ORLANDO – A once-weekly formulation of growth hormone was found to be noninferior to a once-daily product in a phase III study, with no significant differences in annualized height velocity at 12 months.
A total of 86 children with growth hormone deficiency were randomized to 0.5 mg/kg per week injections of long-acting growth hormone (LB03002, LG LifeSciences/Biopartners). Another 83 deficient children were randomized to injections of 0.03 mg/kg per day of somatropin (Genotropin, Pharmacia and Upjohn). All participants were prepubertal, treatment-naive, and diagnosed with idiopathic (about 90%) or organic growth hormone deficiency.
"Noninferiority to Genotropin was demonstrated," Dr. Paul Saenger said at a symposium on IGF-1, growth hormone and ghrelin/GHS, sponsored by the University of South Florida, St. Petersburg.
Annualized height velocity was the primary outcome of this open-label, parallel-group multicenter study. Mean increases at 12 months were 11.7 cm in the weekly injection group and 12.2 cm in the daily injection group.
All participants were offered a rollover into the LB03002 treatment arm for up to 24 months, and all but nine of the once-daily patients opted to continue this study extension. In the second year, annual height velocity slowed to a mean 8.3 cm increase in the once-weekly group vs. 7.3 cm in the once-daily group. There was "some attenuation as usual" after higher initial gains, as observed in most pediatric growth hormone studies, Dr. Saenger said.
Twelve-month growth rates were similar in both groups, Dr. Saenger said. A secondary parameter, gain in height standard deviations (SDs) at 1 year, was the same in each group, a mean 1.3 SDs.
"Also, we paid particular attention to bone age maturation, because it should not be faster," said Dr. Saenger, pediatric endocrinologist at Albert Einstein College of Medicine, New York. There was no difference between the two modalities so the height prediction was not affected.
Thirty patients in the LB03002 group tested positive for potentially biologically relevant anti-hGH antibodies, compared with three patients in the somatropin group. "So, while we recognize that there were antibodies, they did not seem to have an effect on growth rate or pharmacodynamic changes such as IGF-1 [insulinlike growth factor–1]," Dr. Saenger said.
Both groups showed increases in IGF-1 and IGF binding protein–3 to the normal range by 12 months, Dr. Saenger said. Also, no significant differences were observed in hemoglobin A1c or glucose levels at 12 months between treatment arms. One patient in each group had impaired glucose tolerance.
LB03002 was "considered ultimately safe and well tolerated," Dr. Saenger said.
Local tolerability was "overall good to very good" with the once-weekly subcutaneous injection, Dr. Saenger said. Incidence of injection site reactions (for example, pain, tenderness, erythema, warmth, and swelling) was higher in patients treated with LB03002. The most common local adverse event was injection site swelling that was "often mild and transient," he said.
All five serious adverse events were considered unrelated to treatment, Dr. Saenger said. There was one report of neoplasm progression in the LB03002 arm, one report of dengue fever, and one upper respiratory tract infection in the somatropin arm, and one case of tonsillitis in each group.
Dr. Saenger said the once-weekly formulation might improve long-term adherence to growth hormone therapy. "We have ample data that daily growth hormone compliance declines, and that may affect the efficacy of this drug."
LB03002 is a sustained-release formulation of growth hormone incorporated in a matrix of sodium hyaluronate and lecithin, which are reconstituted in an oil base of medium-chain triglycerides prior to injection. The primary structure is identical to endogenous 22 kD pituitary growth hormone, Dr. Saenger said.
A long-acting growth hormone approved by the Food and Drug Administration in 1999 (Nutropin Depot, Genentech) and intended for use once every 2 weeks or once per month was withdrawn from the market in 2004. This was a business decision based on an inability of this formulation to match the clinical efficacy of once-daily growth hormone products, Dr. Saenger said.
A meeting attendee asked about bioavailability with LB03002. "The bioavailability of all the long-acting compounds is not as good as the daily [formulations]," Dr. Saenger replied. "At a dose of 0.5 mg/kg per week the bioavailability would be 67%."
Early phase II trials are currently underway to assess additional formulations of growth hormone that could be administered once every 2 weeks or monthly, Dr. Saenger said.
Dr. Saenger said that he is a consultant to LG Life Sciences/Biopartners.