Letter to the Editor From Chatelain et al: “Weekly Somapacitan Is Effective and Well Tolerated in Children With GH Deficiency: The Randomized Phase 3 REAL4 Trial”

We read with interest the report from Miller et al “Weekly Somapacitan Is Effective and Well Tolerated in Children With GH Deficiency: The Randomized Phase 3 REAL4 Trial” (1). The authors described safety and efficacy of somapacitan, a human GH derivative, compared with daily somatropin. The study shows that long-acting growth hormone (LAGH) may be able to improve adherence to therapy. Patients receiving once weekly therapy with somapacitan had a mean adherence rate of 95.8% vs 88.3% for daily somatropin. The authors demonstrated that 52-week annualized height velocity for somapacitan (11.2 cm/year) was non-inferior to that of daily somatropin (11.7 cm/year). Insulin-like growth factor 1 (IGF-1) levels were slightly higher in the somapacitan arm and, as expected for LAGH therapy, had a different IGF-1 profile vs daily somatropin.

A similar number of participants experienced injection site reactions for both arms in the study; an important finding in a pediatric setting, where tolerability of a LAGH should be comparable to that of established daily therapies. The authors proceed to reference injection site tolerability of TransCon hGH from the completed phase 2 study published in 2017 (2), and correctly calculated the percentages of recorded injection site reactions but failed to include the relevant comparison to daily somatropin where a similar tolerability was reported. We agree with the authors that cross-trial comparisons should be performed carefully to avoid biased and potentially misleading conclusions. Inclusion of comparator arm data in such comparisons will help avoid bias.

On molecular basis all daily somatropins are identical; in contrast, all LAGHs differ, each having its unique molecular characteristics and clinical profile (3) highlighting the importance of ensuring a similar safety, tolerability, and efficacy compared with daily somatropin. In that regard, lonapegsomatropin (or TransCon hGH) is a once-weekly long-acting prodrug and the only LAGH releasing unmodified somatropin identical to daily somatropin (4).

On tolerability, our Phase 2 trial concluded that injection site tolerability was similar for TransCon hGH and daily somatropin (2). For clarity, this Phase 2 trial (n = 53) compared 3 doses of TransCon hGH (0.14, 0.21, and 0.30 mg/kg/week, cohort 1-3) to daily somatropin (0.21 mg/kg/week, cohort 4). Following close examination of the injection sites, reactions were similar to daily somatropin (58.3%, 42.9%, 42.9%, and 46.2% for cohort 1-4, respectively). Likewise, pain was reported equally across cohorts, and was numerically higher for daily somatropin. In the Phase 3 trial (n = 161) injection site reactions for lonapegsomatropin were comparable to daily somatropin (1.9% and 1.8%, respectively) (4).

On efficacy, the pivotal study of lonapegsomatropin reported noninferiority and superiority compared with daily somatropin even with similar treatment adherence (99.6% vs 98.6%, respectively), as similarly reported in an independent Phase 3 trial (5).

With the unique molecular and clinical characteristics of each LAGH, it is also important to closely evaluate immunogenicity, metabolic parameters, development of body mass index, bone age advancement, and efficacy, when selecting therapy for growth hormone replacement. Given the established safety and efficacy of daily somatropin, no tradeoff on long term safety, tolerability, or efficacy should be made when initiating LAGH therapy.

Abbreviations

GH

growth hormone

IGF-1

insulin-like growth factor 1

LAGH

long-acting growth hormone

Disclosures

P.C. is a past consultant for Ascendis Pharma (2017); M.K.-H. and K.S. are employees of Ascendis Pharma A/S.