medwireNews: One-year findings from the REAL5 trial show a continued growth response with use of long-acting human growth hormone (LAhGH) treatment with somapacitan at a dose of 0.24 mg/kg per week in children born small for gestational age (SGA).
The findings uphold the initial positive results for the reversible albumin-binding hGH derivative published after 26 weeks of follow-up, report Anders Juul (Copenhagen University Hospital, Rigshospitalet, Denmark) and colleagues.
LAhGH provided “similar efficacy, safety and tolerability, as well as comparable bioactive and total IGF-I [insulin-like growth factor-I] response, as daily GH (0.067 mg/kg/day)”, the researchers write in the Journal of Clinical Endocrinology & Metabolism.
The study recruited 62 prepubertal short children born SGA and naïve to GH therapy who were attending one of 38 clinics in 12 countries, 61 of whom completed their initial 26-week assigned treatment and continued for a further 26-week extension period. The participants are now undergoing 4 years’ follow-up for safety.
The patients were randomly assigned to receive LAhGH at a weekly dose of 0.16 (n=12), 0.20 (n=13) or 0.24 mg/kg (n=12), or to receive daily hGH at a dose of 0.035 (n=12) or 0.067 mg/kg (n=13).
The children were aged an average of 6 years, 30.8–50.0% were girls, and they were born at a gestational age of 37–38 weeks. At baseline, the groups had a height standard deviation score (SDS) of between –2.92 and –3.15, an IGF-I level of 88.19–120.21 ng/mL, and a bioactive IGF-I level of 0.42–0.62 ng/mL.
The majority of children remained prepubertal at week 52 of treatment; one girl given LAhGH progressed to Tanner stage II by week 52 and one girl given daily hGH progressed from Tanner stage II to III between weeks 26 and 52. There was no acceleration of change in bone age versus that expected for chronological age with any of the treatments between baseline and week 52.
The estimated mean height velocity (HV) at week 52 for patients receiving LAhGH 0.16, 0.20 and 0.24 mg/kg were 8.5, 10.4 and 10.7 cm/year. These did not significantly differ from the mean HVs of 9.3 and 11.2 cm/year for the participants who instead received daily hGH 0.035 and 0.067 mg/kg, respectively.
Both LAhGH and daily hGH achieved a “clinically relevant dose-dependent increase” in average height SDS and average height velocity SDS between baseline and week 52 and there was no significant difference in values between the treatments.
As expected, there was a difference in the pattern of IGF-I levels associated with the weekly and daily GH therapies, Juul and co-authors report. LAhGH led to an IGF-I peak 2–3 days after dosing followed by a trough at day 7, while there were “minor” day-to-day fluctuations with daily hGH, they say.
Nevertheless, there were “[c]onsistent dose-dependent increases” at week 52 relative to baseline in total IGF-I SDS when samples were taken 4–6 days after the weekly dose. The observed average total IGF-I SDS at week 52 was 0.85, 1.69 and 2.75 with LAhGH 0.16, 0.20 and 0.24 mg/kg, respectively, versus 1.10 and 1.83 for daily hGH 0.035 and 0.067 mg/kg.
Modelling indicated that for total IGF-I SDS, the average change between baseline and week 52 were a corresponding 1.29, 2.09 and 2.97 versus 1.98 and 2.44.
“The overlap of total IGF-I SDS was most pronounced for somapacitan 0.24 mg/kg/week dose and daily GH 0.067 mg/kg/day,” the researchers comment.
The team also assessed the fraction of circulating IGF-I bioactivity – defined as the fraction of IGF-I able to bind to the IGF-1 receptor – across all groups before and after treatment. At peak sampling, both the 0.20 and 0.24 mg/kg LAhGH doses showed “comparable” bioactive concentrations to the 0.067 mg/kg daily hGH dose, while at trough sampling, bioactive IGF-I levels were lower with all three weekly LAhGH doses than the daily doses, the investigators say.
However, the researchers emphasize that “further research is required to assess IGF-I bioactivity in a larger SGA population over a longer treatment period and compared to a reference population of healthy children.”
The team describes the LAhGH therapy as being “well-tolerated at all doses without safety or local tolerability issues” and “consistent” with the adverse event (AE) profile for daily hGH therapy. AEs were all mild or moderate, and the majority of AEs in each group were judged “unlikely” to be related to treatment, such as rhinitis, contusion or vomiting.
During the 26-week extension phase, one child given LAhGH had a mild injection site reaction, and one child given daily hGH had two such events. One child using LAhGH developed type 1 diabetes and discontinued therapy; this was considered unlikely to be associated with their LAhGH treatment.
Among the LAhGH treatment groups, 33–75% of patients had excessive levels of total IGF-I, defined as greater than 2.0 SDS for two or more consecutive visits, as did 25–46% of those given daily hGH, the researchers point out.
Juul and co-authors say that in addition to use for all participants in the extension phase of REAL5, the LAhGH 0.24 mg/kg dose has now been chosen for the REAL8 and REAL9 phase 3 trials for short stature in SGA children, and those with Turner syndrome, Noonan syndrome or idiopathic short stature.
By Lynda Williams
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