF-1 SD score (SDS) over 52 weeks of treatment. (C) Observed IGF-1 SDS at baseline, peaks, and troughs for the lonapegsomatropin group. (A) shows the IGF-1 profile from a lonapegsomatropin population subset (n = 11) over 7 days following the 13th dose, with a steady state SDS difference between peak and trough of approximately 2. The box-and-whisker plots in (B) show the derived average (lonapegsomatropin) and observed (daily somatropin) IGF-1 SDS over 52 weeks in the intention-to-treat population. For the daily somatropin group, average IGF-1 SDS were represented by observed values given the relative stability of IGF-1 levels with daily somatropin. At all visits, the lonapegsomatropin group had a higher average IGF-1 SDS, thus reaching a range of IGF-1 SDS 0-2 (shaded grey area) sooner than did the daily somatropin group. For each box-and-whisker plot, the upper and lower box edges represent the 75th and 25th percentiles. Within the box, the horizontal bar indicates the median, while the circle (for lonapegsomatropin) or plus sign (for daily somatropin) corresponds to the mean. The upper and lower ends of the whiskers represent the highest and lowest observed values within 1.5 times the interquartile range above and below the 75th and 25th percentiles, respectively. Outside the box, open circles (lonapegsomatropin) and plus signs (daily somatropin) correspond to observed values beyond 1.5 times the interquartile range above and below the 75th and 25th percentiles. Similarly, the box-and-whisker plots for observed IGF-1 levels for lonapegsomatropin-treated subjects at baseline, troughs (weeks 5 and 52), and peaks (weeks 13, 26, and 39) are presented in (C). The circles represent individual subject levels.