The novel long-acting recombinant human growth hormone may lower number of growth hormone treatments from daily to 2 times per month.
A novel, extended, long-acting recombinant human growth hormone (rhGH) used to treat adults with growth hormone deficiency (AGHD) may help potentially lower the number of GH treatments to 2 times per month, according to recent results from a phase 2 trial published in the European Journal of Endocrinology.
“Traditional GHD treatment includes the use of daily subcutaneous injections of rhGH. However, this schedule is too frequent to be convenient for many patients, raising concerns about poor adherence to treatment, which can lead to reduced efficacy,” Cheol Ryong Ku, MD, PhD, from the Yonsei University College of Medicine in Seoul, Republic of Korea, and colleagues wrote in their study. “Long-acting rhGH preparations not only allow less frequent injections, but also improve compliance by reducing the inconvenience of daily injections and potentially contribute to improving the efficacy of GH treatment.”
GX-H9, a novel, extended, long-acting rhGH fused to hybrid Fc (hyFc), is made up of human immunoglobulin D and human immunoglobulin G4. The half-life of GX-H9 increases through the expansion of size from its fusion to hGH, which reduces renal clearance. “IgG4 further increases the half-life of GX-H9 via neonatal Fc receptor-mediated endocytosis and recycling of the Fc-fusion protein,” the authors explained.
To test the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of weekly and every other week (EOW) GX-H9 dosage, Ku and colleagues performed a randomized, open-label, active-controlled and dose-escalation phase 1B/2 study, which included 45 AGHD patients from 16 endocrinology centers in Europe and Korea. Inclusion criteria were an insulin tolerance test result of <3.0 ng/mL peak GH, or a combination GH releasing hormone and arginine stimulation test with peak GH <4.0 ng/mL; minimum 3 months of stable hormone replacement therapies; and an insulin-like growth factor 1 (IGF-1) standard deviation <−1.
Patients were aged 20 to 65 years, had childhood-onset GHD or AGHD, and received GH administration at least 1 month before the study. They were randomized to 15 patients per treatment group in a 4:1 ratio to receive 0.1 mg/kg weekly (group 1), 0.3 mg/kg EOW (group 2) or 0.2 mg/kg EOW (group 3) of GX-H9 or once-daily doses of 6 µg/kg Genotropin,® with treatment beginning from the first group.
“Before proceeding to the next group, safety and IGF-1 level data were reviewed by the safety monitoring committee (SMC) and the decision to proceed to the next group was only made if the previous lower dose was found to be safe and well tolerated,” Ku and colleagues wrote.
Two patients discontinued treatment in the Genotropin group and 1 patient discontinued in the 0.1mg/kg GX-H9 weekly group. The investigators found no significant differences among least squares (LS) mean differences in IGF-1 scores at weeks 1, 3, 5, 7, 9, and 11 between all GX-H9 and Genotropin groups except for the 0.3mg/kg GX-H9 EOW group (P=0.023).
There were no significant differences in adverse events among treatment regimens and groups for patients receiving GX-H9 and Genotropin. Regarding secondary endpoints, there were no week-12 LS mean differences for body mass index, waist circumference, hip circumference, waist-to-hip ratio and lipids between the GX-H9 and Genotropin groups.
A single dose of GX-H9 was associated with a dose-dependent increase in mean peak GX-H9 and total exposure, investigators said, with much higher concentrations seen in the 0.3 mg/kg EOW group. “[A]fter gathering PK, PD and safety data from the 0.1 mg/kg weekly and 0.3 mg/kg EOW GX-H9 groups, the sponsor and members of the SMC agreed to use 0.2 mg/kg EOW for Group 3 rather than proceed with the planned dosage regimen of 0.3 mg/kg weekly and then 0.6 mg/kg EOW because significant increments in IGF-I were observed in the 0.3 mg/kg EOW GX-H9 group,” Ku and colleagues said.
After administration of 0.1 mg/kg weekly, 0.3 mg/kg, and 0.2 mg/kg EOW GX-H9 and daily administration of Genotropin, there was a significant increase in IGF-1 levels that peaked between 48 hours and 72 hours after the dose. In the 0.1 mg/kg GX-H9 group, the mean IGF-1 response sustained above baseline “over the intended dose interval” of 168 hours compared with 336 hours in the 0.2 mg/kg and 0.3 mg/kg EOW groups.
The authors noted potential limitations in the study, such as the small patient sample, an all-Asian demographic in the 0.1 mg/kg GX-H9 weekly group, and no significant changes in metabolic parameters at 12 weeks in patients randomly assigned GX-H9 and Genotropin. The investigators said a phase 3 clinical trial is under development that will have more patients and a longer treatment period to further study GX-H9.
Source: Ku CR, Brue T, Schilbach K, et al. Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults. Eur J Endocrinol. 2018;179:169-179.